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Abstract Objective Immunotherapy has led to changes in cervical cancer guidelines. Therefore, additional biomarkers to identify the ideal patient who would experience the most benefit may be important. Methods We retrospectively collected 208 patients with R/M CC and recorded clinicopathologic information, peripheral blood markers and treatments to analyze the prognostic factors of clinical outcomes. Response rate comparison, univariate, and multivariate analyses were performed to assess the efficacy of different factors. Results A total of 43.27% patients achieved objective responses, including 18 with complete response and 72 with partial response. Patients receiving first‐line immunotherapy had much higher objective response rate (ORR) than the remaining patients (53.8% vs. 34.8%, p = 0.006). CRP >3 ECOG ≥1 and recurrence in 6 months predicted shorter progression free survival (PFS). CRP >3, GLU >6.1 independently predicted unfavorable overall survival (OS). Compared with no antiangiogenic therapy, previous antiangiogenic therapy reduced the median OS by nearly 14 months. Immunotherapy rechallenge was still effective after first immunotherapy failure, and combined with dual‐immunotherapy or bevacizumab combined with chemoradiotherapy resulted in a 60.00% or 62.50% ORR, respectively. Patients with squamous cell carcinoma, with stable disease or objective response in the first immunotherapy or without chemotherapy in second immunotherapy had favorable clinical outcome. Conclusion The baseline CRP levels in serum was an independent factor for PFS and OS of R/M CC patients treated with immunotherapy, and previous antiangiogenic therapy was associated with poor OS. Patients still show response to immunotherapy rechallenge and combined treatment with bevacizumab or candonilimab showed higher response rate than anti‐PD‐1 after immunotherapy failure.

Abstract Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2‐like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum‐free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum‐induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP‐ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient‐derived xenografts, especially those with wild‐type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

Abstract Background An immunosuppressive tumor microenvironment in ovarian cancer facilitates tumor progression and resistance to immunotherapy. The function of MYB Proto-Oncogene Like 2 (MYBL2) in the tumor microenvironment remains largely unexplored. Methods A syngeneic intraovarian mouse model, flow cytometry analysis, and immunohistochemistry were used to explore the biological function of MYBL2 in tumor progression and immune escape. Molecular and biochemical strategies—namely RNA-sequencing, western blotting, quantitative reverse transcription–polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, multiplex immunofluorescence, chromatic immunoprecipitation assay (CHIP) and luciferase assay—were used to reveal the mechanisms of MYBL2 in the OVC microenvironment. Results We found tumor derived MYBL2 indicated poor prognosis and selectively correlated with tumor associated macrophages (TAMs) in ovarian cancer. Mechanically, C-C motif chemokine ligand 2 (CCL2) transcriptionally activated by MYBL2 induced TAMs recruitment and M2-like polarization in vitro. Using a syngeneic intraovarian mouse model, we identified MYBL2 promoted tumor malignancyand increased tumor-infiltrating immunosuppressive macrophages. Cyclin-dependent kinase 2 (CDK2) was a known upstream kinase to phosphorylate MYBL2 and promote its transcriptional function. The upstream inhibitor of CDK2, CVT-313, reprogrammed the tumor microenvironment and reduced anti-PD-1 resistance. Conclusions The MYBL2/CCL2 axis contributing to TAMs recruitment and M2-like polarization is crucial to immune evasion and anti-PD-1 resistance in ovarian cancer, which is a potential target to enhance the efficacy of immunotherapy.

ABSTRACTEndophytic fungi of medicinal plants are symbiotic with the host and play an important role in determining metabolites. To understand the relationship between the accumulation of Sophora alopecuroides’ medicinal bioactive compounds and the ecological succession of endophytic fungi, here we collected samples from S. alopecuroides at four developmental stages (adult, flowering, podding, and mature) and different organs (roots, stems, leaves, and seeds) at the mature stage. We then used high-performance liquid chromatography-mass spectrometry and high-throughput sequencing on the internal transcribed spacer region to identify the medicinal compounds and endophytic fungal communities in each sample. The endophytic fungal community characteristics and accumulation of medicinally bioactive compounds of S. alopecuroides varied with the host’s developmental stages and organs, with the highest total alkaloids content of 111.9 mg/g at the mature stage. Membership analysis and network connection analysis showed a total of 15 core endophytic fungi in different developmental stages and 16 core endophytic fungi in different organs at the mature stage. The unclassified Ascomycota, Aspergillus, and Alternaria were significantly and positively correlated with the medicinal compounds of S. alopecuroides at the mature stage (r > 0.6 or r < −0.6; P < 0.05). In this study, we identified key endophytic fungal resources that affect the content of medicinally bioactive compounds in S. alopecuroides. This discovery could lay the foundation for enhancing the yield of medicinally bioactive compounds in S. alopecuroides and the development and application of functional endophytic fungi.IMPORTANCESophora alopecuroides is a traditional Chinese herbal medicine. The major medicinal chemicals are considered to be quinolizidine alkaloids. Quinolizidine alkaloids have been widely used for the treatment of tumors, dysentery, and enteritis. Previous studies have found that endophytic fungi in S. alopecuroides can promote the accumulation of host quinolizidine alkaloids. However, the relationship between the accumulation of S. alopecuroides’ medicinal bioactive compounds and the ecological succession of endophytic fungi remains unclear. In this study, we screened the key endophytic fungal resources affecting the content of medicinally bioactive compounds and laid the foundation for subsequent research on the mechanism by which endophytic fungi promote the accumulation of medicinally bioactive compounds in S. alopecuroides.

BackgroundHepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for ~90% of the total cases. DnaJ heat shock protein family member C8 (DNAJC8), belonging to the heat shock protein 40 (HSP40) family, is known to regulate cancer biology function. However, the role of DNAJC8 on HCC development remains unknown.MethodsThe Cancer Genome Atlas, GTEx, cBioPortal, and Human Protein Atlas were used to analyze the expression and clinical significance of DNAJC8 in HCC. Two HCC cell lines, MHCC-97H and Huh-7, were utilized to determine the biological function of DNAJC8.ResultsDNAJC8 expression was upregulated in HCC tissues and correlated with poor clinical prognosis. It was closely related to spliceosome, nucleocytoplasmic transport, and cell cycle and might be involved in the formation of tumor immunosuppressive microenvironment. Knockdown of DNAJC8 severely inhibited HCC cell proliferation and induced apoptosis.ConclusionOur study demonstrate that DNAJC8 functions as an oncogene in HCC and hence may be used as a potential therapeutic target and prognostic marker for HCC.

Objective: To develop a nomogram for predicting lymph node metastasis (LNM) in patients with epithelial ovarian cancer (EOC). Methods: Between December 2012 and August 2022, patients with EOC who received computed tomography (CT) and serological examinations and were treated with upfront staging or debulking surgery were included. Systematic pelvic and para-aortic lymphadenectomy was performed in all patients. Univariate and multivariate analysis was used to identify significant risk factors associated with LNM. A nomogram was then constructed to assess the risk of LNM, which was evaluated with respect to its area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness. Results: Of 212 patients enrolled in this study, 78 (36.8%) had positive LNs. The nomogram integrating CT-reported LN status, child-bearing status, tumour laterality, and stage showed good calibration and discrimination with an AUC of 0.775, significantly improving performance over the CT results (0.699, p = 0.0002) with a net reclassification improvement of 0.593 (p < 0.001) and integrated discrimination improvement of 0.054 (p < 0.001). The decision curve analysis showed the nomogram was of clinical use. Conclusions: A nomogram was constructed and internally validated, which may act as a decision aid in patients with EOC being considered for systemic lymphadenectomy.

BackgroundTislelizumab is an anti-programmed cell death 1 (PD-1) monoclonal antibody engineered to minimize binding to Fcγ receptors. It has been used to treat several solid tumors. However, its efficacy and toxicity, and the predictive and prognostic value of baseline hematological parameters in patients with recurrent or metastatic cervical cancer (R/M CC) receiving tislelizumab remain unclear.MethodsWe reviewed 115 patients treated for R/M CC with tislelizumab from March 2020 to June 2022 in our institute. The antitumor activity of tislelizumab was assessed using RECIST v1.1. Associations between the baseline hematological parameters and efficacy of tislelizumab in these patients were analyzed.ResultsWith a median follow-up of 11.3 months (range, 2.2–28.7), the overall response rate was 39.1% (95% CI, 30.1–48.2) and the disease control rate was 77.4% (95% CI, 69.6–85.2). The median progression-free survival (PFS) was 19.6 months (95% CI, 10.7 to not reached). The median overall survival (OS) was not reached. Treatment-related adverse events (TRAEs) of any grade occurred in 81.7% of the patients and only 7.0% of the patients experienced grade 3 or 4 TRAEs. Univariate and multivariate regression analyses showed that the level of pretreatment serum C-reactive protein (CRP) was an independent risk factor for the response (complete or partial response) to tislelizumab and the PFS of R/M CC patients treated with tislelizumab (P = 0.0001 and P = 0.002, respectively). R/M CC patients with elevated baseline CRP levels had a short PFS (P = 0.0005). Additionally, the CRP-to-albumin ratio (CAR) was an independent risk factor for the PFS and OS of R/M CC patients treated with tislelizumab (P = 0.001 and P = 0.031, respectively). R/M CC patients with an elevated baseline CAR had short PFS and OS (P < 0.0001 and P = 0.0323, respectively).ConclusionsTislelizumab showed promising antitumor activity and tolerable toxicity in patients with R/M CC. The baseline serum CRP levels and CAR showed potential for predicting the efficacy of tislelizumab and the prognosis of R/M CC patients receiving tislelizumab.

Sophora alopecuroides L. is a traditional Chinese medicine used for the treatment of several different disease states including bacillary dysentery and enteritis. But importantly, it also plays a role as an anti-tumor agent. That said, little is known about the role endophytes play regarding the clinically bioactive metabolites in S. alopecuroides. In order to explore the effects of endophytic fungi on the accumulation, quality, and correlation in the content of the medicinal compounds, the structural diversity of endophytic fungi in S. alopecuroides was analyzed. The relationship between endophytes and quinolizidine alkaloids (QAs), housed within the seeds of S. alopecuroides, which were interpreted based on established methods of high-throughput sequencing and high-performance liquid chromatography. A total of 1,034,418 effective sequence reads and 257 operational taxonomic units (OTUs) were obtained from 33 samples which were sourced from 11 different sampling sites and further classified into 9 phyla, 20 classes, 45 orders, 85 families, and 118 genera. Ascomycota was found to be the dominant phylum of endophytic fungi in S. alopecuroides, with a relative abundance ranging from 60.85 to 98.30%. Alternaria, Cladosporium, Filobasidium, and an unidentified Ascomycota were the core-shared endophytes, accounting for 49.96, 27.12, 14.83, and 7.88%, respectively. Correlation analysis showed that the Simpson’s diversity index of endophytic fungal community in S. alopecuroides was significantly positively correlated with the Oxymatrine (OMA) content in different areas, while the Chao and Shannoneven indexes were significantly negatively correlated with OMA. The endophytic fungi of Alternaria were positively correlated with the content of OMA, Oxysophocarpine (OSC), and total QAs. This study has mastered the endophytic fungi resources of S. alopecuroides, explored potential functional endophytic fungi, and provided a scientific basis for using biological fertilization strategies to improve the quality of S. alopecuroides.

Sophora alopecuroides L. has great medicinal and ecological value in northwestern China. The host and its microbiota are mutually symbiotic, collectively forming a holobiont, conferring beneficial effects to the plant. However, the analysis of diversity, mycobiota composition, and the ecological function of endophytic fungi in the holobiont of S. alopecuroides is relatively lacking. In this article, the fungal community profiling of roots, stems, leaves, and seeds of S. alopecuroides (at the fruit maturity stage) from Huamachi and Baofeng in Ningxia, China were investigated based on the ITS1 region, using high-throughput sequencing technology. As a result, a total of 751 operational taxonomic units (OTUs) were obtained and further classified into 9 phyla, 27 classes, 66 orders, 141 families, 245 genera, and 340 species. The roots had the highest fungal richness and diversity, while the stems had the highest evenness and pedigree diversity. There also was a significant difference in the richness of the endophytic fungal community between root and seed (p < 0.05). The organ was the main factor affecting the community structure of endophytic fungi in S. alopecuroides. The genera of unclassified Ascomycota, Tricholoma, Apiotrichum, Alternaria, and Aspergillus made up the vast majority of relative abundance, which were common in all four organs as well. The dominant and endemic genera and biomarkers of endophytic fungi in four organs of S. alopecuroides were different and exhibited organ specificity or tissue preference. The endophytic fungi of S. alopecuroides were mainly divided into 15 ecological function groups, among which saprotroph was absolutely dominant, followed by mixotrophic and pathotroph, and the symbiotroph was the least. With this study, we revealed the diversity and community structure and predicted the ecological function of the endophytic fungi of S. alopecuroides, which provided a theoretical reference for the further development and utilization of the endophytic fungi resources of S. alopecuroides.