Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mammalian target of rapamycin complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing co-mutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas (ADCs) and squamous cell carcinomas (SCCs). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1 mutant human cell lines and genetically engineered mouse models of NSCLC that develop both ADCs and SCCs. Specifically, we found that KRAS/LKB1 mutant lung ADCs responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1 mutant adenocarcinomas and squamous cell tumors.
<p>Treatment of LKB1 mutant and LKB1 wildtype NSCLC lines with phenformin, MLN0128 or combination leads to loss of cellular ATP (S1); Metabolite analysis of NSCLC human cell line expressing dox inducible 4E-BP1 4Ala protein and control vector (S2); Biomarker analysis of normal lung tissue in response to drug treatments (S3); Treatment of Kluc mice with phenformin, MLN0128 or combination does not result in therapeutic benefit (S4); Tumor burden does not decrease in response to phenformin, MLN0128 or combination therapy in Kluc mice (S5); Biomarker analysis in tumors treated with phenformin, MLN0128 or combination (S6); Biomarker analysis of mouse tumors lysates, human NSCLC cell lines and mouse embryonic fibroblasts (S7).</p>
Introduction: Local outbreaks of measles infection are primarily mediated by international travel of persons from endemic areas, with subsequent spread of the virus via undervaccinated populations. Recent resurgences of measles in communities where vaccination rates are non-ideal secondary to philosophical objections require the emergency physician to more routinely consider the diagnosis. In cases of measles complicated by acute encephalitis or encephalopathy, the diagnosis can be especially difficult to make due to lack of a reliable primary historian.
Case report: Here we present a case of altered mental status and new-onset bilateral lower extremity weakness in a fully vaccinated young woman diagnosed with measles infection caused by acute disseminated encephalomyelitis in the setting of vaccine failure.
Conclusion: Despite a documented history of immunization, acute measles infection and its uncommon sequelae are possible. Recognizing vaccine failure and appropriately isolating patients are of paramount importance.
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