Sirt7/HIC1 complex participates in hyperglycaemia-mediated EndMT via modulation of SDC1 expression in diabetic kidney disease and metabolic memory.

Diabetic kidney disease (DKD), a primary microvascular complication arising from diabetes, may result in end-stage renal disease. Epigenetic regulation of endothelial mesenchymal transition (EndMT) has been recently reported to exert function in metabolic memory and DKD. Here, we investigated the mechanism which Sirt7 modulated EndMT in human glomerular endothelial cells (HGECs) in the occurrence of metabolic memory in DKD. Lower levels of SDC1 and Sirt7 were noted in the glomeruli of both DKD patients and diabetes-induced renal injury rats, as well as in human glomerular endothelial cells (HGECs) with high blood sugar. Endothelial-to-mesenchymal transition (EndMT) was sustained despite the normalization of glycaemic control. We also found that Sirt7 overexpression associated with glucose normalization promoted the SDC1 expression and reversed EndMT in HGECs. Furthermore, the sh-Sirt7-mediated EndMT could be reversed by SDC1 overexpression. The ChIP assay revealed enrichment of Sirt7 and H3K18ac in the SDC1 promoter region. Furthermore, hypermethylated in cancer 1 (HIC1) was found to be associated with Sirt7. Overexpression of HIC1 with normoglycaemia reversed high glucose-mediated EndMT in HGECs. The knockdown of HIC1-mediated EndMT was reversed by SDC1 upregulation. In addition, the enrichment of HIC1 and Sirt7 was observed in the same promoter region of SDC1. The overexpressed Sirt7 reversed EndMT and improved renal function in insulin-treated diabetic models. This study demonstrated that the hyperglycaemia-mediated interaction between Sirt7 and HIC1 exerts a role in the metabolic memory in DKD by inactivating SDC1 transcription and mediating EndMT despite glucose normalization in HGECs.

MRI-based Machine Learning Radiomics Can Predict CSF1R Expression Level and Prognosis in High-grade Gliomas.

The purpose of this study is to predict the mRNA expression of CSF1R in HGG non-invasively using MRI (magnetic resonance imaging) omics technology and to evaluate the correlation between the established radiomics model and prognosis. We investigated the predictive value of CSF1R in the Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA) database. The Support vector machine (SVM) and the Logistic regression (LR) algorithms were used to create a radiomics_score (Rad_score), respectively. The effectiveness and performance of the radiomics model was assessed in the training (n = 89) and tenfold cross-validation sets. We further analyzed the correlation between Rad_score and macrophage-related genes using Spearman correlation analysis. A radiomics nomogram combining the clinical factors and Rad_score was constructed to validate the radiomic signatures for individualized survival estimation and risk stratification. The results showed that CSF1R expression was markedly elevated in HGG tissues, which was related to worse prognosis. CSF1R expression was closely related to the abundance of infiltrating immune cells, such as macrophages. We identified nine features for establishing a radiomics model. The radiomics model predicting CSF1R achieved high AUC in training (0.768 in SVM and 0.792 in LR) and tenfold cross-validation sets (0.706 in SVM and 0.717 in LR). Rad_score was highly associated with tumor-related macrophage genes. A radiomics nomogram combining the Rad_score and clinical factors was constructed and revealed satisfactory performance. MRI-based Rad_score is a novel way to predict CSF1R expression and prognosis in high-grade glioma patients. The radiomics nomogram could optimize individualized survival estimation for HGG patients.

Case report: Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay: Three cases and a literature review.

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is a serious autosomal recessive syndrome caused by biallelic mutations in cytosine-cytosine-adenosine tRNA nucleotidyltransferase 1 (TRNT1). The main clinical features of SIFD are periodic fevers, developmental delay, sideroblastic or microcytic anemia, and immunodeficiency. Herein, we report three cases of SIFD with compound heterozygous variants of TRNT1. Patients 1 and 2 were siblings; they presented with periodic fevers, arthritis, low immunoglobulin A, bilateral cataracts, anemia, and neurodevelopmental and developmental delay. Patient 3 had severed clinical features with recurrent fever and infections. She was treated with infliximab and symptomatic treatments but without therapeutic effect. She received a stem cell transplantation of umbilical cord blood but died of posttransplant infection and posttransplant graft-vs.-host disease 17 days after transplantation. Finally, a literature review revealed that TRNT1 variants differed among SIFD patients. Our cases and literature review further expand existing knowledge on the phenotype and TRNT1 variations of SIFD and suggest that the early genomic diagnosis of TRNT1 is valuable to promptly assess bone marrow transplantation and tumor necrosis factor inhibitor treatments, which might be effective for the immunodeficiency and inflammation caused by SIFD.

Influence of Perioperative Anesthesia on Cancer Recurrence: from Basic Science to Clinical Practice.

PURPOSEOF REVIEW: In this review, we will summarize the effects of these perioperative anesthetics and anesthetic interventions on the immune system and tumorigenesis as well as address the related clinical evidence on cancer-related mortality and recurrence. RECENT FINDINGS: Cancer remains a leading cause of morbidity and mortality worldwide. For many solid tumors, surgery is one of the major therapies. Unfortunately, surgery promotes angiogenesis, shedding of circulating cancer cells, and suppresses immunity. Hence, the perioperative period has a close relationship with cancer metastases or recurrence. In the perioperative period, patients require multiple anesthetic management including anesthetics, anesthetic techniques, and body temperature control. Preclinical and retrospective studies have found that these anesthetic agents and interventions have complex effects on cancer outcomes. Therefore, well-planned, prospective, randomized controlled trials are required to explore the effects of different anesthetics and techniques on long-term outcomes after cancer surgery. Due to the conflicting effects of anesthetic management on cancer recurrence, further preclinical and clinical trials are required and beneficial to the development of systemic cancer therapies.

Phenomic Analysis of Chronic Granulomatous Disease Reveals More Severe Integumentary Infections in X-Linked Compared With Autosomal Recessive Chronic Granulomatous Disease.

Background: Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI), characterised by recurrent bacterial and fungal infections. It is inherited either in an X-linked (XL) or autosomal recessive (AR) mode. Phenome refers to the entire set of phenotypes expressed, and its study allows us to generate new knowledge of the disease. The objective of the study is to reveal the phenomic differences between XL and AR-CGD by using Human Phenotype Ontology (HPO) terms. Methods: We collected data on 117 patients with genetically diagnosed CGD from Asia and Africa referred to the Asian Primary Immunodeficiency Network (APID network). Only 90 patients with sufficient clinical information were included for phenomic analysis. We used HPO terms to describe all phenotypes manifested in the patients. Results: XL-CGD patients had a lower age of onset, referral, clinical diagnosis, and genetic diagnosis compared with AR-CGD patients. The integument and central nervous system were more frequently affected in XL-CGD patients. Regarding HPO terms, perianal abscess, cutaneous abscess, and elevated hepatic transaminase were correlated with XL-CGD. A higher percentage of XL-CGD patients presented with BCGitis/BCGosis as their first manifestation. Among our CGD patients, lung was the most frequently infected organ, with gastrointestinal system and skin ranking second and third, respectively. Aspergillus species, Mycobacterium bovis, and Mycobacteirum tuberculosis were the most frequent pathogens to be found. Conclusion: Phenomic analysis confirmed that XL-CGD patients have more recurrent and aggressive infections compared with AR-CGD patients. Various phenotypic differences listed out can be used as clinical handles to distinguish XL or AR-CGD based on clinical features.

BaBao Dan Suppresses Tumor Growth of Pancreatic Cancer Through Modulating Transcriptional Reprogramming of Cancer-Related Genes.

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of refractory malignancies without efficient therapeutics. Babao Dan (BBD) was partially effective to suppress tumor growth of PDAC in clinical practice. However, the molecular mechanisms were unclear. METHODS: We established PDAC mice models and treated them with BBD through intragastric administration. Treatment and control groups were then subjected to high-throughput RNA sequencing. We presented the transcriptional changes upon BBD treatment by using computational analysis comparing BBD treatment and control groups. Functional enrichment analysis was employed to investigate the biological processes or pathways that BBD modulates. RESULTS: BBD treatment showed strong suppression on tumor growth of PDAC, even stronger than Gemcitabine. Through differential analysis comparing BBD treatment and control groups, we identified 638 up-regulated and 259 down-regulated genes in the BBD treatment group. BBD was found to activate tumor suppressor genes, such as MTUS1, PDGFB, SOD3, and UCHL1. Furthermore, we revealed that BBD treatment inhibited cancer-related pathways and elevated activities of metabolism-related processes. The BBD-modulated metabolic genes were further showed to be associated with patient survival in an independent cohort with pancreatic cancer. CONCLUSION: BBD repressed the tumor growth of PDAC. BBD treatment modulated expression of cancer-related genes in PDAC. BBD suppressed cancer-related pathways and activated metabolic processes in PDAC. Our study suggests BBD treatment as potential effective therapeutics for patients with pancreatic cancer.

SET8 suppression mediates high glucose-induced vascular endothelial inflammation via the upregulation of PTEN.

Hyperglycemia-mediated endothelial inflammation participates in the pathogenesis of cardiovascular complications in subjects with diabetes. Previous studies reported that phosphatase and tensin homolog deleted on chromosome ten (PTEN) and SET8 participate in high glucose-mediated endothelial inflammation. In this study, we hypothesize that SET8 regulates PTEN expression, thus contributing to high glucose-mediated vascular endothelial inflammation. Our data indicated that plasma soluble intercellular adhesion molecule-1 (sICAM-1) and endothelial selectin (e-selectin) were increased in patients with diabetes and diabetic rats. PTEN expression was augmented in the peripheral blood mononuclear cells of patients with diabetes and in the aortic tissues of diabetic rats. Our in vitro study indicated that high glucose increased monocyte/endothelial adhesion, endothelial adhesion molecule expression and p65 phosphorylation in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose led to endothelial inflammation via upregulation of PTEN. Furthermore, high glucose inhibited SET8 expression and histone H4 lysine 20 methylation (H4K20me1), a downstream target of SET8. SET8 overexpression reversed the effects of high-glucose treatment. shSET8-mediated endothelial inflammation was counteracted by siPTEN. Furthermore, SET8 was found to interact with FOXO1. siFOXO1 attenuated high glucose-mediated endothelial inflammation. FOXO1 overexpression-mediated endothelial inflammation was counteracted by siPTEN. H4K20me1 and FOXO1 were enriched in the PTEN promoter region. shSET8 increased PTEN promoter activity and augmented the positive effect of FOXO1 overexpression on PTEN promoter activity. Our in vivo study indicated that SET8 was downregulated and FOXO1 was upregulated in the peripheral blood mononuclear cells of patients with diabetes and the aortic tissues of diabetic rats. In conclusion, SET8 interacted with FOXO1 to modulate PTEN expression in vascular endothelial cells, thus contributing to hyperglycemia-mediated endothelial inflammation.

Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression.

Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression.

BACKGROUND: Hepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear. METHODS: We used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1In vivo experiments were performed to verify the conclusions from the in vitro experiments. RESULTS: Our data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro experiments. in vivo experiments were performed to verify the conclusions from the α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1. CONCLUSIONS: The results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1.

Propofol attenuates the adhesion of tumor and endothelial cells through inhibiting glycolysis in human umbilical vein endothelial cells.

Propofol is one of the most commonly used intravenous anesthetics and plays an important role in tumor suppression. In the present study, we aimed to investigate the mechanism by which propofol attenuates tumor endothelial cells (TECs) and tumor cell adhesion to inhibit tumor metastasis in vitro. Human umbilical vein endothelial cells (HUVECs) cultured in Dulbecco's modified Eagle's medium were treated with tumor conditioned medium for 24 h, followed by 4 h of treatment with or without 25 µM of propofol, 10 µM of KN93, 500 µM of MK801, or 20 µM of rapastinel. It was found that propofol inhibited TEC adhesion and the glycolysis level of TECs. Consistently, propofol inhibited the expressions of adhesion molecules (E-selectin, ICAM-1, and VCAM-1) and glycolysis proteins (GLUT1, HK2, and LDHA) in TECs. Moreover, propofol attenuated the expression of HIF-1α, the phosphorylation of AKT and Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the Ca2+ concentration in TECs. MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMKII, both inhibited the expressions of adhesion molecules and glycolysis proteins, in a manner similar to propofol. Additionally, rapastine, an activator of NMDA receptor, could counteract the effects of propofol. Our results indicated that propofol attenuates intracellular Ca2+ concentration, CaMKII and AKT phosphorylation, and HIF-1α expression, probably via inhibiting the NMDA receptor, thus inhibiting glycolysis and adhesion of tumor and endothelial cells.

Monomethyltransferase SET8 facilitates hepatocellular carcinoma growth by enhancing aerobic glycolysis.

Hepatocellular carcinoma (HCC) is one of the most aggressive cancers worldwide. Despite such a public health importance, efficient therapeutic agents are still lacking for this malignancy. Most tumor cells use aerobic glycolysis to sustain anabolic growth, including HCC, and the preference of glycolysis often leads to a close association with poorer clinical outcomes. The histone methyltransferase SET8 plays crucial roles in controlling cell-cycle progression, transcription regulation, and tumorigenesis. However, it remains largely undefined whether SET8 affects the glucose metabolism in HCC. Here, we report that upregulation of SET8 is positively correlated with a poor survival rate in HCC patients. Both in vitro and in vivo studies revealed that SET8 deficiency conferred an impaired glucose metabolism phenotype and thus inhibited the progression of HCC tumors. By contrast, SET8 overexpression aggravated the glycolytic alterations and tumor progression. Mechanistically, SET8 directly binds to and inactivates KLF4, resulting in suppression of its downstream SIRT4. We also provided further evidence that mutations in SET8 failed to restrain the transactivation of SIRT4 by KLF4. Our data collectively uncover a novel mechanism of SET8 in mediating glycolytic metabolism in HCC cells and may provide a basis for targeting SET8 as a therapeutic strategy in HCC.

Effects of baicalein on pancreatic cancer stem cells via modulation of sonic Hedgehog pathway.

Recent studies have suggested that sonic Hedgehog (Shh) signaling pathway is aberrantly activated in cancer stem cells (CSCs). A seven-herb Chinese medicinal formula composed of Amorphophallus rivieri Durieu, Oldenlandia diffusa (Wild) Roxb, Scutellaria barbata D. Don, Gynostemma pentaphyllum (Thunb.) Mak and Amomum cardamomum L, i.e. Qingyihuaji (QYHJ) formula, has been shown to inhibit proliferation of pancreatic CSCs by inhibiting Shh signaling pathway and thereby prolong the overall survival of pancreatic cancer patients. Mass spectrometry analysis revealed that baicalein is one of the major compounds of QYHJ formula. The objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms of baicalein involved in pancreatic cancer treatment. We examined the effects of baicalein on pancreatic CSCs both in vivo and in vitro. The results indicated that baicalein attenuated the pluripotency of pancreatic CSCs. Then, we investigated the underlying mechanism and found that nuclear transcription factors, such as Sox-2 and Oct-4 as well as members in Shh signaling pathway, e.g. SHH, SMO, and Gli-2, were downregulated after baicalein treatment. Furthermore, silencing Gli-2 expression by small interfering RNA decreased Sox-2 expression and blocked the inhibitory effects of baicalein, suggesting that the effects of baicalein may be mediated through inhibition of Shh pathway. Our results suggested that baicalein, an active compound in QYHJ formula, could suppress the self-renewal of pancreatic CSCs through inhibition of Shh signaling pathway.

Propofol Disrupts Aerobic Glycolysis in Colorectal Cancer Cells via Inactivation of the NMDAR-CAMKII-ERK Pathway.

BACKGROUND/AIMS: To investigate the effect of propofol on glucose metabolism in colorectal cancer cells and in an in vivo xenograft model. METHODS: Glucose metabolism was assessed by measuring the extracellular acidification rate in HT29 and SW480 colorectal cancer cells. Quantitative real-time PCR and western blot analyses were used to detect mRNA and protein levels, respectively. Intracellular calcium was assessed by using a Fluo-3 AM fluorescence kit. Micro-positron emission tomography/computed tomography (microPET/CT) imaging was used to analyze glucose metabolism in the tumors of the xenograft model. RESULTS: Propofol exposure induced a dose-dependent decrease of aerobic glycolysis in HT29 and SW480 colorectal cancer cells. MicroPET/CT indicated that propofol also inhibited 18F-FDG uptake in the xenograft model. In addition, hypoxia-inducible factor 1α (HIF1α) was also reduced by propofol dose-dependently. Propofol repressed the NMDAR-CAMKII-ERK pathway to inactivate HIF1α and therefore reduced glycolysis. CONCLUSION: Propofol inhibited aerobic glycolysis in colorectal cancer cells through the inactivation of the NMDAR-CAMKII-ERK pathway, which may facilitate a better understanding of the use of propofol in the clinical setting.

Nalmefene attenuates malignant potential in colorectal cancer cell via inhibition of opioid receptor.

Morphine is postulated a risk factor in promoting tumor growth and metastasis during the preoperative period, and high glycolysis of tumor cells is proved to accelerate tumor progression. In this study, we investigated whether nalmefene, an opioid receptor inhibitor, could inhibit CT26 colon cancer cell growth through influencing cell glycolysis. CCK8 and transwell migration assays showed that nalmefene inhibited CT26 cells viability and migration in a concentration-dependent manner. Extracellular acidification rate and oxygen consumption rate showed that nalmefene inhibited glycolysis of CT26 cells. Moreover, western blot analysis and quantitative real-time PCR revealed that nalmefene decreased the expressions of enzymes related to glycolysis. Flow cytometry results revealed that intracellular calcium (Ca2+) level was changed by nalmefene, western blot analysis showed that nalmefene decreased calmodulin expression and calcium/calmodulin dependent protein kinases II (CaMK II) phosphorylation, thus inhibiting the serine/threonine kinase (AKT)-glycogen synthase kinase-3ß (GSK-3ß) pathway. Furthermore, the effects of KN93, an inhibitor of CaMK II, were similar to the effects of nalmefene, and the anti-tumor effect of nalmefene could be counteracted by morphine. In conclusion, the anti-tumor effect of nalmefene may be achieved by inhibiting opioid receptor and down-regulating calmodulin expression and CaMK II phosphorylation, thus inhibiting AKT-GSK-3ß pathway and the glycolysis of CT26 cells.

Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages.

Dietary restriction has been recognized as a healthy and natural therapy for cancer. It is reported that different forms of dietary restriction can promote anti-tumor immunity. However, it is not clear how fasting affects tumor-associated macrophages (TAMs). This study aims to investigate the relationship between fasting and antitumor immunity in terms of tumor-associated macrophages. In vivo, the results showed that alternate day fasting for 2 weeks inhibitted the tumor growth of mice without causing a reduction of body weight. Meanwhile, M2 polarization of tumor-associated macrophages in tumor tissues of alternate day fasting group was also decreased. In vitro, fasting induced the autophagy of CT26 cells, decreased the generation of extracellular adenosine by supressing the expression of CD73 in CT26 cells. Decreasing adenosine inhibitted M2 polarization of RAW264.7 cells through inactivating JAK1/STAT3 signal pathway in fasting condition. Eventually, the proliferation of CT26 cancer cells declined on account of fasting-facilitated antitumor immunity. These results suggested that fasting suppressed M2 polarization of tumor-associated macrophages to inhibit tumor growth through decreasing the level of adenosine in the tumor microenvironment both in vivo and in vitro. This process was associated with increasing autophagy of tumor cells.

Propofol attenuates pancreatic cancer malignant potential via inhibition of NMDA receptor.

Propofol is a commonly used intravenous anesthetic, and could attenuate cancer cells malignant potential via inhibiting hypoxia-inducible factor-1α (HIF-1α) expression. However, the mechanism is still inclusive. In the present study, we mainly focus on the mechanism by which propofol down-regulated HIF-1α expression and malignant potential in pancreatic cancer cells. Human pancreatic cancer cells (Miapaca-2 and Panc-1) in vitro and murine pancreatic cancer cell (Panc02) in vivo were used to assess the effect of propofol on vascular endothelial growth factor (VEGF) expression and migration of pancreatic cancer cells. Propofol inhibited cells migration, expression of VEGF and HIF-1α, phosphorylation of extracellular regulated protein kinases (ERK), AKT, Ca2+/calmodulin dependent protein kinases II (CaMK II), and Ca2+ concentration in a concentration-dependent manner (5, 25, 50, 100µM). Furthermore, MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMK II, could inhibit the expression of VEGF, HIF-1a, p-AKT, p-ERK, p-CaMK II in vitro, growth of tumor and VEGF expression in vivo, which were similar to the effect of propofol. In addition, the anti-tumor effect of propofol could be counteracted by rapastinel, an activator of NMDA receptor. Our study indicated that propofol suppressed VEGF expression and migration ability of pancreatic cancer cells in vitro and in vivo, probably via inhibiting NMDA receptor.

Ski modulate the characteristics of pancreatic cancer stem cells via regulating sonic hedgehog signaling pathway.

Evidence from in vitro and in vivo studies shows that Ski may act as both a tumor proliferation-promoting factor and a metastatic suppressor in human pancreatic cancer and also may be a therapeutic target of integrative therapies. At present, pancreatic cancer stem cells (CSCs) are responsible for tumor recurrence accompanied by resistance to conventional therapies. Sonic hedgehog (Shh) signaling pathway is found to be aberrantly activated in CSCs. The objectives of this study were to investigate the role of Ski in modulating pancreatic CSCs and to examine the molecular mechanisms involved in pancreatic cancer treatment both in vivo and in vitro. In in vitro study, the results showed that enhanced Ski expression could increase the expression of pluripotency maintaining markers, such as CD24, CD44, Sox-2, and Oct-4, and also components of Shh signaling pathway, such as Shh, Ptch-1, Smo, Gli-1, and Gli-2, whereas depletion of Ski to the contrary. Then, we investigated the underlying mechanism and found that inhibiting Gli-2 expression by short interfering RNA (siRNA) can decrease the effects of Ski on the maintenance of pancreatic CSCs, indicating that Ski mediates the pluripotency of pancreatic CSCs mainly through Shh pathway. The conclusion is that Ski may be an important factor in maintaining the stemness of pancreatic CSCs through modulating Shh pathway.

Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells.

Resistance of cancer cells to chemoradiotherapy is a major clinical problem in pancreatic cancer treatment. Therefore, understanding the molecular basis of cellular resistance and identifying novel targets are essential for improving treatment efficacy for pancreatic cancer patients. Previous studies have demonstrated a significant role for Pim-3 in pancreatic cancer survival against gemcitabine-induced genotoxic stress. Here, we observed that radiation treatment enhanced Pim-3 expression in human pancreatic cancer cells in vitro. Stable overexpression of Pim-3 in pancreatic cancer cells significantly protected cells against radiation treatment by attenuating G2/M phase cell cycle arrest and DNA damage response. Silencing of Pim-3 expression significantly elevated the phosphorylation of histone variant H2AX, a marker of DNA double strand breaks, and decreased the activation of ataxia-telangiectasia-mutated (ATM) kinase, along with its downstream targets, eventually enhancing the radiosensitivity of human pancreatic cancer cells in vitro and in vivo. Hence, we demonstrated a novel function for Pim-3 in human pancreatic cancer cell survival against radiation. Targeting Pim-3 may be a promising way to improve treatment efficacy in combination with radiotherapy in human pancreatic cancer.

Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children.

Severe combined immunodeficiencies (SCID) are a group of rare inherited disorders with profound defects in T cell and B cell immunity. From 2005 to 2010, our unit performed testing for IL2RG, JAK3, IL7R, RAG1, RAG2, DCLRE1C, LIG4, AK2, and ZAP70 mutations in 42 Chinese and Southeast Asian infants with SCID adopting a candidate gene approach, based on patient's gender, immune phenotype, and inheritance pattern. Mutations were identified in 26 patients, including IL2RG (n = 19), IL7R (n = 2), JAK3 (n = 2), RAG1 (n = 1), RAG2 (n = 1), and DCLRE1C (n = 1). Among 12 patients who underwent hematopoietic stem cell transplantation, eight patients survived. Complications and morbidities during transplant period were significant, especially disseminated bacillus Calmette-Guérin disease which was often difficult to control. This is the first cohort study on SCID in the Chinese and Southeast Asian population, based on a multi-centered collaborative research network. The foremost issue is service provision for early detection, diagnosis, management, and definitive treatment for patients with SCID. National management guidelines for SCID should be established, and research into an efficient platform for genetic diagnosis is needed.