Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 3 (PLOD3) is related to a variety of human diseases. However, its function in Colorectal cancer (CRC) remains uncertain. PLOD3 expression was analyzed using The Cancer Genome Atlas (TCGA) pan-cancer data. DAVID was used for enrichment analysis of PLOD3-related genes. The correlation between PLOD3 expression and immune cell infiltration was evaluated. Four expression profile datasets (GSE17536, GSE39582, GSE74602, and GSE113513) from Gene Expression Omnibus, and two proteomic datasets were used as validation cohorts for assessing the diagnostic and prognostic value of PLOD3 in CRC. What’s more, we performed immunohistochemistry (IHC) staining for PLOD3 in 160 paired CRC specimens and corresponding adjacent non-tumor tissues. PLOD3 was highly expressed in many tumors including CRC. PLOD3 was upregulated in advanced stage CRCs, and high PLOD3 expression was associated with poor survival. High PLOD3 expression was associated with low levels of B cells, CD4+ T cells, M1 macrophages, CD8+ T cells, and multiple immunerelated characteristics. In addition, the high PLOD3 expression group had a higher TIDE score and a lower tumor mutation burden and microsatellite instability, indicating that patients with high PLOD3 expression may be resistant to immunotherapy. Additional datasets and IHC analysis were used to validate the diagnostic and prognostic value of PLOD3 at the mRNA and protein levels in CRC. Patients with non-response to immunotherapy showed increased PLOD3 expression in an immunotherapy treated dataset. PLOD3 is a potential biomarker for CRC diagnosis and prognosis prediction. CRCs with high PLOD3 expression may be resistant to immune checkpoint therapy.
Antiangiogenic therapy, as a new anticancer method, can improve the anticancer effect of traditional therapies. Different antiangiogenic drugs may have different vascular normalization time windows. Whether the antiangiogenic treatment is within the vascular normalization time window is very important in the treatment of cancers. Previous studies have indicated that recombinant human endostatin (rh-ES) can transiently normalize tumor microvessels. Yet the molecular mechanism and the time window of rh-ES remains unclear. The aim of the present study was to explore the optimal time window and molecular mechanism of rh-ES in inhibiting Lewis lung cancer (LLC). By comparatively accessing the changes in microvascular and hypoxic conditions of tumors in host mice treated with rh-ES or saline for different days, the authors aimed to investigate the best administration time of rh-ES treatment on human lung cancers and obtain a better understanding concerning the involved molecular mechanism. A total of 40 C57/BL6 mice with LLC xenografts were randomly divided into normal saline (NS) and rh-ES groups (20 mice/group). 0.2 ml NS or 5 mg/kg rh-ES were administrated via intraperitoneal injection (i.p.) into each mouse each day during the 9-day experiment. A total of 5 mice from each group were sacrificed at day 2, 4, 6 or 9. CA9 and RGS5 expression levels of both groups were compared using immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and ELISA. Rh-ES caused vascular normalization and improved hypoxia at days 4 and 6. Compared with the control (NS) group, both CA9 and RGS5 expression in rh-ES group were significantly decreased at days 4 and 6 (P<0.05), while no significant change between two groups was observed at days 2 and 9. Rh-ES can induce transient tumor vascular normalization and improves tissue hypoxia in LLC tumors. The vascular normalization window is accompanied by the reduction in RGS5 and CA expression.
Background: Metformin (MET) is a well-known anti-diabetic drug that also has anti-cancer effects. However, high therapeutic doses of MET on cancer cells and the low efficacy of combinatory therapeutic approaches limit its clinical application. Recent studies have shown that chrysin (CHR) can improve the pharmaceutical efficacy of MET by suppressing human telomerase reverse transcriptase (hTERT) and cyclin D1 gene expression. Objective: This study aimed to develop different ratios of methoxy poly(ethylene glycol)-b-poly(e-caprolactone) (MPEG-PCL) micelles for breast cancer to co-deliver a synergistic CHR/MET combination. Methods: CHR/MET drug-loaded micelles were prepared by modified thin-film hydration. Fourier infrared spectrum, gel permeation chromatography, transmission electron microscopy, and high-performance liquid chromatography were used to evaluate the physicochemical properties of nanostructures. Cell proliferation and cell apoptosis were assessed by MTT and Annexin V-FITC/PI double staining method. The gene expression of hTERT and cyclin D1 was measured by real-time PCR assay. A subcutaneous mouse T47D xenograft model was established to evaluate the in vivo efficiency. Results: When the ratio of MPEG-PCL was 1:1.7, the highest drug loading rate and encapsulation efficiency of CHR (11.31±0.37) and MET (12.22±0.44) were observed. Uniform MPEG-PCL micelles of 51.70±1.91 nm allowed MET to incorporate with CHR, which were co-delivered to breast cancer cells. We demonstrated that CHR/MET co-delivery micelles showed a good synergistic effect on inhibiting proliferation in T47D cells (combination index=0.87) by suppressing hTERT and cyclin D1 gene expression. Compared with the free CHR/MET group, the apoptosis rate on T47D cells by CHR/MET nano-micelles significantly improved from 71.33% to 79.25%. The tumour volume and tumour weight of the CHR/MET group increased more slowly than that of the single-drug treatment group (P<0.05). Compared with the CHR/MET group, the tumour volume and tumour weight of the CHR/MET nano-micelle group decreased by 42% and 59%, respectively. Conclusions: We demonstrated that ratiometric CHR/MET micelles could provide an effective technique for the treatment of breast cancer.
ObjectivesPlatelet count is an independent predictor of mortality in patients with cancer. It remains unknown whether the platelet count is related to in-hospital mortality in severely ill patients with tumours.DesignA retrospective study based on a dataset from a multicentre cohort.SettingThis was a secondary analysis of data from one Electronic Intensive Care Unit Collaborative Research Database survey cycle (2014–2015).ParticipantsThe data pertaining to severely ill patients with tumours were collected from 208 hospitals located across the USA. This study initially a total of 200 859 participants. After the population was limited to patients with combined tumours and platelet deficiencies, the remaining 2628 people were included in the final data analysis.Primary and secondary outcome measuresThe main measure was the platelet count, and the main outcome was in-hospital mortality.ResultsAfter adjustment for the covariates, the platelet count had a curvilinear relationship with in-hospital mortality (p<0.001). The first inflection point was 18.4 (per 10 change). On the left side of the first inflection point (platelet count ≤184 'x10ˆ9/L), an increase of 10 in the platelet count was negatively associated with in-hospital mortality (OR 0.92, 95% CI 0.89 to 0.95, p<0.001). The second inflection point was 44.5 (per 10 change). Additional increases of 10 in the platelet count thereafter were positively associated with hospital mortality (OR 1.13, 95% CI 1.00 to 1.28, p=0.0454). The baseline platelet count was in the range of 184 'x10ˆ9/L–445 'x10ˆ9/L(p=0.0525), and the hospital mortality was lower than the baseline platelet count in other ranges.ConclusionsThe relationship between platelet count and in-hospital mortality in critically ill patients with tumours was curvilinear. The lowest in-hospital mortality was associated with platelet count between 184 'x10ˆ9/Land 445 'x10ˆ9/L. This indicates that both high and low platelet count should receive attention in clinical practice.
5 Gy/f, once per day, continuous irradiation 3d or 5d. After the irradiation, the E group and MHD 15+E group were given recombinant human endostatin 6mg/kg intraperitoneal injection, once per day, for 14 consecutive days. At 1, 3, and 6 months after intervention, 5 rats in each group were randomly selected for HE, Masson, and immunohistochemical CD34 microvessel staining, and Western Blot detected mitochondrial Complex II protein expression. Two-way ANOVA statistics. Results: Compared with C group, edema and disorder of myocardial cells, infiltration of inflammatory cells and decrease of microvessel density was observed at 1 month after intervention in HE staining in MHD 15 and MHD 15+E group. The expression of complex II protein decreased at 6 months, and the degree of decrease was less than that in MHD 25 group (positive control group) (P < 0.05). The microvessel density was further decreased compared with 1 month. Myocardial fibrosis induced by 15 Gy/3f low-dose irradiation of SD rat heart mainly occurred at 6 months, which observed myocardial cord or reticular fibrosis and collagen deposition. Semi-quantitative analysis of myocardial collagen volume fraction CVF significantly increased (P < 0.001) in HE and Masson staining. Details is shown in the table below. Compared with C group, E group observed myocardial edema and decreased microvessel density. There was no significant difference between MHD 15 and MHD 15+E group. Conclusion: Low dose irradiation of 15 Gy/3f (BED = 40 Gy) still cause myocardial fibrosis and damage of cardiac function in SD rats. RIHD were observed after 6 months, which was equal to about 1/5 of the rat's life span, and the time was delayed when compared with the time of RIHD caused by high dose irradiation. Cardiotoxicity was not increased significantly combining recombinant human endostatin on the basis of low-dose cardiac.
Objective To understand the effects of clock gene BMAL1 and HIF-1α(Hypoxia inducible factor-1α) on proliferation, migration and sensitivity to radiotherapy of nasopharyngeal carcinoma cells HONE1.At the same time, whether the biological clock gene BMAL1 can affect the expression of HIF-1α protein was investigated.It will lay the foundation for further study on the correlation between clock gene BMAL1 and HIF pathway. Methods BMAL1 gene overexpression and interference lentivirus and HIF-1α gene interference lentivirus were constructed respectively, and were transfected into nasopharyngeal carcinoma cells HONE1. Western blot was used to verify the establishment of overexpressed and knockdown BMAL1 cell lines and HIF-1α gene knockdown cell line, and to investigate the expression of HIF-1α protein in overexpressed and knockdown BMAL1 cell lines.CCK-8 cell proliferation test and scratch test were used to analyze the proliferation and migration ability of cells.Cell apoptosis after radiotherapy was analyzed by flow cytometry.The effects of BMAL1 and HIF-1α on the sensitivity of HONE1 radiotherapy in nasopharyngeal carcinoma cells after X-ray irradiation at different doses (0Gy, 2Gy, 4Gy, 6Gy) were detected by clone formation assay. Results The overexpression of BMAL1 gene and lentivirus interference were constructed to effectively up regulate and down regulate the expression of BMAL1 protein in nasopharyngeal carcinoma cells HONE1.Meanwhile, HIF-1α gene interference lentivirus was constructed to effectively down-regulate the expression of HIF-1α protein in nasopharyngeal carcinoma cell line HONE1, and successfully screen out stable nasopharyngeal carcinoma cell lines.Western blot results showed that overexpression of BMAL1 gene could inhibit the expression of HIF-1α protein in HONE1 of nasopharyngeal carcinoma cells, while knockdown of BMAL1 gene promoted the expression of HIF-1α protein in HONE1 of nasopharyngeal carcinoma cells(P < 0.05).CCK-8 cell proliferation and scratch test showed that overexpression of BMAL1 gene or knockdown of HIF-1α gene could inhibit the proliferation and migration of HONE1 cells (P < 0.05).Flow cytometry results showed that after 8Gy irradiation for 72 h, the apoptosis rate of BMALl gene overexpression group was higher than that of the overexpression control group, similarly, the apoptosis rate of HIF-1α gene knockdown group was higher than that of the knockdown control group (P < 0.05).After X-ray irradiation at different doses (0Gy, 2Gy, 4Gy, 6Gy), clon-formation experiment showed that the clon-formation rate and cell survival fraction of BMALl overexpression group or HIF-1α knockdown group were lower than those of negative control group (P < 0.05).Sigmaplot analysis showed that the D0, Dq and SF2 of the BMAL1 overexpression group or HIF-1α knockdown group were lower than those of the negative control group, and the radiosensitization ratios were 1.381 and 1.063, respectively. Conclusion Overexpression of BMAL1 gene can inhibit the proliferation and migration of nasopharyngeal carcinoma cell line HONE1, increase apoptosis after radiotherapy and improve radiosensitivity.Knock down HIF-1α Gene can inhibit the proliferation and migration of nasopharyngeal carcinoma cell line HONE1, increase apoptosis after radiotherapy and improve radiosensitivity.In nasopharyngeal carcinoma cells HONE1, overexpression of BMAL1 gene can inhibit the expression of HIF-1α protein while knockdown of BMAL1 gene can promote the expression of HIF-1α protein.
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