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  • 1
    In: Cancers, MDPI AG, Vol. 14, No. 3 ( 2022-01-29), p. 708-
    Abstract: Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 2
    In: Clocks & Sleep, MDPI AG, Vol. 4, No. 2 ( 2022-05-31), p. 287-299
    Abstract: Kleine–Levin syndrome (KLS) is characterized by episodes of hypersomnia. Additionally, these patients can present with hyperphagia, hypersexuality, abnormal behavior, and cognitive dysfunction. Functional neuroimaging studies such as fMRI-BOLD, Positron Emission Tomography (PET) or SPECT help us understand the neuropathological bases of different disorders. We conducted a systematic review to investigate the neuroimaging features of KLS patients and their clinical correlations. This systematic review was conducted by following the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and PRISMA protocol reporting guidelines. We aim to investigate the clinical correlation with neuroimaging among patients with KLS. We included only studies written in the English language in the last 20 years, conducted on humans; 10 studies were included. We excluded systematic reviews, metanalysis, and case reports. We found that there are changes in functional imaging studies during the symptomatic and asymptomatic periods as well as in between episodes in patients with K.L.S. The areas most reported as affected were the hypothalamic and thalamic regions, which showed hypoperfusion and, in a few cases, hyperperfusion; areas such as the frontal, parietal, occipital and the prefrontal cortex all showed alterations in cerebral perfusion. These changes in cerebral blood flow and regions vary according to the imaging (SPECT, PET SCAN, or fMRI) and the task performed while imaging was performed. We encountered conflicting data between studies. Hyper insomnia, the main feature of this disease during the symptomatic periods, was associated with decreased thalamic activity. Other features of K.L.S., such as apathy, hypersexuality, and depersonalization, were also correlated with functional imaging changes. There were also findings that correlated with working memory deficits seen in this stage during the asymptomatic periods. Hyperactivity of the thalamus and hypothalamus were the main features shown during the asymptomatic period. Additionally, functional imaging tends to improve with a longer course of the disease, which suggests that K.L.S. patients outgrow the disease. These findings should caution physicians when analyzing and correlating neuroimaging findings with the disease.
    Type of Medium: Online Resource
    ISSN: 2624-5175
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2966788-4
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