Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts.

Copyright: 2013 Hermann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.PURPOSE: In spite of intense research efforts, pancreatic ductal adenocarcinoma remains one of the most deadly malignancies in the world. We and others have previously identified a subpopulation of pancreatic cancer stem cells within the tumor as a critical therapeutic target and additionally shown that the tumor stroma represents not only a restrictive barrier for successful drug delivery, but also serves as a paracrine niche for cancer stem cells. Therefore, we embarked on a large-scale investigation on the effects of combining chemotherapy, hedgehog pathway inhibition, and mTOR inhibition in a preclinical mouse model of pancreatic cancer. EXPERIMENTAL DESIGN: Prospective and randomized testing in a set of almost 200 subcutaneous and orthotopic implanted whole-tissue primary human tumor xenografts. RESULTS: The combined targeting of highly chemoresistant cancer stem cells as well as their more differentiated progenies, together with abrogation of the tumor microenvironment by targeting the stroma and enhancing tissue penetration of the chemotherapeutic agent translated into significantly prolonged survival in preclinical models of human pancreatic cancer. Most pronounced therapeutic effects were observed in gemcitabine-resistant patient-derived tumors. Intriguingly, the proposed triple therapy approach could be further enhanced by using a PEGylated formulation of gemcitabine, which significantly increased its bioavailability and tissue penetration, resulting in a further improved overall outcome. CONCLUSIONS: This multimodal therapeutic strategy should be further explored in the clinical setting as its success may eventually improve the poor prognosis of patients with pancreatic ductal adenocarcinoma

Reservoir engineering using quantum optimal control for qubit reset

We determine how to optimally reset a superconducting qubit which interacts with a thermal environment in such a way that the coupling strength is tunable. Describing the system in terms of a time-local master equation with time-dependent decay rates and using quantum optimal control theory, we identify temporal shapes of tunable level splittings which maximize the efficiency of the reset protocol in terms of duration and error. Time-dependent level splittings imply a modification of the system-environment coupling, varying the decay rates as well as the Lindblad operators. Our approach thus demonstrates efficient reservoir engineering employing quantum optimal control. We find the optimized reset strategy to consist in maximizing the decay rate from one state and driving non-adiabatic population transfer into this strongly decaying state

Early life stress regulates cardiac development through an IL4-glucocorticoid signaling balance

Stressful experiences early in life can increase the risk of cardiovascular diseases. However, it remains largely unknown how stress influences susceptibility to the disease onset. Here, we show that exposure to brain-processed stress disrupts myocardial growth by reducing cardiomyocyte mitotic activity. Activation of the glucocorticoid receptor (GR), the primary stress response pathway, reduces cardiomyocyte numbers, disrupts trabecular formation, and leads to contractile dysfunction of the developing myocardium. However, a physiological level of GR signaling is required to prevent cardiomyocyte hyperproliferation. Mechanistically, we identify an antagonistic interaction between the GR and the cytokine interleukin-4 (IL-4) as a key player in cardiac development. IL-4 signals transcription of key regulators of cell-cycle progression in cardiomyocytes via signal transducer and activator of transcription 3 (Stat3). GR, on the contrary, inhibits this signaling system. Thus, our findings uncover an interplay between stress and immune signaling pathways critical to orchestrating physiological growth of the heart

Inflammation and frailty in the elderly: A systematic review and meta-analysis

The pathogenesis of frailty and the role of inflammation is poorly understood. We examined the evidence considering the relationship between inflammation and frailty through a systematic review and meta-analysis. A systematic literature search of papers providing data on inflammatory biomarkers and frailty was carried out in major electronic databases from inception until May 2016. From 1856 initial hits, 35 studies (32 cross-sectional studies n=3232 frail, n=11,483 pre-frail and n=8522 robust, and 563 pre-frail+robust; 3 longitudinal studies n=3402 participants without frailty at baseline) were meta-analyzed. Cross-sectional studies reported that compared to 6757 robust participants, both 1698 frail (SMD=1.00, 95%CI: 0.40-1.61) and 8568 pre-frail (SMD=0.33, 95%CI: 0.04-0.62) participants had significantly higher levels of C-reactive protein (CRP). Frailty (n=1057; SMD=1.12, 95%CI: 0.27-2.13) and pre-frailty (n=4467; SMD=0.56, 95%CI: 0.00-1.11) were associated with higher serum levels of interleukin-6 compared to people who were robust (n=2392). Frailty and pre-frailty were also significantly associated with elevated white blood cell and fibrinogen levels. In three longitudinal studies, higher serum CRP (OR=1.06, 95%CI: 0.78-1.44,) and IL-6 (OR=1.19, 95%CI: 0.87-1.62) were not associated with frailty. In conclusion, frailty and pre-frailty are associated with higher inflammatory parameters and in particular CRP and IL-6. Further longitudinal studies are needed

Tinnitus and equilibrium disorders in COVID-19 patients: preliminary results

Purpose: Tinnitus and equilibrium disorders such as dizziness and vertigo have been reported by patients with COVID-19; however, they have been rarely investigated. The aim of this study was to study the prevalence of subjective tinnitus and dizziness in a sample of COVID-19 patients using an online 10-item close-ended questionnaire. Methods: A multicentric study that included 15 Italian hospitals in different regions was conducted using an online 10-item close-ended questionnaire developed to identify the presence of tinnitus and balance disorders in patients with COVID-19 between May 5 and June 10, 2020. The questionnaire was administered to 185 patients in a period of > 30 – < 60 days after diagnosis of COVID-19; responses were recorded in an online Excel spreadsheet. The questionnaire was composed of three sections: (1) demographic information; (2) presence and characteristics of tinnitus and dizziness after COVID-19 diagnosis; (3) possible association with migraine. Results: Thirty-four patients (18.4%) reported equilibrium disorders after COVID-19 diagnosis. Of these, 32 patients reported dizziness (94.1%) and 2 (5.9%) reported acute vertigo attacks. Forty-three patients (23.2%) reported tinnitus; 14 (7.6%) reported both tinnitus and equilibrium disorders. Conclusion: This study suggests that the presence of subjective otoneurological symptoms such as tinnitus and balance disorders can affect COVID-19 patients; further studies are necessary to investigate the prevalence and pathophysiological mechanisms underlying these subjective symptoms in COVID-19 patients

PNPLA3 148M Carriers with Inflammatory Bowel Diseases Have Higher Susceptibility to Hepatic Steatosis and Higher Liver Enzymes

BACKGROUND: Inflammatory bowel diseases (IBD) are characterized by chronic relapsing inflammation of the gastrointestinal tract and encompass Crohn's disease and ulcerative colitis. IBD are often associated with extraintestinal manifestations affecting multiple organs including the liver. Increased levels of serum aminotransferases, possibly related to nonalcoholic fatty liver disease, constitute one of the most frequently described IBD-related liver diseases. The PNPLA3 I148M substitution is a major common genetic determinant of hepatic fat content and progression to chronic liver disease. The aim of this study was to investigate whether carriers of PNPLA3 148M allele with IBD have higher risk of liver steatosis and increase in transaminases levels. METHODS: The PNPLA3 I148M (rs738409) genotype was performed by Taqman assays in 158 individuals from Southern Italy (namely, Catanzaro cohort) and in 207 individuals from Northern Italy (namely, Milan cohort) with a definite diagnosis of IBD. Demographic and clinical data and also alanine transaminase levels were collected for both cohorts. The Catanzaro cohort underwent liver evaluation by sonography and liver stiffness and controlled attenuation parameter measurements by transient elastography. RESULTS: Here, we show for the first time that carriers of the PNPLA3 148M allele with IBD have a greater risk of hepatic steatosis (odds ratio, 2.9, and confidence interval, 1.1-7.8), higher controlled attenuation parameter values (P = 0.029), and increased circulating alanine transaminase (P = 0.035) in the Catanzaro cohort. We further confirm the higher alanine transaminase levels in the Milan cohort (P < 0.001). CONCLUSIONS: Our results show that PNPLA3 148M carriers with IBD have higher susceptibility to hepatic steatosis and liver damage