Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo

We observed a co-upregulation of the insulin-like growth factor receptor (IGF-1R)/AKT/mammalian target of rapamycin (mTOR) [InAT] axis and the mevalonate-isoprenoid biosynthesis (MIB) pathways in colorectal cancer stem cells (CSCs) in an unbiased approach. Hence, we hypothesized that the InAT axis might regulate the MIB pathway to govern colorectal CSCs growth. Stimulation (IGF-1) or inhibition (IGF-1R depletion and pharmacological inhibition of IGF-1R/mTOR) of the InAT axis produced induction or attenuation of CSC growth as well as expression of CSC markers and self-renewal factors respectively. Intriguingly, activation of the InAT axis (IGF-1) caused significant upregulation of the MIB pathway genes (both mRNA and protein); while its inhibition produced the opposite effects in colonospheres. More importantly, supplementation with dimethylallyl- and farnesyl-PP, MIB metabolites downstream of isopentenyl-diphosphate delta isomerase (IDI), but not mevalonate and isopentenyl-pp that are upstream of IDI, resulted in a near-complete reversal of the suppressive effect of the InAT axis inhibitors on CSCs growth. The latter findings suggest a specific regulation of the MIB pathway by the InAT axis distal to the target of statins that inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Effects of IGF-1R inhibition on colonic CSCs proliferation and the MIB pathway were confirmed in an ‘in vivo’ HCT-116 xenograft model. These observations establish a novel mechanistic link between the InAT axis that is commonly deregulated in colorectal cancer and the MIB pathway in regulation of colonic CSCs growth. Hence, the InAT-MIB corridor is a novel target for developing paradigm shifting optimum anti-CSCs therapies for colorectal cancer.     

Dexamethasone pretreatment for 24 h versus 6 h for prevention of postextubation airway obstruction in children: a randomized double-blind trial

Purpose

Multidose steroid pretreatment is effective in preventing postextubation airway obstruction (PEAO) in adults, however controversy continues for children. This study was designed as a randomized, placebo-controlled, double-blind trial to compare the effect of 24-h pretreatment with dexamethasone (24hPD) versus 6-h pretreatment (6hPD) on PEAO and reintubation in children at a tertiary care hospital in a developing economy.

Methods

Hundred twenty-four children (3 months to 12 years) intubated for ≥48 h and planned to have extubation during next 24 h were randomized to receive 24hPD (0.5 mg/kg/dose, q6h, total of six doses; n = 66) or 6hPD (total of three doses; n = 58). Patients with preexistent upper airway conditions, chronic respiratory diseases, steroid therapy in last 7 days, gastrointestinal bleeding, hypertension, and hyperglycemia and those likely to have poor airway reflexes were excluded.

Results

The two groups were similar at baseline. 24hPD reduced the incidence of PEAO (43/66 versus 48/58; p = 0.027) with absolute risk reduction of 17 %. It also reduced the incidence of reintubation, though nonsignificantly, by half [5/61 versus 9/58; relative risk (RR), 1.09; 95 % confidence interval (CI), 0.96–1.25]. Time to recovery from PEAO among non-reintubated patients was shorter among 24hPD patients (p = 0.016). No adverse event was noted with dexamethasone use. Intubation duration >7 days and cuffed tracheal tubes were found to be independent risk factors for PEAO (odds ratio 6 and 3.12, respectively).

Conclusions

24-h pretreatment with multidose dexamethasone reduced the incidence of PEAO and the time to recover from it. 24hPD should be considered for high-risk children intubated for >48 h in the study setting. Further studies with larger sample size from different socioeconomic background are desirable to validate these findings.     

The clinical and molecular spectrum of ETV6 mutated myeloid neoplasms

ETV6 mutations are rare but recurrent somatic events in myeloid neoplasms and are negatively prognostic in myelodysplastic syndrome. We set out to examine the clinical and molecular characteristics of patients undergoing investigation for myeloid neoplasms, found to have deleterious ETV6 mutations. ETV6 mutations occurred in 33 of 5793 (0.6%) cases investigated and predominantly in high-risk disease entities including MDS with increased blasts, primary myelofibrosis and AML, myelodysplasia-related. In three cases, isolated iso (17q) karyotype was concurrently detected, an otherwise rare karyotype in myeloid neoplasms. ETV6 mutations were frequently subclonal and never occurred as an isolated abnormality with ASXL1 (n = 22, 75%), SRSF2 (n = 14, 42%) and SETBP1 (n = 11, 33%) the predominant co-mutations. Restricting to patients with MDS, higher rates of ASXL1, SETBP1, RUNX1 and U2AF1 mutations occurred in ETV6 mutated cases, relative to a consecutive control cohort with wild-type ETV6. The median OS of the cohort was 17.5 months. This report highlights the clinical and molecular associations of somatic ETV6 mutations in myeloid neoplasms, suggests their occurrence as a later event, and proposes further translational research questions for their role in myeloid neoplasia.     

Phenotypic heterogeneity of spontaneous lymphomas of CWD mice

Animals of the inbred mouse strain, CWD, express endogenous murine leukemia viruses early in life and have a high incidence of spontaneous neoplasms. We found that approximately one half of these animals died of malignant lymphoma by the age of 16 months. Splenic enlargement was seen in all mice, but thymic involvement was unusual. One half of the CWD tumors were diffuse lymphoblastic or immunoblastic lymphomas while the remainder were large cell, small cell, or mixed cell lymphomas. Analysis of DNAs from 12 tumors for immunoglobulin and T-cell receptor gene rearrangements revealed that all six of the lymphoblastic and immunoblastic lymphomas were of T-cell origin, as was one tumor of small cleaved cells. Four of the others were clonal B-cell lymphomas and one was of uncertain lineage. Assays of a limited number of tumors for the expression of the Thy 1.2 and IgM molecules confirmed the diversity in the cellular phenotype. The results indicate that CWD mice develop primarily splenic lymphomas with an unusual degree of heterogeneity in the tumor cell phenotypes as compared with the thymic lymphomas found in other high leukemia strains. The CWD strain is a useful new model for studies of retroviral leukemogenesis and the relationship between the histopathology and immunophenotype of malignant lymphomas.