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INTRODUCTION:Ventricular septal rupture (VSR) following acute myocardial infarction (AMI) is a rare but serious complication often causing cardiogenic shock (CS). The timing of surgery is a difficult problem for surgeons because of high mortality and surgical complexity. We present a case of successful use of extracorporeal membrane oxygenation (ECMO) for maintaining haemodynamic stability preoperative and delaying surgical repair of VSR patient in severe CS. CASE REPORT:A 57-year-old man with AMI complicated by severe CS due to an massive VSR. Emergency surgery was considered a too high mortality risk. The patient was implanted with a percutaneous veno-arterial ECMO (VA-ECMO) system as a bridge to surgery for stabilizing general condition. On the 31th day after ECMO implantation, the ventricular septal defect was successfully repaired and weaning from the ECMO. DISCUSSION:This case study illustrates that it may be considered to use long term ECMO preoperative to delayed surgery which leads to higher survival in cases of massive VSR patient after AMI in hemodynamically compromised patients. Still the optimal duration of mechanical circulatory support and the optimal timing for surgery need more research to define. CONCLUSION:This case indicates the feasibility of preoperative using of a long term VA-ECMO as a bridge to surgical repair of VSR patient after AMI in severe CS. The optimal duration of mechanical circulatory support and the optimal timing for surgery still require further investigation.

Eight new stigmasterol derivatives possessing 1,2,3-triazoles moiety were synthesized by a 1,3-dipolar cycloaddition reaction. All the compounds were characterized by IR, NMR, and HR-MS. In addition, human cervical cancer cells (HeLa), human gastric cancer cells (HGC-27), and human renal epithelial cells (HEK-293T) were selected to study the antitumor activity of the synthesized compounds. The results demonstrated that compounds 3c and 3d exhibited better inhibitory activity against the tested tumor cell lines. The IC 50 value of the inhibitory activity on HeLa was 52.3 μmol·L –1 and 31.4 μmol·L –1 , and 40.6 μmol·L –1 and 44.6 μmol·L –1 for HGC-27, respectively.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs. This study of Chinese endometrioid endometrial carcinomas describes the proteogenomic differences between early-onset and late-onset tumors, finding that SIGLEC10 mutation may contribute to tumorigenesis and progestin resistance in early cases.

Plant-derived triterpenoid saponins have been shown to play a powerful role in enhancing the cytotoxic activity of protein therapeutics. However, the mechanism of how saponins are acting is not clearly understood. In this study, momordin Ic (MIC), a triterpenoid saponin derived from Kochia scoparia (L.) Schrad., specifically enhance the antiproliferative effect of recombinant MAP30 (a type I ribosome inactivating protein, RIP) in breast cancer cells. Subsequently, the possible mechanism of how MIC enhanced the cytotoxicity of MAP30 was analyzed in detail. We observed the level of intracellular labeled MAP30 using fluorescence microscopy and flow cytometry. And a reporter protein, GAL9, was used to monitor the role of MIC in promoting endosomal escape. We found endosomal escape does not play a role for the enhancer effect of MIC while the effect of MIC on MAP30 is cholesterol dependent and that ganglioside GM1, a lipid raft marker, can competitively inhibit cytotoxicity of MAP30 enhanced by MIC. Finally, we provided some insights into the correlation between the sugar side chain of MIC and its role in enhancing of RIP cytotoxicity and altering of drug cell tropism.

Ovarian serous carcinoma (OC) is a common cause of mortality among gynecological malignancies. Although tumor-infiltrating CD8 T cells are associated with a favorable prognosis of OC, the underlying mechanisms are not clearly understood. The present study identified the key genes and potential molecular mechanisms associated with CD8 T-cell infiltration in OC. The score of CD8 T cells in The Cancer Genome Atlas dataset (376 samples from patients with OC) was estimated using the quanTIseq and MCP-counter algorithms. Thereafter, a protein-protein interaction network of differentially expressed genes was constructed and the hub genes were identified using cytoHubba in Cytoscape. The results revealed that signal transducer and activator of transcription 4 (STAT4) was strongly correlated with CD8 T-cell infiltration in OC. Furthermore, the prognostic value of STAT4 in OC was verified by Kaplan-Meier curve, and univariate and multivariate analyses. The biological functions of STAT4 were determined by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, which revealed that STAT4 is closely related to cytokines in OC. Moreover, Spearman correlation analysis suggested that STAT4 was most positively correlated with CC chemokine ligand 5 (CCL5). CCL5 was revealed to be critical for orchestrating T-cell infiltration in tumors. Moreover, immunohistochemistry and reverse transcription-quantitative PCR showed that STAT4, CCL5 and CD8A (a marker for CD8 T cells) were closely related in OC. Moreover, in vitro analysis revealed that STAT4 knockdown led to a decrease in CCL5 expression and CD8 T-cell migration. Taken together, the present study suggested that STAT4 may regulate CD8 T-cell infiltration in OC tissues by inducing CCL5 secretion. Furthermore, STAT4 may be considered a promising prognostic biomarker for OC.

Abstract Endometrial carcinoma (EC) remains a public health concern with a growing incidence particularly in younger women. Women with early-onset endometrioid EC (EEEC) who wish to maintain fertility are a worldwide concern. To illuminate the molecular characteristics of EEEC, we undertook a large-scale proteogenomic study of 222 EECs encompassing 81 EEEC who were 40 or younger. In contrast to late-onset EEC, integrated multi-omics analysis unexpectedly revealed an exposome-related mutational signature to be associated with EEEC leading to EEEC specific CTNNB1 and SIGLEC10 hotspot mutations and downstream protein pathway disturbance. Interestingly, in EEECs SIGLEC10Q144K mutation resulted in aberrant Siglec-10 protein expression and promoted progestin resistance by interacting with ERα. Collectively, our study provides a unique high-quality proteogenomic resource of EEECs while enabling insights into interactions between exposome and genomic susceptibilities for primary prevention and early detection of EEECs. Furthermore, we identified biomarkers for progestin response in EEEC fertility-sparing treatment.

The CDK4/6 inhibitor, palbociclib has recently entered clinic-trial stage for breast cancer treatment. However, translating its efficacy to other solid tumors has been challenging, especially for aggressive solid tumors. We found that the effect of palbociclib as a single agent was limited due to primary and acquired resistance in multiple ovarian cancer (OC) models. Among these, patient-derived organoid and xenograft models are two most representative models of drug responsiveness in patients with OC. In preclinical models, this study demonstrated that activated MAPK/PI3K-AKT pathway and cell cycle-related proteins induced the resistance to palbociclib, which was overcome by the addition of the bromodomain protein 4 (BRD4) inhibitor AZD5153. Moreover, this study revealed that AZD5153 and palbociclib had a synergistic lethal effect on inducing the cell cycle arrest and increasing apoptosis, even in RB-deficient cell lines. Based on these results, it is anticipated that this class of drugs, including AZD5153, which inhibit the cell cycle-related protein and MAPK/PI3K-AKT pathway, will exhibit synergistic effects with palbociclib in OC.

Targeting the G2/M checkpoint mediator WEE1 has been explored as a novel treatment strategy in ovarian cancer, but mechanisms underlying its efficacy and resistance remains to be understood. Here, it is demonstrated that the WEE1 inhibitor AZD1775 induces endoplasmic reticulum stress and activates the protein kinase RNA-like ER kinase (PERK) and inositol-required enzyme 1α (IRE1α) branches of the unfolded protein response (UPR) in TP53 mutant (mtTP53) ovarian cancer models. This is facilitated through NF-κB mediated senescence-associated secretory phenotype. Upon AZD1775 treatment, activated PERK promotes apoptotic signaling via C/EBP-homologous protein (CHOP), while IRE1α-induced splicing of XBP1 (XBP1s) maintains cell survival by repressing apoptosis. This leads to an encouraging synergistic antitumor effect of combining AZD1775 and an IRE1α inhibitor MKC8866 in multiple cell lines and preclinical models of ovarian cancers. Taken together, the data reveal an important dual role of the UPR signaling network in mtTP53 ovarian cancer models in response to AZD1775 and suggest that inhibition of the IRE1α-XBP1s pathway may enhance the efficacy of AZD1775 in the clinics.

Background Ovarian cancer (OC) is one of the most lethal gynecologic cancers. Growing evidence has proven that CDK4/6 plays a key role in tumor immunity and the prognosis of many cancers. However, the expression and function of CDK4/6 in OC remain unclear. Therefore, we aimed to explore the influence of CDK4/6 in OC, especially on immunity. Methods We analyzed CDK4/6 expression and prognosis using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Genotype Tissue Expression (GTEx) data. Subsequently, we used the cytoHubba plug-in of Cytoscape software and starBase to identify the noncoding RNAs (ncRNAs) regulating CDK4/6. Finally, we verified the effect of CDK4/6 on immunity in OC cell lines and animal models. Results CDK4/6 expression was higher in OC tissues than in normal ovarian tissues, and the high expression levels of CDK4/6 contributed to the immunosuppressive state of OC and were thus related to the poor prognosis of OC patients. This was also in general agreement with the results of OC cell line and animal experiments. Mechanistically, the CDK4/6 inhibitor palbociclib increased the secretion of interferon (IFN)-γ and the interferon-stimulated gene (ISG) response, thereby upregulating the expression of antigen-presenting molecules; this effect was partly dependent on the STING pathway and thus activated immunity in OC. Additionally, according to public data, the LRRC75A-AS1-hsa-miR-330-5p axis could inhibit the immune response of OC patients by upregulating CDK4/6, leading to a poor prognosis. Conclusion CDK4/6 affects the immune microenvironment of OC and correlates with the prognosis of OC patients.

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is an aggressive tumor with a high mortality rate because of the limited systemic and locoregional treatment modalities. The development and progression of HCC depend on epigenetic changes that result in the activation or inhibition of some signaling pathways. The mTOR signaling pathway is essential for many pathophysiological processes and is considered a major regulator of cancer. Increasing evidence has shown that epigenetics plays a key role in HCC biology by regulating the mTOR signaling pathway. Therefore, epigenetic regulation through the mTOR signaling pathway to diagnose and treat HCC will become a very promising strategy.

BACKGROUND AND PURPOSE:Cisplatin-paclitaxel (TP) combination chemotherapy as the first-line therapy for numerous cancers is hindered by its inadequate accumulation in tumors and severe side effects resulting from non-specific distribution. The aim of this study is to explore whether TMTP1-modified, cisplatin and paclitaxel prodrugs co-loaded nanodrug could improve cervical cancer chemotherapy and relieve its side effects through active and passive tumor targeting accumulation and controlled drug release.METHODS:TDNP, with capacities of active targeting for tumors and controlled drug release, was prepared to co-deliver cisplatin and paclitaxel prodrugs. The characteristics were investigated, including the diameter, surface zeta potential, stability and tumor microenvironment (TME) dependent drug release profiles. Cellular uptake, cytotoxicity, drug accumulation in tumors, antitumor effects and safety analysis were evaluated in vitro and in vivo.RESULTS:The oxidized cisplatin and the paclitaxel linked to the polymer achieved a high loading effciency of over 80% and TME-dependent sustained drug release. Moreover, TMTP1 modification enhanced cellular uptake of TDNP and further improved the cytotoxicity of TDNP in vitro. In vivo, TDNP showed an extended blood circulation and increased accumulation in SiHa xenograft models with the aid of TMTP1. More importantly, TDNP controlled tumor growth without life-threatening side effects.CONCLUSION:Our study provided a novel TP co-delivery platform for targeted chemotherapy of cervical cancer, which was promising to improve the therapeutic effcacy of TP and may also have application in other tumors.

Siomycin A is a type of thiopeptide antibiotic that is isolated from the fermentation products of an endophytic actinomycin, which is derived from the medicinal plant Acanthopanax senticosus. The present study investigated whether siomycin A has antitumor effects in vitro on a variety of cell lines. A Cell Counting Kit-8 assay was performed to detect the effects of siomycin A on cell viability; morphological changes in the MiaPaCa-2 cell line were analyzed using an inverted phase contrast microscope. A Transwell migration assay was applied to detect cell migration ability. The cytoskeleton was observed by laser confocal microscopy, and apoptosis was detected using flow cytometry. A western blot assay was used to detect the expression of matrix metalloproteinase (MMP)-2, MMP-9 and α-tubulin. The results revealed that siomycin A inhibited the proliferation of human tumor cell lines of different origins. As the concentration of siomycin A increased, the cell density decreased gradually and cells exhibited a morphological change from spindle to spherical shape. Furthermore, 24 h after administration, the cell migration ability was inhibited. The cytoskeleton complexity and morphological changes were increased after administration of siomycin A. The percentage of apoptotic cells was significantly increased and the expression levels of MMP-2, MMP-9 and α-tubulin were downregulated by siomycin A. Therefore, siomycin A was determined to effectively inhibit the proliferative ability of a variety of human tumor cell lines. Siomycin A was also determined to affect the cytoskeleton of tumor cells by downregulating the expression of α-tubulin protein.

BACKGROUND:Small cell lung cancer (SCLC) is a special type of lung cancer and it is responsive to chemotherapy. Blood parameters have been proved to be associated with survival for many types of malignancies. This study aimed to investigate the prognostic significance of platelet-to-lymphocyte ratio (PLR) and mean platelet volume (MPV) for SCLC patients with etoposide-based first-line treatment. METHODS:We retrospectively identified 138 patients diagnosed as SCLC who underwent etoposide-based first-line chemotherapy. The patients' baseline clinical characteristics and blood parameters were collected. Kaplan-Meier analysis and Cox regression methods were used to determine the factors associated with progression-free survival (PFS). RESULTS:The optimal cut-off value of diagnosis was depended on the ROC curve, the cut-off value of pretreatment PLR was 190 (sensitivity 39.0%, specificity 88.5%), and the cut-off value of pretreatment MPV was 10.0 (sensitivity 60.7%, specificity 61%). Kaplan-Meier analysis showed patients with high PLR levels in baseline had worse PFS than those with low PLR levels (P <0.001). Multivariate analysis revealed pretreatment MPV was an independent prognostic factor for PFS (HR: 0.815, 95% CI: 0.711-0.933, P =0.003). Further research suggested continuous high PLR indicated a poor therapy outcome (P =0.002). CONCLUSION:Pretreatment MPV can be an independent predictor for first-line treatment outcome and a continuously high level of PLR suggested inferior PFS in etoposide-treated SCLC patients.

Metastasis is one of the most threatening aspects of cervical cancer. We developed a method to intraoperatively map the primary tumor, metastasis and metastatic sentinel lymph nodes (SLNs), providing real-time intraoperative guidance in cervical cancer. Methods: TMTP1, a tumor metastasis targeting peptide, was employed to modify the indocyanine green (ICG)-loaded poly (ethylene glycol)- poly (lactic-co-glycolic acid) (PEG-PLGA) micelles. The cervical cancer subcutaneous tumor model and lung metastasis model were established to determine the active targeting of ICG-loaded TMTP1-PEG-PLGA micelles (ITM) for the primary tumor and occult metastasis of cervical cancer. Human cervical cancer HeLa cells engineered by firefly luciferase were injected into the right hocks of BALB/c nude mice to develop the SLN metastasis model. The ITM and control ICG-loaded PEG-PLGA micelles (IM) were injected into the right hind footpads in the SLN metastasis model, and the migration and retention of micelles were recorded under near-infrared fluorescence. K14-HPV16 transgenic mice were also used to detect the image capability of ITM to target cancerous lesions. Results: ITM could actively target imaging of the primary tumor and cervical cancer metastasis. ITM quickly diffused from the injection site to SLNs along lymphatic capillaries and remained in the SLNs for 12 h. Moreover, ITM specifically accumulated in the tumor metastatic SLNs (T-SLNs), which could be successfully distinguished from normal SLNs (N-SLNs). Conclusion: ITM could achieve active targeting of the primary tumor, metastasis and T-SLNs, providing precise and real-time intraoperative guidance for cervical cancer.

Purpose Peroxiredoxin 4 (PRDX4) has been reported to play a dual role in the progression of hepatocellular carcinoma (HCC). As yet, however, the underlying molecular mechanism has not been fully elucidated. Methods We examined the effects of PRDX4 on the growth and survival of HCC cells in an anchorage-independent microenvironment. The regulation of β-catenin stability and activity by PRDX4 was investigated. Results We found that PRDX4 depletion reduced, and PRDX4 overexpression increased, both anchorage-dependent and anchorage-independent growth of HCC cells. We also found that PRDX4 depletion caused an overproduction of reactive oxygen species (ROS) in HCC cells, especially under suspension conditions. PRDX4 knockdown predisposed HCC cells to anoikis, whereas PRDX4 overexpression induced resistance to anoikis. Subsequent in vivo studies confirmed that PRDX4 deficiency blocks HCC tumor growth and pulmonary metastasis. Mechanistically, we found that RDX4 reduced β-TrCP-mediated β-catenin ubiquitination and enhanced β-catenin protein stability, consequently leading to activation of β-catenin signaling. Silencing of β-catenin impaired PRDX4-mediated anchorage-independent growth and survival, whereas β-catenin overexpression increased the survival and growth of PRDX4-depleted cells under anchorage-independent conditions. Further investigation revealed that the β-catenin downstream gene ID2 is responsible for the oncogenic activity of PRDX4 in HCC cells, promoting anchorage-independent growth and anoikis resistance. Conclusions PRDX4 reduces anoikis and promotes tumorigenesis and metastasis of HCC cells through stabilization of the β-catenin protein and upregulation of ID2. Targeting of PRDX4 may represent a promising strategy to block HCC cell growth and metastasis.

BACKGROUND The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a prognostic factor in patients who have some types of malignant tumors. The aim of this study was to investigate the prognostic significance of the HALP score in patients with small cell lung cancer (SCLC) before first-line treatment with etoposide. MATERIAL AND METHODS A retrospective study included 178 patients with SCLC who received first-line chemotherapy with etoposide between September 2015 and May 2019. The baseline clinical characteristics and blood parameters were recorded. Univariate and multivariate analysis and Kaplan-Meier plots were used to identify the factors associated with progression-free survival (PFS). RESULTS The optimal cut-off values of the HALP score was determined by X-tile software to be 25.8. Univariate and multivariate analysis showed that in 178 patients, the HALP score, body mass index (BMI), and serum albumin levels had no prognostic significance. In the patient age group <65 years, a BMI ≥24 kg/m² was an independent prognostic factor (HR, 1.943; 95% CI, 1.251-3.018) (P=0.003). In the patient age group ≥65 years, a HALP score >25.8 was an independent positive prognostic factor for outcome following first-line treatment with etoposide (HR, 0.483; 95% CI, 0.270-0.865) (P=0.014). CONCLUSIONS In patients <65 years with SCLC who underwent first-line treatment with etoposide, a BMI ≥24 kg/m² an independent prognostic factor, and in patients ≥65 years, a HALP score >25.8 was an independent predictor of improved outcome, associated with increased PFS.

Background Drug resistance prevents the effective treatment of cancers. DNA methylation has been found to participate in the development of cancer drug resistance. Methods We performed the wound-healing and invasion assays to test the effect of the paraoxonase gene PON3 on esophageal cancer (EC) cells. In addition, in vivo EC-derived tumor xenografts in nude mice were generated to test the effect of PON3 on the chemoresistance of EC cells. Results We found that PON3 is hypermethylated in drug-resistant EC cell line K150, which in-return down-regulates its expression. The following experiments by the forced changes of PON3 level in vitro and in vivo demonstrated that the PON3 expression negatively correlates with drug resistance in EC cells. Further wound-healing and invasion assays showed that PON3 suppresses the migration and invasion of EC cells. Conclusion Our data established that PON3 is associated with the EC drug resistance, which may serve as a biomarker for the potential therapeutic treatment of EC.

Molecular imaging agents are considered to be promising tracers for tumor imaging and guided therapy. TMTP1 was screened through the FliTrx bacterial peptide display system in our laboratory previously and shown to specifically target to primary tumors and metastatic foci. In this study, small peptide TMTP1 was designed to conjugate to a near-infrared fluorescent agent ICG derivative ICG-OSu through PEG4, forming the novel probe TMTP1-PEG4-ICG. It was successfully synthesized and certified. CCK-8 assay showed that it was nontoxic to normal cells and cancerous cells. Dynamics study indicated that the probe was cleared through the liver-intestine and kidney-bladder pathway. Tumor targeting capability of this probe in vitro was evaluated on 4T1, SiHa, HeLa, S12, and HaCaT cells by flow cytometry. In vivo imaging of 4T1 and HeLa tumor-bearing mice further identified the tumor homing ability. As we had expected, the probe showed excellent affinity to cancer cells not only in vitro but also in vivo, whether in murine tumor or humanized tumor. In conclusion, TMTP1-PEG4-ICG demonstrated ideal imaging effects on tumor-bearing mice model, providing new opportunities for tumor diagnostic or guiding resection.