Combining cisplatin with Pinellia pedatisecta Schott lipid-soluble extract induces tumor immunogenic cell death in cervical cancer.

BACKGROUND: Pinellia pedatisecta Schott extract (PE) is extracted from Pinellia pedatisecta Schott (PPS), a traditional Chinese medicinal plant with the potential for direct anticancer effects or eliciting an anti-tumor response by activating the immune system. PURPOSE: To explore PE's ability and mechanism to reconstruct cisplatin's immunogenicity. METHODS: Cervical cancer cells were treated with cisplatin (CDDP) and/or PE. The exposure of calreticulin (CRT) on cell membrane was investigated by flow cytometry. The extracellular of ATP and HMGB1 was investigated by Western blot analysis, immunofluorescence and ELISA assay. Changes in immune profiles were using flow cytometry in vaccination and anti-tumor assays in vivo. Lastly, the mechanism of PE influenced the ROS/ERS pathway was examined by ROS assay kit, flow cytometry and Western blotting. RESULTS: PE treatment induced translocation of CRT from the endoplasmic reticulum to the cell membrane of tumor cells, concomitantly triggering immunogenic cell death (ICD). In terms of mechanisms, endoplasmic reticulum (ER) stress relievers could impede the ability of PE to induce immunogenicity. This indicates that PE is activated by ER stress, leading to subsequent induction of ICD. Upon analyzing RNA-seq data, it was observed that PE primarily induces programmed cell death in tumors by impeding upstream antioxidant mechanisms. Additionally, it transforms dying tumor cells into vaccines, activating a series of immune responses. CONCLUSIONS: This study observed for the first time that PE-induced CRT exposure on the membrane of cervical cancer cells compensates for the defect of nonimmunogenic cell death inducer CDDP thereby stimulating potent ICD. This ability restores the immunogenicity of CDDP through ER stress induced by the ROS signal. ROS played a role in PE's ability to induce ICD, leading to increased expression of ER stress-related proteins, including ATF3 and IRE-1α. PE exerted anti-cancer effects by increasing the ROS levels, and ROS/ERS signaling may be a potential avenue for cervical cancer treatment. Hence, the synergistic use of PE and CDDP holds potential for enhancing immunochemotherapy in cancer treatment.

Biotic and abiotic drivers of ecosystem multifunctionality: Evidence from the semi-arid grasslands of northern China.

Ecosystem functioning plays a crucial role in maintaining human welfare. Terrestrial ecosystems provide multiple ecosystem services simultaneously, such as carbon sequestration, nutrient cycling, water purification, and biodiversity conservation, known as ecosystem multifunctionality (EMF). However, the mechanisms by which biotic and abiotic factors, and their interactions regulate EMF in grasslands are unclear. We conducted a transect survey to illustrate the single and combined effects of biotic factors (including plant species diversity, trait-based functional diversity, community-weighted mean (CWM) of traits, and soil microbial diversity) and abiotic factors (including climate and soil) on EMF. Eight functions were investigated, including aboveground living biomass and litter biomass, soil bacterial biomass, fungal biomass, arbuscular mycorrhizal fungi biomass, and soil organic carbon storage, total carbon storage and total nitrogen storage. We detected a significant interactive effect between plant species diversity and soil microbial diversity on the EMF; Structural equation model showed that soil microbial diversity indirectly affected EMF by regulating plant species diversity. These findings highlight the importance of the interaction effect of above- and below-ground diversity on EMF. Both plant species diversity and functional diversity had similar explanatory power for the variation in EMF, implying that niche differentiation and multifunctional complementarity among plant species and traits are essential in regulating the EMF. Furthermore, the effects of abiotic factors on EMF were stronger than those of biotic factors via direct and indirect pathways affecting above- and below-ground biodiversity. As a dominant regulator, the soil sand content was negatively correlated with EMF. These findings indicate the vital role of abiotic mechanisms in affecting EMF, and deepen our understanding of the single and combined effects of biotic and abiotic factors on EMF. We conclude that soil texture and plant diversity, representing crucial abiotic and biotic factors, respectively, are important determinants of the EMF of grasslands.

The Relationship and Influencing Factors between Endangered Plant Tetraena mongolica and Soil Microorganisms in West Ordos Desert Ecosystem, Northern China.

Soil microorganisms play crucial roles in improving nutrient cycling, maintaining soil fertility in desert ecosystems such as the West Ordos desert ecosystem in Northern China, which is home to a variety of endangered plants. However, the relationship between the plants-microorganisms-soil in the West Ordos desert ecosystem is still unclear. Tetraena mongolica, an endangered and dominant plant species in West Ordos, was selected as the research object in the present study. Results showed that (1) there were ten plant species in the Tetraena mongolica community, belonging to seven families and nine genera, respectively. The soil was strongly alkaline (pH = 9.22 ± 0.12) and the soil nutrients were relatively poor; (2) fungal diversity was more closely related to shrub diversity than bacterial and archaeal diversity; (3) among the fungal functional groups, endomycorrhizal led to a significant negative correlation between shrub diversity and fungal diversity, because endomycorrhizal had a significant positive effect on the dominance of T. mongolica, but had no significant effect on other shrubs; (4) plant diversity had a significant positive correlation with the soil inorganic carbon (SIC), total carbon (TC), available phosphorus (AVP) and available potassium (AVK). This study revealed the effects of soil properties and soil microorganisms on the community structure and the growth of T. mongolica and provided a theoretical basis for the conservation of T. mongolica and the maintenance of biodiversity in desert ecosystems.

Grassland Degradation Has Stronger Effects on Soil Fungal Community Than Bacterial Community across the Semi-Arid Region of Northern China.

Soil microbes play crucial roles in grassland ecosystem functions, such as soil carbon (C) pool and nutrient cycle. Soil microbes in grasslands are susceptible to the degradation mediated by climate change and anthropogenic disturbance. However, research on how the degradation influences the diversity and community structure of different soil microbial taxa is relatively scarce. We conducted a large-scale field survey to describe the effects of four degradation levels (PD: potential degradation, LD: light degradation, MD: moderate degradation, and SD: severe degradation) on soil bacterial and fungal community in the semi-arid grasslands of northern China. We found that soil moisture, nutrients, and clay content decreased, but soil sand content increased along the increasing degradation gradient. However, the degradation had no effects on soil pH and the C:N ratio. Grassland degradation had non-significant effect on soil bacterial diversity, but it significantly affected soil bacterial community structure. The degradation decreased soil fungal diversity and had a relatively larger influence on the community structure of soil fungi than that of bacteria. The community composition and structure of soil fungi were mainly affected by soil nutrients and texture, while those of soil bacteria were mainly affected by soil pH. These results indicate that changes in soil properties induced by grassland degradation mainly drive the variation in the soil fungal community and have less effect on the soil bacterial community. This study reveals the sensitivity of soil fungal community to grassland degradation, highlighting the priority of soil fungal community for the management and restoration of degraded grasslands.

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.

Clinical analysis of uterine intravenous leiomyomatosis: A retrospective study of 260 cases.

METHODS: We collected the clinical data of 260 patients admitted to the hospital from April 2003 to September 2019 with pathologically confirmed intravenous leiomyomatosis (IVL) and followed up with these patients regularly. Univariate and multivariate logistic regression analyses were carried out on the relevant recurrence factors. RESULTS: A total of 166 patients were regularly followed up, the median follow-up time was 36 (range 2-168) months, 14 (5.4%) patients eventually relapsed, and the median recurrence time was 8.5 (range 2-42) months. The univariate analysis showed that age (p = 0.003) and surgical type (p < 0.001) were associated with recurrence, and multivariate regression analysis demonstrated that surgical type was the only factor associated with recurrence (p < 0.001, OR 20.01). CONCLUSIONS: The use of gonadotrophin releasing hormone agonist (GnRHa) cannot reduce the postsurgical recurrence rate of patients with UIVL. Compared to total hysterectomy and bilateral salpingo-oophorectomy (TH-BSO), total hysterectomy (TH) does not increase the odds of recurrence, but the chance of recurrence with tumorectomy (TE) is 20 times higher than that of TH-BSO.