Sustaining Life versus Altering Life-Saving Drugs: Insights to Explain the Paradoxical Effect of Extracorporeal Membrane Oxygenation on Drugs.

There has been a substantial increase in the use of extracorporeal membrane oxygenation (ECMO) support in critically ill adults. Understanding the complex changes that could affect drugs' pharmacokinetics (PK) and pharmacodynamics (PD) is of suitable need. Therefore, critically ill patients on ECMO represent a challenging clinical situation to manage pharmacotherapy. Thus, clinicians' ability to predict PK and PD alterations within this complex clinical context is fundamental to ensure further optimal and, sometimes, individualized therapeutic plans that balance clinical outcomes with the minimum drug adverse events. Although ECMO remains an irreplaceable extracorporeal technology, and despite the resurgence in its use for respiratory and cardiac failures, especially in the era of the COVID-19 pandemic, scarce data exist on both its effect on the most commonly used drugs and their relative management to achieve the best therapeutic outcomes. The goal of this review is to provide key information about some evidence-based PK alterations of the drugs used in an ECMO setting and their monitoring.

Prevalence and Risk Factors of New-onset Diabetes after Transplant in East Africans.

Very little is known about the prevalence of new-onset diabetes after transplant (NODAT) in sub-Saharan and Eastern Africans. Most of the data are related to African Americans and to North and South Africans. The aims of this study were to examine the prevalence of NODAT in Sudanese renal transplant recipients, compare it with the published literature, and identify the risk factors for developing NODAT. In total, 150 patients who received a living-related kidney transplant between January 2015 and January 2016 were included in this study. Patients with diabetic nephropathy and pretransplant diabetes were excluded. Follow-up was for 2 years after the transplant. The variables studied were age, sex, body mass index, a family history of diabetes mellitus (DM), pretransplant steroid therapy, dyslipidemia, and hepatitis C virus infection. Twenty- three patients (15.3%) developed NODAT during the study period. The mean age of the patients who developed NODAT was 39 ± 14 years, and the mean time to develop NODAT was 5.78 ± 5.9 months. In the multivariate analysis, the risk factors for developing NODAT were a family history of DM (P = 0.01) and pretransplant steroid therapy (P = 0.01). The prevalence of NODAT in this study was 15.3%, which is in line with the reported literature from North Africa. However, it was significantly lower than the reported prevalence in African Americans.

Peripartum veno-venous extracorporeal membrane oxygenation in patients with severe CoViD-19-related-ARDS.

We describe a case series of five pregnant or postpartum women with severe CoViD-19-related ARDS requiring VV ECMO at our centre between Jan 1 and Sep 30, 2021. All patients were cannulated at the referring hospitals by our team before transferring to our centre. None of the women were vaccinated against CoViD-19. All had severe ARDS with Murray's Lung Injury Score of 3-4 and met the severity threshold for ECMO initiation that was used in the EOLIA study. All patients were discharged alive to home, acute rehabilitation, or lung transplant centre. One patient suffered intrauterine death before ECMO initiation and another while on ECMO. VV ECMO for refractory CoViD-19 related ARDS in the peripartum period is safe, and in this small series, it was associated with good maternal survival rates.

Does Vitamin D Have a Role in Diabetes?

Vitamin D, a fat-soluble vitamin, acts in the calcium and phosphorus metabolism in its active form (1,25-dihydroxy vitamin D). It may help prevent and treat autoimmune diseases, including diabetes mellitus. Diabetes has become a significant global health issue with a rising incidence and prevalence. A recent focus has been on vitamin D supplementation as part of efforts to discover novel ways to prevent and treat diabetes. Most evidence points to the vitamin D receptors (VDRS) gene in both types of diabetes. The main objective of this study is to analyze how vitamin D affects both type 1 and type 2 diabetes. In this literature review, we searched the PubMed and Google Scholar databases to collect related articles from 13 papers of different study designs. We found a significant association between vitamin D deficiency and type 1 and type 2 diabetes development. It has been shown that vitamin D supplements have a promising effect in reducing glycated hemoglobin (HbA1c) in patients with type 1 diabetes, with no significant impact on the incidence or improvement of type 2 diabetes. Patients with diabetes and people at high risk of diabetes need the appropriate amount of vitamin D; therefore, regular testing and vitamin D supplementation are advised for the management and prevention of diabetes. Additional randomized studies with bigger sample sizes and longer-term trials are required to fully explore the benefits of vitamin D supplementation in patients with type 1 and type 2 diabetes.

Regulation of IGF2BP1 by miR-186 and its impact on downstream lncRNAs H19, FOXD2-AS1, and SNHG3 in HCC.

AIM: We have previously characterized oncogenic properties of IGF2BP1 in HCC, and its regulation by short noncoding RNAs (ncRNAs). Recent evidence suggests that IGF2BP1 itself may regulate long ncRNAs (lncRNAs). Therefore, this study aimed at exploring the interplay between IGF2BP1 and various upstream and downstream ncRNAs and its link to HCC pathogenesis. MATERIALS AND METHODS: Bioinformatic analysis was used to identify up- and downstream ncRNAs interacting with IGF2BP1. Huh-7 cells were transfected with siRNAs against IGF2BP1 and microRNA mimics. Relative gene expression was determined using RTqPCR and IGF2BP1 protein was quantified by western blot. Luciferase binding assay was used to explore the targeting of IGF2BP1 3'UTR. HCC tumorigenesis was measured by MTT assay, BrdU-incorporation assay, colony-forming assay, and scratch assay. KEY FINDINGS: Bioinformatic analysis identified three oncogenic lncRNAs - namely H19, FOXD2-AS1, and SNHG3 - potentially regulated by IGF2BP1. Knockdown of IGF2BP1 decreased the expression of all three oncogenic lncRNAs and inhibited malignant cell behaviors. miR-186 was revealed as a possible upstream regulator of IGF2BP1. miR-186 mimics decreased IGF2BP1 mRNA and protein levels. miR-186 was significantly lower while IGF2BP1 was elevated in cancerous tissues from ten HCC patients compared to five healthy controls. In addition, miR-186 mimics caused a downregulation of the oncogenic lncRNAs H19, SNHG3, and FOXD2-AS1 and a concomitant decrease in cell viability, proliferation, migration, and clonogenicity. SIGNIFICANCE: miR-186 may exert tumor suppressor effects in HCC by repressing oncogenic lncRNAs H19, SNHG3, and FOXD2-AS1 through its effect on IGF2BP1.

The optimum inhibitory effects of Alpha Interferon and Cisplatin in colon cancer, a comparative in vitro study.

Cisplatin is well known as a potent anti-cancer agent against colon cancer. However, alpha interferons are also widely used for cancer suppression. This in vitro study was designed to investigate and compare the cancer suppression function of alpha interferon in colon cancer with Cisplatin. The analysis used a human SW 480 cancer cell line with RPMI-1630 culture media. Six dilutions of interferon (2.5 µg/ml, 1.25 µg/ml, 0.562 µg/ml, 0.286 µg/ml, 0.143 µg/ml, and 0.057 µg/ml) and six dilutions of cisplatin (100 µg/ml, 50 µg/ml, 25 µg/ml, 6.25 µg/ml, and 3.125) were used at 24, 48 and 72 hours along with the presence of control groups. Following this, results were observed by ELISA plate reader, and percentage inhibition was calculated using ANOVA analysis. The interferon and cisplatin percentage of inhibition was comparable with higher inhibition rates observed with alpha interferon. The statistical analysis showed that the maximum inhibition was observed at a 0.143 µg/ml interferon concentration when exposed for 48 to 72 hours. This in vitro analysis demonstrated the anti-cancer activity of alpha interferon and its advanced inhibitory activity compared to Cisplatin.

Oncological outcomes of laparoscopic versus open gastrectomy after neoadjuvant chemotherapy for locally advanced gastric cancer: a retrospective multicenter study.

BACKGROUND: The oncological outcomes of laparoscopic gastrectomy (LG) and open gastrectomy (OG) following neoadjuvant chemotherapy have been investigated in a few studies. Our purpose was to evaluate the oncological outcomes of LG and OG after neoadjuvant chemotherapy in patients with locally advanced gastric cancer (GC) and to determine the advantages, preferences, and ease of use of the two techniques after chemotherapy. METHODS: We conducted a retrospective chart review of all patients who underwent either OG (n = 43) or LG (n = 41). The neoadjuvant treatment regimen consisted of capecitabine plus oxaliplatin for three cycles, which was then repeated 6 to 12 weeks after the operation for four cycles. RESULTS: The hospital stay time and intraoperative blood loss in the LG group were significantly lower than those in the OG group. The mortality rate and the 3-year survival rate for patients in the LG group were comparable to those of patients in the OG group (4.6% vs. 9.7% and 68.3% vs. 58.1%, respectively). Similar trends were observed regarding the 3-year recurrence rate and metastasis. The mean survival time was 52.9 months (95% confidence interval [CI], 44.2-61.6) in the OG group compared with 43.3 (95% CI, 36.6-49.8) in the LG group. Likewise, the mean disease-free survival was 56.1 months (95% CI, 46.36-65.8) in the LG group compared with 50.9 months (95% CI, 44.6-57.2) in the OG group. CONCLUSION: LG is a feasible and safe alternative to OG for patients with locally advanced GC receiving neoadjuvant chemotherapy.

Vestibular function assessment following cochlear implantation using rotatory chair testing.

PURPOSE: Study aimed to assess short- and long-term impact of unilateral cochlear implantation in children on the angular vestibulo-ocular reflex using rotatory chair test. METHODS: Two groups; A (early postoperative evaluation) and B (later on evaluation) were included, each consisted of 23 cochlear implant candidates' children with unilateral implant surgeries were performed in El-Galaa Hospital, Cairo, Egypt. They were assessed by rotatory chair test; sinusoidal harmonic acceleration paradigm. Three parameters: average gain, asymmetry, and phase results of each group were compared with the manufacturer's norms and with each other. Further analysis by comparing each group implanted side specific gain results with the same group non-implanted side specific gain and with the other group implanted side specific gain results. RESULTS: Group A versus norms showed only significant differences in average gain and phase at 0.02 Hz and 0.01 Hz test frequencies respectively. However, three parameters in group B showed no significant differences when compared with norms. When comparing the results of both groups relieved significant differences only in average gain at 0.02 Hz and in phase at both 0.01 Hz and 0.04 Hz. Comparing specific gain results for both sides of group A showed significance at 0.32 Hz test frequency, while those of group B showed no significant differences. The analysis of implanted sides gain results of both groups showed differences at 0.16 Hz and 0.32 Hz. CONCLUSION: Bilateral restoration and improvement of angular vestibulo-ocular reflexes after unilateral cochlear implantation was reported with long-term assessment by rotatory chair test.

Laparoscopic gastrectomy with D2 lymphadenectomy for gastric cancer: initial Egyptian experience at the National Cancer Institute.

BACKGROUND: Laparoscopic gastrectomy has been used as a superior alternative to open gastrectomy for the treatment of early gastric cancer. However, the application of laparoscopic D2 lymphadenectomy remains controversial. This study aimed to evaluate the feasibility and outcomes of laparoscopic gastrectomy with D2 lymphadenectomy for gastric cancer. RESULTS: Between May 2016 and May 2018, twenty-five consecutive patients with gastric cancer underwent laparoscopic D2 gastrectomy: eighteen patients (72%) underwent distal gastrectomy, four patients (16%) underwent total gastrectomy, and three patients (12%) underwent proximal gastrectomy. The median number of lymph nodes retrieved was 18 (5-35). A positive proximal margin was detected in 2 patients (8%). The median operative time and amount of blood loss were 240 min (200-330) and 250 ml (200-450), respectively. Conversion to an open procedure was performed in seven patients (28%). The median hospital stay period was 8 days (6-30), and the median time to start oral fluids was 4 days (3-30). Postoperative complications were detected in 4 patients (16%). There were two cases of mortality (8%) in the postoperative period, and two patients required reoperation (8%). CONCLUSIONS: Laparoscopic gastrectomy with D2 lymphadenectomy can be carried out safely and in accordance with oncologic principles.

Competing Endogenous RNAs in Hepatocellular Carcinoma-The Pinnacle of Rivalry.

The role of noncoding transcripts in gene expression is nowadays acknowledged to keep various diseases at bay-despite being referred to as "junk" DNA several years ago. Believed to be at the heart of multiple regulatory pathways, microRNAs (miRNAs) are small noncoding RNAs (ncRNAs) involved in posttranscriptional gene regulation. Recently, the discovery of ncRNAs that compete for shared miRNA pools has dimmed the light on the solo performance of miRNAs in genomic regulation. Indeed, several studies describe RNAs such as long noncoding RNAs, mRNAs, circular RNAs, pseudogenes, and viral RNAs as competing endogenous RNAs (ceRNAs) that sequester miRNAs, allowing for de-repression of downstream miRNA targets. Such integration between coding and noncoding transcripts forms complex ceRNA networks that when dysregulated lead to several diseases such as hepatocellular carcinoma. Here, the authors review perturbed ceRNA networks in hepatocellular carcinoma, describe the role of each in tumorigenesis, and discuss their various clinical implications.

Epigallocatechin gallate (EGCG) and miR-548m reduce HCV entry through repression of CD81 receptor in HCV cell models.

Epigallocatechin gallate (EGCG) is the most abundant component in green tea extract, that has powerful antioxidant and antiviral effects. It has been previously reported to inhibit HCV entry via several mechanisms. Hence, this study aimed at further investigating the potential impact of EGCG on HCV entry through regulation of the expression of tetraspanin receptor CD81 by the novel predicted miR-548m. Liver biopsies were obtained from 29 HCV patients and 10 healthy controls for expression profiling. Huh7 cells were stimulated with EGCG and subsequently miR-548m expression was assessed. Naïve, HCV- ED43/JFH-1 and HCV-JFH-1 infected Huh7 cells were transfected by miR-548m mimics and inhibitors. Consequently, CD81 protein and mRNA levels were assessed using flow cytometry and qRT-PCR, respectively. Additionally, these cells were used to investigate HCV permissiveness into Huh7 cells using qRT-PCR for viral quantification. Direct binding confirmation of miR-548m to CD81 was done using luciferase reporter assay. In-silico analysis revealed miR-548m to have two potential binding sites in the 3'UTR of CD81 mRNA. EGCG boosted miR-548m expression in Huh7 cells. Additionally, miR-548m caused a downregulation of CD81 protein and mRNA levels as well as reduction in HCV infectivity of Huh7 cells. Luciferase binding assay confirmed the binding of miR-548m to CD81 mRNA at the two predicted binding sites. Intriguingly, miR-548m expression was not detected in healthy liver biopsies but was found in liver biopsies of HCV patients. This study shows that EGCG might act as an anti-HCV agent that reduces cellular infectivity via enhancing miR-548m expression and repressing CD81 receptor.

Peritoneal carcinomatosis in colorectal cancer: Defining predictive factors for successful cytoreductive surgery and hyperthermic intraperitoneal chemotherapy - A pilot study.

BACKGROUND: Peritoneal carcinomatosis originating from colorectal cancer (PC-CRC) carries a dismal prognosis. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) have been offered to those patients with substantial health and economic burden, nevertheless not all patients are fitting this treatment modality and outcome is generally still poor. OBJECTIVE: To elicit predictive factors associated with the success of CRS and HIPEC in PC-CRC patients. PATIENTS AND METHODS: This is a pilot study including 30 consecutive patients with PC-CRC; 20 of them (66.7%) presented with metachronous peritoneal disease. All patients were planned for CRS and HIPEC with Mitomycin-C after receiving preoperative systemic chemotherapy for 3 months. RESULTS: On exploration, CRS and HIPEC were successful in 17 patients (56.6%) who had completeness of cytoreduction score 0-1 (CC-0/1), whereas failure (CC-2) was encountered in 13 patients (43.3%). The presence of ascites, extensive peritoneal disease (PCI > 20) was significantly correlated with failure to achieve CRS and HIPEC (p < 0.001); also, the primary rectal site showed a trend towards significance (p = 0.08). The cumulative overall survival (OS) and progression-free survival (PFS) at 2 years were 66.6 and 62.6%, respectively. Patients who achieved CC-0/1 had significantly prolonged OS compared to CC-2 (p < 0.001). On multivariate analysis, the CC score and the original site were independent prognostic factors for OS (p = 0.04 and 0.02, respectively). CONCLUSION: In patients with PC-CRC, malignant ascites and PCI > 20 are poor prognostic factors associated with failure to accomplish CRS with consequent poor survival.

Trace elements and oxidative stress in children with type 1 diabetes mellitus.

BACKGROUND: The early imbalances of trace elements in type 1 diabetes (T1D) may cause disturbance of glucose metabolism and more oxidative stress that may enhance the development of insulin resistance and diabetic complications. We aim to evaluate the serum level of selenium (Se), zinc (Zn), magnesium (Mg), and copper (Cu), the degree of oxidative stress and evaluate their relations to glycemic control in children with T1D. METHODS: A case-control study which included 100 diabetic children and 40 healthy children age, sex, and ethnicity-matched as a control group. The diabetic children were divided into poor and good controlled patients according to glycosylated hemoglobin (A1c %). Studied children underwent history taking, clinical examination and laboratory measurement of serum Se, Zn, Mg, and Cu levels, erythrocyte reduced glutathione (GSH) and peroxidase enzyme activity (GPx). RESULTS: Serum Se, Zn, Mg, Cu, erythrocyte GSH, and GPx were significantly lower in the diabetic group in comparison to the control group (P<0.05) and their levels were lower in poorly controlled patients compared to good controlled patients (P<0.05). The serum Se, Zn, Mg, erythrocyte GSH, and GPx showed a negative correlation with A1c %. The serum Se showed a positive correlation with erythrocyte GSH and GPx ([r=0.56, P<0.001], [r=0.78, P<0.001], respectively). CONCLUSION: Children with T1D, especially poorly controlled cases, had low serum Se, Zn, Mg, Cu, GSH, and GPx. Low serum Se in diabetic children may affect the erythrocyte GSH-GPx system.

Correction to: Ectopic delivery of miR-200c diminishes hepatitis C virus infectivity through transcriptional and translational repression of Occludin.

The author would like to correct the errors in the online published article.

Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation.

Context: The etiology of primary ovarian insufficiency (POI) remains unknown in most cases. Objective: We sought to identify the genes causing POI. Design: The study was a familial genetic study. Setting: The study was performed at two academic institutions. Patients: We identified a consanguineous Yemeni family in which four daughters had POI. A brother had azoospermia. Intervention: DNA was subjected to whole genome sequencing. Shared regions of homozygosity were identified using Truploidy and prioritized using the Variant Annotation, Analysis, and Search Tool with control data from 387 healthy subjects. Imaging and quantification of protein localization and mitochondrial function were examined in cell lines. Main Outcome: Homozygous recessive gene variants shared by the four sisters. Results: The sisters shared a homozygous stop gain mutation in exon 6 of PSMC3IP (c.489 C>G, p.Tyr163Ter) and a missense variant in exon 1 of CLPP (c.100C>T, p.Pro34Ser). The affected brother also carried the homozygous PSMC3IP mutation. Functional studies demonstrated mitochondrial fragmentation in cells infected with the CLPP mutation. However, no abnormality was found in mitochondrial targeting or respiration. Conclusions: The PSMC3IP mutation provides additional evidence that mutations in meiotic homologous recombination and DNA repair genes result in distinct female and male reproductive phenotypes, including delayed puberty and primary amenorrhea caused by POI (XX gonadal dysgenesis) in females but isolated azoospermia with normal pubertal development in males. The findings also suggest that the N-terminal missense mutation in CLPP does not cause substantial mitochondrial dysfunction or contribute to ovarian insufficiency in an oligogenic manner.

MiR-615-5p depresses natural killer cells cytotoxicity through repressing IGF-1R in hepatocellular carcinoma patients.

miR-615-5p was characterized by our group as a tumour suppressor. IGF-1 R activates a downstream signalling pathway, well characterized in liver cells, however, its role in immunity especially Natural Killer cells (NKs) remains vague. This study aimed at investigating the regulatory role of miR-615-5p on IGF signalling and its impact on NKs cytotoxicity in HCC. Our results showed an upregulation in miR-615-5p and IGF-1 R in NKs of 130 HCC patients compared to 35 controls. Forcing the expression of miR-615-5p, repressed IGF-IR, attenuated NKs cytotoxicity, decreased CD56dim, increased CD56bright NK subsets and reduced the cytotoxic markers NKG2D, TNF-α and perforins. It repressed NKG2D ligand (ULBP2) in Huh-7 cells. In conclusion, miR-615-5p represses IGF-1 R in NKs and their target hepatocytes; however, it has a contradicting impact on HCC progression on both cell types. These findings might pave the way for better understanding the role of microRNAs in NKs function and HCC immune-pathogenesis.

New-Onset Diabetes After Transplant in a Sudanese Renal Transplant Population: Prevalence and Risk Factors.

OBJECTIVES: New-onset diabetes after transplant is a well-recognized complication of solid-organ transplant. The true incidence of this complication in Sudan is not known. The aim of this study was to define the prevalence of new-onset diabetes after transplant in a Sudanese renal transplant population and to identify the contributing risk factors. MATERIALS AND METHODS: Fifty-nine patients who underwent living-donor related kidney transplant and who were followed for 2 years were included in this pilot study. Only patients who were not diabetic before transplant were included. Patients who developed new-onset diabetes after transplant were compared with those who did not develop type 2 diabetes mellitus. The variables analyzed were age, sex, body mass index, family history of type 2 diabetes mellitus, and interval between time of transplant and onset of diabetes. RESULTS: Five patients (5/58) developed diabetes after transplant (8.62%). There was no association between new-onset diabetes after transplant and age, sex, and body mass index. However, there was a strong association between family history of diabetes and new-onset diabetes after transplant. The mean duration for developing new-onset diabetes after transplant was 10 months posttransplant. Patients in the new-onset diabetes after transplant group had no graft loss or deterioration in graft function compared with those who did not develop diabetes. CONCLUSIONS: The prevalence of new-onset diabetes after transplant in our studied Sudanese population was found to be < 10%. There was no association between new-onset diabetes after transplant and age, sex, and body mass index. However, there was a significant association with family history of diabetes mellitus.

Ectopic delivery of miR-200c diminishes hepatitis C virus infectivity through transcriptional and translational repression of Occludin.

Occludin (OCLN) is an essential factor for HCV entry through interacting with other surface receptors. The aim of this study was to investigate the epigenetic regulation of Occludin expression and to study its impact on viral infectivity. microRNAs expression was assessed using qRT-PCR, while OCLN protein expression was investigated by indirect immunofluorescence and Western blotting. Viral infectivity was assessed by measuring viral-load using qRT-PCR. In silico analysis predicted that miR-200c targeted the OCLN 3'UTR, which was further experimentally confirmed. miR-122 was previously validated to target the 3'UTR of OCLN and was used as a control. We report a significant down-regulation of miR-200c in liver tissues of HCV-infected patients. Ectopic expression of both miR-122 and miR-200c in Huh7 cells reduced OCLN mRNA and protein levels. Viral infectivity was significantly reduced by miR-200c but enhanced by miR-122. This work sheds light on miR-200c as a novel regulator of HCV infectivity through the regulation of OCLN.

MicroRNA-486-5p enhances hepatocellular carcinoma tumor suppression through repression of IGF-1R and its downstream mTOR, STAT3 and c-Myc.

The insulin-like growth factor (IGF)-axis has been paradigmatically involved in hepatocellular carcinoma (HCC) tumor initiation, progression and drug resistance. Consequently, members of the IGF-axis and most importantly, IGF-1 receptor (IGF-1R) have been considered as intriguing targets for HCC therapy. Few miRNAs have been recently reported to be associated with IGF-1R regulation. The present study aimed to investigate the role of microRNA (miRNA/miR)-486-5p in the regulation of IGF-1R and its downstream signaling cascades. miR-486-5p was markedly downregulated in hepatitis C virus-induced HCC tissues and Huh-7 cells. Forcing the expression of miR-486-5p in Huh-7 cells resulted in the repression of IGF-1R, mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3) and c-Myc mRNA levels. Ectopic expression of miR-486-5p in Huh-7 cells markedly repressed cellular viability, proliferation, migration and clonogenicity in a similar pattern to IGF-1R small interfering RNAs, and were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, BrdU incorporation, wound healing and colony forming assays, respectively. Overall, the study findings demonstrated that miR-486-5p acts as a tumor suppressor in HCC through the repression of essential members of the IGF-axis, including IGF-1R and its downstream mediators mTOR, STAT3 and c-Myc.