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Guang-Ang Tian, Chun-Jie Xu, Kai-Xia Zhou, Zhi-Gang Zhang, Jian-Ren Gu, Xue-Li Zhang, Ya-Hui Wang, "MPC1 Deficiency Promotes CRC Liver Metastasis via Facilitating Nuclear Translocation of β-Catenin", Journal of Immunology Research, vol. 2020, Article ID 8340329, 11 pages, 2020. https://doi.org/10.1155/2020/8340329
MPC1 Deficiency Promotes CRC Liver Metastasis via Facilitating Nuclear Translocation of β-Catenin
Accumulating evidence has pointed out that metastasis is the leading cause of death in several malignant tumor, including CRC. During CRC, metastatic capacity is closely correlated with reprogrammed energy metabolism. Mitochondrial Pyruvate Carrier 1 (MPC1), as the carrier of transporting pyruvate into mitochondria, linked the glycolysis and TCA cycle, which would affect the energy production. However, the specific role of MPC1 on tumor metastasis in CRC remains unexplored. Here, by data mining of genes involved in pyruvate metabolism using the TCGA dataset, we found that MPC1 was significantly downregulated in CRC compared to nontumor tissues. Similar MPC1 expression pattern was also found in multiple GEO datasets. IHC staining in both human sample and AOM/DSS induced mouse CRC model revealed significant downregulation of MPC1. What is more, we found that MPC1 expression was gradually decreased in normal tissue, primary CRC, and metastasis CRC. Additionally, poor prognosis emerged in the MPC1 low expression patients, especially in patients with metastasis. Following, functional tests showed that MPC1 overexpression inhibited the motility of CRC cells in vitro and MPC1 silencing enhanced liver metastases in vivo. Furthermore, we uncovered that decreased MPC1 activated the Wnt/β-catenin pathway by promoting nuclear translocation of β-catenin to mediate the expression of MMP7, E-cadherin, Snail1, and myc. Collectively, our data suggest that MPC1 has the potential to be served as a promising biomarker for diagnosis and a therapeutic target in CRC.
Colorectal carcinoma (CRC), as one of the most common gastrointestinal malignancies, has developed the world’s fourth most deadly cancer with a high rate of incidence and mortality [1, 2]. Liver metastasis, which is the most common form for CRC metastasis, is the leading cause of high mortality for this severe malignancy . However, few clinical prevention and treatment measures could be available for tumor metastasis. Therefore, it is really urgent to develop new biomarkers and explore the underlying mechanism for CRC metastasis, and eventually develop new therapeutic strategies for CRC patients.
During cancer progression, metabolic reprograming with increasing glucose utilization is termed as Warburg affect, which is accompanied by altered pyruvate and mitochondrial metabolism . The fate of pyruvate is the core manifestation to distinguish normal cells and tumor cells through metabolism. In normal cells, pyruvate was used for efficient ATP production directly into mitochondria. However, pyruvate was converted into lactate in cytosol despite of normoxic and hypoxic conditions in cancer cells . This may be due to the impaired process of pyruvate from the cytosol into the mitochondrial matrix, which is a critical metabolic step linking glycolysis and mitochondrial oxidative phosphorylation. The Mitochondrial Pyruvate Carrier (MPC), a multimeric complex containing two distinct proteins MPC1 and MPC2, which is located in the inner mitochondrial membrane, is responsible for efficient mitochondrial pyruvate uptake . Loss of MPC expression or activity blocks pyruvate entry into the TCA cycle, which results in a metabolism switch to increase glycolysis and the compensatory usage of glutamine [6, 7].
Existed studies have reported that MPC1 was related with immunoregulation, stemness, metabolism, cellular morphology, etc. [3, 8–10]. Currently, the important role of MPC1 was uncovered in several tumors. In CRC and esophageal squamous cell carcinoma, decreased MPC1 results in accelerated aerobic glycolysis and malignant progression [11, 12]. In lung adenocarcinoma, MPC1 deficiency accelerates lung adenocarcinoma progression through the STAT3 pathway . In prostate cancer, MPC1 was reported to be involved in stemness and metabolism which regulated by COUPTFII [14, 15]. In renal cell carcinoma, hypoxia-induced loss of MPC1 enhanced the expression of MMP7 and MMP9 to promote cell invasion . Collectively, these data suggested that MPC1 maybe serves as a suppressor to disrupt tumor malignancy. However, whether MPC1 is involved in CRC metastasis and the underlying mechanisms remain to be illustrated.
In the present study, we figured out the relationship between the MPC1 expression and CRC liver metastasis. We identified that decreased MPC1 was closely correlated with patient’s metastasis, as well as led to poor prognosis. Functionally, MPC1 overexpression could attenuate the migration and invasion capacities of CRC cells both in vitro and in vivo. Mechanically, MPC1 suppressed CRC metastasis through mediating the Wnt/β-catenin signaling. Thus, our finding firstly revealed a critical role of MPC1 in CRC liver metastasis.
2. Materials and Methods
2.1. Data Mining
Seven GEO datasets (GSE21510, GSE5206, GSE20916, GSE9348, GSE89393, GSE67675, and GSE4183) and TCGA were used to analyze the MPC1 expression pattern in CRC. The primary data for TCGA datasets were downloaded https://www.cancer.gov/. The primary data for GEO datasets were downloaded at https://www.ncbi.nlm.nih.gov/geo. The OncoLnc database (http://www.oncolnc.org/) was used to detect the prognostic value of MPC1 in the TCGA cohort.
2.2. Patients and Clinical Specimens
In our study, a total of 392 patients containing paired CRC tissues and adjacent nontumor tissues were enrolled from the Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University. Among them, 30 cases of liver metastases were collected. And only 225 cases were available with complete follow-up data for survival analysis. Informed consents were signed by all patients. The research was approved by the Research Ethics Committee of Renji Hospital and carried out in accordance with ethical standards as formulated in the Helsinki Declaration.
2.3. Cell Culture and Cell Transduction
Human CRC cell lines (HCT116, HT29, SW620, RKO, SW480, and Lovo) and mouse CRC cell line MC38 were gained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). All cells were cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% antibiotics at 37°C in a humidified incubator with 5% CO2.
MC38 cells were transfected with lentivirus containing a luciferase reporter plasmid. Stable transfection cells were screened with 5 μg/ml blastisidin for 14 days, which termed MC38-Luc. In addition, one short hairpin RNA (shRNA) sequence against MPC1 was packaged as lentivirus and transfected into MC38-luc cells. Lovo and SW480 were transfected with lentivirus containing full-length human MPC1 cDNA or empty vehicle control. Stable transfection cells were screened under 2 μg/ml puromycin for 14 days and verified by western blot. In those assays, all lentiviral transfections were performed in the presence of 6 μg/ml polybrene.
2.4. Immunohistochemical (IHC)
The protocol of this assay and quantify the MPC1 protein expression level were performed according to previously reported . Primary antibodies used as follows: MMP7 (YT2663, Immunoway), E-cadherin (14472, CST), Snail1 (ab53519, Abcam), and MYC (YP0861, Immunoway).
2.5. Cellular Immunofluorescence
Assays were performed according to the previous description . Briefly, cells were incubated with antibodies against β-catenin (ab32572, Abcam) and incubated with Alexa 488-conjugated secondary antibody (1 : 200). The nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI).
2.6. Western Blotting
Whole-cell lysates or nuclear protein was extracted using a protein extraction buffer (Beyotime, Shanghai, China) or nucleoprotein extraction kit (Sangon Biotech, C500009), respectively. Proteins were resolved by SDS-PAGE and transferred onto nitrocellulose (NC) membranes using standard methods. Primary antibodies used as follows: MPC1 (ab74871, Abcam), β-catenin (ab32572, Abcam), lamin A/C (ab8984, Abcam), and GAPDH (ab9485, Abcam). Species-specific secondary antibodies used as follows: IRDye 680 Goat anti-Mouse IgG (LI-COR) and IRDye 800 Goat anti-rabbit IgG (LI-COR).
2.7. Real-Time PCR
Total RNA was extracted using Trizol (Takara) according to the manufacturer’s instructions. cDNA was synthesized using the PrimeScript reverse transcription-polymerase chain reaction (RT-PCR) kit (Takara). The qPCR was performed using SYBR Green Master Mix (Roche). The 2 −△CT method was used to analyze the data and GAPDH was used as a loading control. The primer sequences are listed in Table 1.
2.8. Liver Metastasis Model
This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals and relevant Chinese laws and regulations. The protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Shanghai Jiao Tong University. The MC38 cells transplanting luciferase-expressing were injected into the spleens of C57BL/6N mice () with a concentration of 106 cells/mouse. Two weeks later, the mice were killed and the liver metastasis tissues were harvested.
2.9. Luciferase Reporter Assay
The protocols of this assay were operated in accordance with previous reported . 100 ng TOP reporter plasmid (Wnt/β-catenin signaling) or 100 ng FOP reporter plasmid (negative control of Wnt/β-catenin signaling) and 10 ng Renilla were mixed and transfected into CRC cells using Lipofectamine 2000. Dual-luciferase reporter assay system (Promega) was used to detect the firefly and Renilla luciferase activities.
3. Statistical Analyses
Data are shown as . SPSS 20.0 (Chicago, IL, USA) and GraphPad Prism 5 software were used to manipulate statistical analyses. Kaplan-Meier method was used to calculate cumulative survival time. The chi-square test or Student’s -test was used for comparison between groups. was considered as statistically significant.
4.1. MPC1 Expression Was Aberrantly Decreased in CRC
Pyruvate is a pivotal intermediate in the process of cell metabolism, which connects glycolysis and the TCA cycle. To determine the potential maladjustment genes involved in pyruvate metabolism, which is located in mitochondria, as shown in Table 2, we analyzed the TCGA dataset containing 50 CRC and their normal counterparts. The results showed that multiple genes are significantly upregulated or downregulated in CRC (T) tissues compared to normal colon (N). Notably, MPC1 had a log2 (fold change) less than -1 (Figures 1(a) and 1(b)). As known to us, pyruvate translocation from the cytoplasm to the mitochondria is the first step into the TCA cycle, which needs MPC1/MPC2 heterodimer. In the analysis, no significant change was found in MPC2. Therefore, MPC1 was selected for further study. The expression pattern of MPC1 was further analyzed in five independent GEO datasets (GSE21510, GSE5206, GSE20916, GSE9348, and GSE4183). Consistently, we found that MPC1 was downregulated with statistical difference in CRC tissues (Figure 1(c)) and inflammatory tissue (Supplementary Figure 1) in comparison to their normal counterparts. Meanwhile, we found decreased MPC1 expression in human CRC tissues compared to their normal counterparts (Figure 1(d)). In addition, a similar phenomenon was revealed in AOM/DSS induced mouse CRC models (Figure 1(e)). Then, we evaluated the protein level of MPC1 used a tissue microarray containing 392 matching cancer and corresponding adjacent nontumor tissues which subjected IHC staining. The expression of MPC1 was scored as “-, +, ++, +++” based on the staining area and intensity (Figure 1(f)). We found that more lower MPC1 expression (score as “-” and “+”) was presented in CRC tissues (Figure 1(g)). Overall, these results revealed that MPC1 was disrupted during CRC.
4.2. Decreased MPC1 Enhanced Tumor Metastasis Capability and Predicated Poor Prognosis in CRC
It is well known that CRC is one of the most malignant tumors given its strong metastasis ability, so we tried to figure out whether the MPC1 expression was correlated with metastasis. We found that lower MPC1 expression was closely correlated with metastasis (), lymph node invasion (), and TNM stage (), which revealed by the analysis between the clinical significance and MPC1 expression in CRC (Table 3). Next, to illuminate the expression pattern of MPC1 in different process of CRC, data mining was carried out by two independent GEO datasets (GSE21510 and GSE89393), which contained normal tissue, primary CRC, and metastatic lesion in the liver (M-CRC). As shown in Figures 2(a) and 2(b), MPC1 expression was gradually downregulated in patients with an increase in metastasis ability. A similar result was found in mice cells CT26 with high liver metastasis (HM-CT26) or poor liver metastasis (PM-CT26) (Figure 2(c)), which isolated by in vivo selection in an orthotopic mouse model of colon cancer metastasis to the liver. Further analysis showed that MPC1 protein expression was gradually downregulated in normal tissue, primary CRC, and liver metastasis CRC (CRLM) tissues (Figure 2(d)). Furthermore, survival analysis showed that patients with lower MPC1 expression had a worse outcome compared to the patients with higher MPC1 expression using the TCGA cohort (Figure 2(e)) and Ren Ji cohort (Figure 2(f)). Additionally, among patients with metastasis, worse prognosis was emerged in the MPC1 low cases (Figure 2(g)), while no significant association was observed in patients without metastasis (Figure 2(h)).
4.3. MPC1 Overexpression Impaired CRC Cells Motility Both In Vitro and In Vivo
To evaluate the role of MPC1 on the motility of CRC cells, the transwell assay was performed. Firstly, we examined low MPC1 protein expression in human and high MPC1 protein expression in mouse MC38 CRC cells by western blot (Figure 3(a)). MPC1-overexpressing stable cell lines were established using a lentivirus carrying the MPC1 gene in Lovo and SW480 cells. And the overexpression efficiency was confirmed by immunoblots (Figure 3(b)). MPC1 knockdown in Luc-MC38 cells were established and verified by WB (Figure 3(c)). MPC1 overexpression exhibited significantly weaker migration and invasion ability than the control cells in both Lovo (Figure 3(d)) and SW480 (Figure 3(e)) cells. Following, the liver metastasis model of CRC was established by spleen orthotopically injecting MC38 cells transplanting luciferase-expressing, which would simulate MC38 metastasis to the liver through splenic vein-portal vein. The results revealed that the MPC1 knockdown promoted MC38 cells metastasis to the liver through detecting the luminescence intensity monitored by bioluminescence imaging (Figure 3(f)). Notably, the number of metastatic liver nodules in the MPC1 silencing group was smaller than that in the control group (Figure 3(g)). Histological examination also proved that MPC1 knockdown decreased the metastatic potential of CRC in vivo (Figure 3(g)).
4.4. Decreased MPC1 Activated the Wnt/β-Catenin Pathway by Promoting Nuclear Translocation of β-Catenin
To further explore the underlying mechanism of MPC1-mediated inhibition of CRC metastasis, the TCGA database was used to perform GSEA analysis. The results indicated that MPC1 was involved in the Wnt/β-catenin signaling when set the mRNA expression median as a cutoff (Figure 4(a)). And dual-luciferase reporter gene assay revealed that MPC1 overexpression obviously inhibited the activity of Wnt/β-catenin pathway (Figure 4(b)), which confirmed the result above. We then tested the distribution changes of β-catenin in nuclear and cytoplasmic, which was a crucial step in Wnt/β-catenin pathway. As shown in Figure 4(c), no significant difference was emerged in the total amount of β-catenin between MPC1 overexpression cells and the control cells (Figure 4(c)). However, obviously decreased distribution of nuclear β-catenin was presented in MPC1 overexpression cells compared to that in the control cells, as revealed by the stronger gray corresponding to β-catenin (Figures 4(c) and 4(d)). Consistently, immunofluorescence (IF) staining showed that MPC1 overexpression weakened nuclear β-catenin localization in both Lovo and SW480 cells when compared to control cells (Figures 4(e) and 4(f)). A Similar phenomenon was observed in mouse liver metastasis tissues by IHC (Figure 4(g)). Following, qPCR analyses displayed some downstream target genes of β-catenin, such as MMP7, E-cadherin, Snail1, and MYC. Obviously increased in E-cadherin and decreased in MMP7, Snail1, and MYC were observed after the MPC1 overexpression in both Lovo and SW480 cells compared to that in the control cells (Figures 4(h) and 4(i)). Meanwhile, the opposite trend was observed in MC38 cell after MPC1 knockdown (Figure 4(j)), and similar results were observed in mouse liver tissue detected by IHC (Figures 4(k)–4(n)). Taken together, the data above indicated that MPC1 mediated CRC cell metastasis through the Wnt/β-catenin pathway.
Accumulating evidences have shown that reprogrammed energy metabolism conduces to the tumor malignant properties, including enhanced CRC liver metastatic capacity [19–21]. Mitochondria, as the primary site of energy production, regulate the pyruvate metabolism under both physiologic and pathologic conditions. The first step of the TCA cycle is mediated by MPC, which transports pyruvate into mitochondrial from cytoplasm . In the beginning, TCGA was used to analyze the relative genes involved in pyruvate metabolism, which is located in mitochondria. The results revealed that MPC1 expression was significantly downregulated in CRC tissues. Meanwhile, the GEO datasets analysis, as well as, IHC staining on CRC patients’ tissue and mouse models confirmed this trend. These phenomena may indicate that loss of MPC activity enhanced tumorigenic glucose utilization by blocking mitochondrial pyruvate uptake and oxidation. Interestingly, in the course of data analysis, we found that the expression of MPC1 was decreased at the stage of intestinal inflammation, which was not different from that in tumor tissue. MPC1 has been reported to be involved in immune regulation of peripheral T cell homeostasis through metabolic regulation . And a decrease in MPC1 was found at the earliest stages of CRC . Hence, we suspect that MPC1 is involved in bowel inflammation to tumorigenesis. And more studies need to be devised to illustrate this process.
Following, in the analysis between the clinical significance and MPC1 expression in CRC, we found that MPC1 expression was especially correlated with metastasis. Inspired by this, we detected the MPC1 expression pattern in normal tissue, primary CRC, and metastasis CRC by GEO datasets and patients’ tissue. All results revealed that gradually downregulated MPC1 was in patients with an increase in metastasis ability. Survival analysis indicated that worse outcome was presented in patients with lower MPC1 expression, especially in patients with metastasis. Additionally, function assays verified that MPC1 overexpression could attenuate the migration and invasion capacities of CRC cells in vitro and MPC1 knockdown could enhance the metastasis capacity in vivo. And existing studies have revealed that the MPC1 was participated in metastatic dissemination of PGC1α-transduced cholangiocarcinoma through elevating reactive oxygen species (ROS) production . Besides, MPC inhibitor UK5099 treatment could trigger strong invasive capacity through blocking pyruvate translocation into the mitochondria so as to attenuate mitochondrial oxidative phosphorylation and trigger aerobic glycolysis . These phenomena together with our results indicate that MPC1 could act as a tumor suppressor through inhibiting tumor metastasis. And existing studies have shown that MPC1 could alter the maintenance and fate of stem cells through regulating cancer metabolism in CRC . However, the relationship between the metabolism and tumor metastasis regulated by MPC1 was not being mentioned. Thus, further evidence should be received to confirm this.
Subsequently, the underlying mechanism of MPC1 in regulating metastasis was explored. For this purpose, GSEA analysis was performed. The results indicated that MPC1 was involved in the Wnt/β-catenin signaling. The next series of experiments also confirmed that MPC1 could mediate the WNT/β-catenin pathway by redistribution of β-catenin. Previous reports showed that cytoplasmic β-catenin phosphorylated in N-terminally localized to sites of cell-cell contact is associated with E-cadherin and was required for intact cell-cell adhesions, without any change detected in the levels of total β-catenin [23–25]. Simultaneously, cell–cell adhesion based on cadherin binding with β-catenin limited Wnt signals . In addition, β-catenin was reported to interact with USP9x to inhibit the degradation of β-catenin through the deubiquitination of β-catenin in breast cancer . A constitutive IRS1 and β-catenin protein interaction activated MYC expression in Acute Lymphoblastic Leukemia Cells . In HCC, β-catenin was reported to interact with Yap1 to lead to rapid tumorigenesis . Hence, it is reasonable to guess that accumulated cytoplasmic β-catenin maybe crosstalk with other genes or involved in other biological processes. What is more, some downstream target genes of β-catenin, such as MMP7, E-cadherin, Snail1, and myc, were changed in expression. As known to us, MMP-7 is a member of the proteolytic enzyme family, which promotes the invasion and metastasis of tumor cells by degrading the basement membrane and extracellular matrix . And previous studies had evidenced for involvement of MMP-7 activation in colorectal cancer liver metastases [30, 31]. E-cadherin and Snail1 were considered as the epithelial-mesenchymal transition (EMT) marker, which was involved in metastasis of malignant tumor . Moreover, E-cadherin was reported to be involved in cell-cell junction to regulate cancer invasion and metastasis [33, 34]. And the GSEA analysis also revealed that MPC1 could affect the cell-cell contacts (data not shown). As described previously, MMP-7 could facilitate morphological transition by cleaving E-cadherin . The communication between the cells is disrupted when E-cadherin was shredded, leading to destructed cell adhesion and induction of EMT, followed by increased cell migration . Inspired by this, we assumed that MPC1 could mediate tumor cell motility through affecting MMP7 activity, cell-cell contacts, and EMT. However, further studies need to be performed to clarify the detailed underlying mechanisms.
In conclusion, we firstly demonstrated that decreased MPC1 was closely correlated with patient’s metastasis, as well as led to poor outcome. Moreover, MPC1-driven nuclear translocation of β-catenin contributed to CRC cell motility. This means that MPC1 has the potential to be a diagnostic biomarker and therapeutic target for metastasis patients.
|MPC:||Mitochondrial pyruvate carrier|
|GSEA:||Gene set enrichment analysis.|
The data used to support the findings of this study are available from the corresponding author upon request.
Conflicts of Interest
All authors declare no conflicts of interest.
Ya-Hui Wang and Guang-Ang Tian conceived and designed the study. Chun-Jie Xu and Kai-Xia Zhou obtained and organized the data. Guang-Ang Tian analyzed the data. Zhi-Gang Zhang and Jian-Ren Gu contributed reagents/materials/analysis tools. Xue-Li Zhang and Guang-Ang Tian wrote the manuscript. Guang-Ang Tian, Chun-Jie Xu, and Kai-Xia Zhou contributed equally to this work.
This work was supported by the National Natural Science Foundation of China (No. 81672358 to Zhi-Gang Zhang) and the Natural Science Foundation of Shanghai (No. 18ZR1436900 to Xueli-Li Zhang).
“Supplementary Figure 1: expression analysis of MPC1 in normal, IBD, and tumor tissues using the GSE4183 dataset. One-way ANOVA was used to analyze the statistical differences between IBD, adenoma, and CRC tissues. ns: No significance. Student’s -test, , , ).” (Supplementary Materials)
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Copyright © 2020 Guang-Ang Tian et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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City Hospitals Sunderland NHS Foundation Trust provides services at two acute hospitals, Sunderland Royal Hospital and Sunderland Eye Infirmary. The trust also provides services at one general practice, Church View General Practice. The trust provides acute hospital services to a population of around 350,000 people across the Tyne, Wear and Durham area. In total the trust has 855 beds across two hospital sites and employs around 4,923 staff.
Sunderland Royal Hospital, which has 833 beds, provides accident and emergency services, medical, surgical, critical care, maternity, children’s and young people’s services. Sunderland Eye Infirmary, which has 22 beds, provides ophthalmology care and treatment in ophthalmic surgery and specialist accident and emergency care. Both hospital sites provide outpatients’ services.
Church View General Practice was inspected at the same time as the acute services by the Care Quality Commission’s Primary Medical Services Directorate team. The findings of this inspection are reported separately to the inspection of the acute services.
We inspected City Hospitals Sunderland NHS Foundation Trust as part of our comprehensive inspection programme. We inspected Sunderland Royal Hospital and Sunderland Eye Infirmary on 16, 17, 18 and 19 September 2014. We also undertook an unannounced inspection on 2 October 2014.
We carried out this in-depth inspection because the trust was placed in risk band 2 in the Care Quality Commission’s (CQC) intelligent monitoring system.
We inspected the following core services:
- Sunderland Royal Hospital – accident and emergency, medical, surgical, critical care, maternity, children’s and young people’s services, end of life and outpatients’ services.
- Sunderland Eye Infirmary – accident and emergency, surgical and outpatients’ services.
Overall, the trust was rated as good. Safety and responsive were rated as requires improvement but all other domains - effectiveness, caring and well led were rated as good.
The trust had an established and stable senior leadership team who staff reported were visible and approachable. There was a clear vision and strategy for the future provision of services, which involved consultation with staff within the trust and fostered innovative practice development.
There were reporting mechanisms from the ward to the Trust Board and clear governance systems within the trust, which included effective communication mechanisms from the Trust Board to the various wards and departments, as well across divisions, services and hospitals. Risk was generally well managed, although the trust faced challenges over the recruitment of medical and nursing staff particularly in the medical wards, which will be compounded by the budget deficit going into next year. Further development was required over the investigating, grading and feeding back from incident reporting.
Staff and public engagement was good, and mechanisms were in place to involve the local service users in decisions about the development of services and feedback on experiences of services received. Staff felt engaged and involved in the development of their services, although some medical staff did not feel fully consulted. Staff expressed pride in the services they provided with the patient’s care as central to their values.
Our key findings were as follows:
- The trust had an overall elevated risk for the Hospital Standardised Mortality Ratio, which was higher than expected for weekend mortality as well as for weekday mortality. It was working with other trusts in the region and with NHS England to improve its mortality rates.
- There were arrangements in place to manage and monitor the prevention and control of infection. There was a dedicated team to support staff and ensure policies and procedures were implemented. We found all areas visited visibly clean. Methicillin Resistant Staphylococcus Aureus (MRSA) and Clostridium difficile (C.difficile) rates were within an acceptable range for the size of trust.
- There were staff shortages at Sunderland Royal Hospital, particularly on the medical wards, mainly due to vacancies for nursing and medical staff. The trust was actively recruiting, the staffing establishment had been reviewed and kept under regular review. In the meantime, bank and locum staff were being used to fill any deficit in numbers.
- There were no concerns about staffing levels or skill mix at Sunderland Eye Infirmary. The staffing establishments and skill mix were maintained and kept under regular review.
- There were arrangements in place for reporting incidents, but improvements were required to improve the investigation processes, including the timeliness and training around root cause analysis and grading of incidents.
- Patients were able to access suitable nutrition and hydration including special diets. Patients reported that on the whole they were content with the quality and quantity of food.
- Patients were provided with care in a compassionate manner and treated with dignity and respect.
- Access and flow within the children’s service was effective, which was achieved in part through close collaborative working between the directorate of paediatrics and emergency medicine. A shared medical consultant staffing approach, which included consultant staff qualified in paediatric emergency medicine, had been developed. The service had a range of facilities and approaches to ensure that the needs of local families were met.
- The children’s and young people’s service had a clear vision and strategy and the well led domain was rated as outstanding with a strong management team who worked together. The service regularly implemented innovative improvements. The service had facilitated the inspection of services by a team of young inspectors, which was excellent practice.
- Staff in the critical care unit demonstrated compassion and empathy to patients and their families. Patients were invited to meetings in the unit to give their stories and provide feedback about their experiences with the aim of improving patient experience on the unit. There was a range of support services provided for patients after they left critical care to ensure they received the right psychological and emotional support to aid recovery.
- Processes were in place for the implementing and monitoring the use of evidence-based guidelines and standards to meet patients’ care needs.
- There was effective communication and collaboration between multidisciplinary teams.
- On the whole, the importance of patients’ and public views were recognised and mechanisms were in place to hear and act on patients’ feedback. The trust was working on improving the complaint procedures, particularly around investigations and timing of responses.
We saw several areas of outstanding practice including:
Sunderland Royal Hospital
- There was close collaborative working between the directorate of paediatrics and emergency medicine, which had developed a shared medical consultant staffing approach, including consultant staff qualified in paediatric emergency medicine.
- The directorate of paediatrics had facilitated the inspection of the service by a team of young service user inspectors.
- The use of the tele-health system in maternity services enabled women to monitor blood glucose levels and blood pressure in their own homes avoiding unnecessary visits to hospital.
- The compassion expressed to families if their family member died whilst on the critical care unit. For example, - nurses placed a locket of hair and the rings of the patient in a small silver bag and handed a printed card to the family with sympathy from the staff at the critical care unit.
Sunderland Eye Infirmary
- The enhanced recovery pathway for cataract surgery and the role of the primary nurse were viewed as an excellent development of the service and resulted in individual surgeon’s cataract audits showing consistently high visual acuity outcomes against bench mark standards (UK Cataract National Dataset Audit).
However, there were also areas of poor practice where the trust needs to make improvements.
Importantly, the trust must for Sunderland Royal Hospital:
- Ensure that there are sufficient qualified, skilled and experienced nursing and medical staff, particularly on medical wards and children’s services. This is to include provision of staff out of hours, bank holidays and at weekends.
- Ensure that staff are suitably skilled and supported through the completion of mandatory training and appraisals particularly in the accident and emergency department (A&E) at Sunderland Royal Hospital.
- Ensure that medicines are managed appropriately. Medicines were not always started promptly when a patient was admitted over the weekend and incidents involved Controlled Drugs (CDs) were not always appropriately investigated and reported within the service.
- Ensure that there is appropriate pharmacist support to ward and units, including with the reconciliation of medication.
- At Sunderland Royal Hospital - ensure that patients are placed on the most appropriate ward to meet their clinical needs.
- In the accident and emergency department at Sunderland Royal Hospital ensure that the hospital fully complies with the four hour wait standard and the 15 minute hand over time for patients arriving by ambulance.
- Continue to review and reduce the mortality outliers for the Summary Hospital-level Mortality Indicator (SHMI) within the trust.
- Ensure that the ‘do not attempt cardio-pulmonary resuscitation’ (DNACPR) orders are signed by the appropriate medical professional and that discussions with patients or family members are recorded.
- Ensure that patient observation and monitoring charts for nutrition and hydration are fully and appropriately completed particularly on medical wards.
For both hospitals, the trust must:
- Ensure that Patient Group Directives (PGDs), which are written instructions for the supply or administration of medicines to groups of patients who may not be individually identified before presentation for treatment, are updated and monitored in line with trust policy.
- Ensure that incidents are investigated, graded and reported appropriately to ensure that lessons can be learnt to improve the safety and quality of services.
In addition, for Sunderland Royal Hospital the trust should:
- Train staff to use the syringe drivers used in the community when transferring end of life patients into the community. Thereby, ensuring that patients are not taken off one piece of equipment prior to discharge and then connected to the other equipment used in the community.
- Provide training on the grading of incidents and ensure that there are effective incident feedback mechanisms in place so that lessons can be learnt.
- Review the arrangements over the storage and supply of surgical instruments to ensure that there is appropriate provision of equipment.
- Review the storage and provision of linen in ward areas so that staff are assured that it is clean before use.
- Ensure that there is assurance systems in place regarding the training, supervision, appraisal and revalidation of the specialist palliative care team who are employed by a different trust.
- Review the specialist palliative care team in accordance with the Commissioning Guidance for Specialist Palliative Care.
For the Sunderland Eye Infirmary, the trust should:
- Review the storage of medical records.
- Review the participation in audits, including clinical audits in the A&E department.
- Review the arrangements for the role of the Eye Infirmary when dealing with major incident/events across the trust.
- Review the practice of recording patient concerns in the electronic nursing evaluation, in line with best practice guidance.
For both hospitals, the trust should:
- Seek ways to further increase the engagement of clinicians in complaint and investigation processes.
- Put in place mechanisms for reviewing and if necessary updating patient information, particularly in the outpatient departments.
- Introduce patient surveys specific to the outpatient department.
Professor Sir Mike Richards
Chief Inspector of Hospitals


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Colorado Springs, Colorado – Dental health is an essential part of both children and adult’s overall health. Apple Grove Dental is a dental clinic in Colorado Springs, Colorado that specializes in family dentistry for both children and adults. The clinic provides a broad variety of dental services based on preventive, conservative, and aesthetic dentistry for families. The workforce at Apple Grove Dental consists of a team of top specialist dentists with adequate experience in family dentistry. They provide oral health education, preventive dental service, and specific dental treatments.
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Basic Questions and Answers About Post-Exposure Prophylaxis (PEP)
March 24, 2015
PEP is the use of antiretroviral drugs after a single high-risk event to stop HIV from making copies of itself and spreading through your body. PEP must be started as soon as possible to be effective -- and always within 3 days of a possible exposure. If you think you may have been exposed to HIV very recently, see a doctor as soon as possible to find out if PEP is right for you.
What Is PEP?
PEP stands for post-exposure prophylaxis. It involves taking antiretroviral medicines as soon as possible, but no more than 72 hours (3 days) after you may have been exposed to HIV, to try to reduce the chance of becoming HIV-positive. These medicines keep HIV from making copies of itself and spreading through your body. Two to three drugs are usually prescribed, and they must be taken for 28 days. PEP is not always effective; it does not guarantee that someone exposed to HIV will not become infected with HIV.
Is PEP Right for Me?
PEP is used for anyone who may have been exposed to HIV very recently during a single event. It is not the right choice for people who may be exposed to HIV frequently. (See "Can I take a round of PEP every time I have unprotected sex?" for more information)
Your health care provider will consider whether PEP is right for you based on the risk of your exposure.
Health care workers are evaluated for PEP if they are exposed to blood or body fluids of a patient who is infected with HIV. The risk of getting HIV infection this way is less than 1 in 100 exposures.
PEP can also be used to treat people who may have been exposed to HIV during a single event unrelated to work (e.g., unprotected sex, needle-sharing injection drug use, or sexual assault).
Keep in mind that PEP should only be used in situations right after a potential HIV exposure. It is not a substitute for regular use of other proven HIV prevention methods, such as correct and consistent condom use or use of sterile injection equipment.
If you are prescribed PEP, you will be asked to return for HIV testing at 4 to 6 weeks, 3 months, and 6 months after the potential exposure to HIV. Because PEP is not always effective, you should keep using condoms with sex partners while taking PEP and should not share injection equipment with others.
When Should I Take PEP?
PEP must begin within 72 hours of exposure, before the virus has time to make too many copies of itself in your body.
Starting PEP as soon as possible after a potential HIV exposure is important: research has shown that PEP has little or no effect in preventing HIV infection if it is started more than 72 hours after HIV exposure. HIV makes copies of itself once it enters your body, and it takes about 3 days for it to spread through your body. When HIV is only in a few cells where it entered your body, it can sometimes be stopped by PEP, but when it is in many cells in many places in your body, PEP will not work.
Two to three drugs are usually prescribed, and they must be taken for 28 days.
Does PEP Have Any Side Effects?
PEP is safe but may cause side effects like nausea in some people. These side effects can be treated and are not life-threatening.
Where Can I Get PEP?
Some of the places you can go to seek treatment include your doctor's office, emergency rooms, urgent care clinics, or a local HIV clinic.
How Can I Pay for PEP?
If you are a health care worker who was exposed to HIV on the job, your workplace health insurance or workers' compensation will usually pay for PEP.
If you are prescribed PEP after sexual assault, you may qualify for partial or total reimbursement for medicines and clinical care costs through the Office for Victims of Crime, funded by the US Department of Justice (see the contact information for each state).
If you are prescribed PEP for another reason, and you cannot get insurance coverage (e.g., Medicaid, Medicare, private, or employer-based), your health care provider can apply for free antiretroviral medicines through the medication assistance programs run by the manufacturers. Online applications can be faxed to the company, or some companies have special phone lines. These can be handled urgently in many cases to avoid delay in getting medicine.
PEP should only be used right after an uncommon situation with potential HIV exposure. If you are often exposed to HIV, for example, because you often have sex without a condom with a partner who is HIV-positive, repeated uses of PEP are not the right choice. That's because, when drugs are given only after an exposure, more drugs and higher doses are needed to block infection than when they are started before the exposure and continued for a time thereafter. That's an approach called pre-exposure prophylaxis, or PrEP. PrEP means taking a daily pill (brand name, Truvada) for months or years. This keeps medication in your body to keep HIV from making copies of itself and spreading infection through your body anytime you are exposed. If you are at ongoing risk for HIV, speak to your doctor about PrEP.
This article was provided by U.S. Centers for Disease Control and Prevention. Visit the CDC's website to find out more about their activities, publications and services.
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