High-risk human papillomavirus oncoproteins E6 and E7 are the major etiological factors of cervical cancer but are insufficient for malignant transformation of cervical cancer. Dysregulated alternative splicing, mainly ascribed to aberrant splicing factor levels and activities, contributes to most cancer hallmarks. However, do E6 and E7 regulate the expression of splicing factors? Does alternative splicing acts as an “accomplice” of E6E7 to promote cervical cancer progression? Here, we identified that the splicing factor SRSF10, which promotes tumorigenesis of cervix, was upregulated by E6E7 via E2F1 transcriptional activation. SRSF10 modulates the alternate terminator of interleukin-1 receptor accessory protein exon 13 to increase production of the membrane form of interleukin-1 receptor accessory protein. SRSF10-mediated mIL1RAP upregulates the expression of the “don’t eat me” signal CD47 to inhibit macrophage phagocytosis by promoting nuclear factor-κB activation, which is pivotal in inflammatory, immune, and tumorigenesis processes. Altogether, these data reveal a close relationship among HPV infection, alternative splicing and tumor immune evasion, and also suggests that the SRSF10-mIL1RAP-CD47 axis could be an attractive therapeutic target for the treatment of cervical cancer.

Background: Endometrial carcinoma (EC) is one of the most common gynecological malignancies among women. Maternal embryonic leucine Zipper Kinase (MELK) is upregulated in a variety of human tumors, where it contributes to malignant phenotype and correlates with a poor prognosis. However, the biological function of MELK in EC progression remains largely unknown. Methods: We explored the MELK expression in EC using TCGA and GEO databases and verified it using clinical samples by IHC methods. CCK-8 assay, colony formation assay, cell cycle assay, wound healing assay and subcutaneous xenograft mouse model were generated to estimate the functions of MELK and its inhibitor OTSSP167. qRT-PCR, western blotting, co-immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assay were performed to uncover the underlying mechanism concerning MELK during the progression of EC. Findings: MELK was significantly elevated in patients with EC, and high expression of MELK was associated with serous EC, high histological grade, advanced clinical stage and reduced overall survival and disease-free survival. MELK knockdown decreased the ability of cell proliferation and migration in vitro and subcutaneous tumorigenesis in vivo. In addition, high expression of MELK could be regulated by transcription factor E2F1. Moreover, we found that MELK had a direct interaction with MLST8 and then activated mTORC1 and mTORC2 signaling pathway for EC progression. Furthermore, OTSSP167, an effective inhibitor, could inhibit cell proliferation driven by MELK in vivo and vitro assays. Interpretation: We have explored the crucial role of the E2F1/MELK/mTORC1/2 axis in the progression of EC, which could be served as potential therapeutic targets for treatment of EC.

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Background: Chronic inflammation is considered as a hallmark of gastric cancer (GC) and plays a critical role in GC progression and metastasis. This study aimed to explore the prognostic values of preoperative fibrinogen-toprealbumin ratio (FPR), fibrinogen-to-albumin ratio (FAR), and novel FPR-FAR-CEA (FFC) score in patients with GC undergoing gastrectomy. Methods: A total of 273 patients with resectable GC were included in this retrospective study. We performed Kaplan-Meier and Cox regression analyses to assess the prognostic role of preoperative FPR, FAR, and FFC score in patients with GC and analyze their relationships with clinicopathological features. Results: Receiver operating characteristic curve (ROC) analysis revealed that the optimal cutoff values for FPR and FAR were 0.0145 and 0.0784, respectively. The FFC score had a higher area under the ROC curve than FAR and CEA. Elevated FPR (≥ 0.0145) and FAR (≥ 0.0784) were significantly associated with old age, large tumor size, tumor invasion depth, lymph nodes metastasis, advanced TNM stage, large Borrmann type, and anemia status. Kaplan-Meier analysis showed that high FPR, FAR, and FFC score were related to poor survival. Multivariate analyses indicated that FPR, FFC score, TNM stage, and tumor size were significant independent factors for survival. Conclusions: Preoperative FPR and FFC score could be used as prospective noninvasive prognostic biomarkers for resectable GC.

Water bloom development due to eutrophication constitutes a case of niche specialization among planktonic cyanobacteria, but the genomic repertoire allowing bloom formation in only some species has not been fully characterized. We posited that the habitat relevance of a trait begets its underlying genomic complexity, so that traits within the repertoire would be differentially more complex in species successfully thriving in that habitat than in close species that cannot. To test this for the case of bloom-forming cyanobacteria, we curated 17 potentially relevant query metabolic pathways and five core pathways selected according to existing ecophysiological literature. The available 113 genomes were split into those of blooming (45) or nonblooming (68) strains, and an index of genomic complexity for each strain’s version of each pathway was derived. We show that strain versions of all query pathways were significantly more complex in bloomers, with complexity in fact correlating positively with strain blooming incidence in 14 of those pathways. Five core pathways, relevant everywhere, showed no differential complexity or correlations. Gas vesicle, toxin and fatty acid synthesis, amino acid uptake, and C, N, and S acquisition systems were most strikingly relevant in the blooming repertoire. Further, we validated our findings using metagenomic gene expression analyses of blooming and nonblooming cyanobacteria in natural settings, where pathways in the repertoire were differentially overexpressed according to their relative complexity in bloomers, but not in nonbloomers. We expect that this approach may find applications to other habitats and organismal groups. IMPORTANCE We pragmatically delineate the trait repertoire that enables organismal niche specialization. We based our approach on the tenet, derived from evolutionary and complex-system considerations, that genomic units that can significantly contribute to fitness in a certain habitat will be comparatively more complex in organisms specialized to that habitat than their genomic homologs found in organisms from other habitats. We tested this in cyanobacteria forming harmful water blooms, for which decades-long efforts in ecological physiology and genomics exist. Our results essentially confirm that genomics and ecology can be linked through comparative complexity analyses, providing a tool that should be of general applicability for any group of organisms and any habitat, and enabling the posing of grounded hypotheses regarding the ecogenomic basis for diversification.

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Purpose. To evaluate visual outcomes and identify prognostic factors after pars plana vitrectomy (PPV) surgery for traumatic endophthalmitis. Methods. Medical records of 121 consecutive patients (121 eyes) diagnosed with traumatic endophthalmitis that had undergone pars plana vitrectomy were retrospectively reviewed. Results. 121 patients, aged from 6 to 71 years, all underwent PPV surgery. 113 cases had improved best corrected visual acuity (BCVA) after surgery and 60% of them obtained BCVA better than fingers counting (FC). Good final visual prognosis was significantly associated with time between trauma and initial treatment less than 12 hrs (40% versus 98%; P < 0.001), time between trauma and PPV treatment less than 24 hrs (62% versus 98%; P < 0.001), laceration length less than 10 mm (63% versus 96%; P < 0.001), and presenting VA better than LP (42% versus 96%; P < 0.001), while gender, type of laceration, presence of IOFB or retinal detachment, and the use of silicone oil tamponade were not significant factors resulting in better BCVA. Bacteria were identified in 43.8% of specimens and most of the microorganisms were identified as nonvirulent ones. Conclusions. Pars plana vitrectomy surgery was preferred as a primary treatment option for traumatic endophthalmitis. A good final visual prognosis was significantly associated with timely treatment, prompt vitrectomy surgery, shorter length of laceration, and better presenting visual acuity.

Cervical cancer (CC) remains highest in the mortality of female reproductive system cancers, while cisplatin (CDDP) resistance is the one of main reasons for the lethality. Preceding evidence has supported that karyopherins are associated with chemoresistance. In this study, we simultaneously compared CDDP-incomplete responders with CDDP-complete responders of CC patients and CDDP‐insensitive CC cell lines with CDDP‐sensitive group. We finally identified that DNA-PKcs (PRKDC) was related to CDDP sensitivity after overlapping in CC sample tissues and CC cell lines. Further functional assay revealed that targeting PRKDC by shRNA and NU7026 (specific PRKDC inhibitor) could enhance CDDP sensitivity in vitro and in vivo, which was mediated by impairing DNA damage repair pathway in CC. Mechanistically, we found that PRKDC was transcriptionally upregulated by CCAAT/enhancer-binding protein delta (CEBPD), while intriguingly, CDDP treatment strengthened the transcriptional activity of CEBPD to PRKDC. We further disclosed that Importin 4 (IPO4) augmented the nuclear translocation of CEBPD through nuclear localization signals (NLS) to activate PRKDC-mediated DNA damage repair in response to CDDP. Moreover, we demonstrated that IPO4 and CEBPD knockdown improved CDDP-induced cytotoxicity in vitro and in vivo. Together, we shed the novel insight into the role of IPO4 in chemosensitivity and provide a clinical translational potential to enhance CC chemosensitivity since the IPO4-CEBPD-PRKDC axis is actionable via NU7026 (PRKDC inhibitor) or targeting IPO4 in combination with CDDP.