Radiation Damage Studies of Silicon Photomultipliers

We report on the measurement of the radiation hardness of silicon photomultipliers (SiPMs) manufactured by Fondazione Bruno Kessler in Italy (1 mm$^2$ and 6.2 mm$^2$), Center of Perspective Technology and Apparatus in Russia (1 mm$^2$ and 4.4 mm$^2$), and Hamamatsu Corporation in Japan (1 mm$^2$). The SiPMs were irradiated using a beam of 212 MeV protons at Massachusetts General Hospital, receiving fluences of up to $3 \times 10^{10}$ protons per cm$^2$ with the SiPMs at operating voltage. Leakage currents were read continuously during the irradiation. The delivery of the protons was paused periodically to record scope traces in response to calibrated light pulses to monitor the gains, photon detection efficiencies, and dark counts of the SiPMs. The leakage current and dark noise are found to increase with fluence. Te leakage current is found to be proportional to the mean square deviation of the noise distribution, indicating the dark counts are due to increased random individual pixel activation, while SiPMs remain fully functional as photon detectors. The SiPMs are found to anneal at room temperature with a reduction in the leakage current by a factor of 2 in about 100 days.Comment: 35 pages, 25 figure

Iron causes lipid oxidation and inhibits proteasome function in multiple myeloma cells: A proof of concept for novel combination therapies

Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk*MYC mice, addition of iron dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies

Quantum dot labeling of mesenchymal stem cells

<p>Abstract</p> <p>Background</p> <p>Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into bone, cartilage, fat and muscle cells and are being investigated for their utility in cell-based transplantation therapy. Yet, adequate methods to track transplanted MSCs <it>in vivo </it>are limited, precluding functional studies. Quantum Dots (QDs) offer an alternative to organic dyes and fluorescent proteins to label and track cells <it>in vitro </it>and <it>in vivo</it>. These nanoparticles are resistant to chemical and metabolic degradation, demonstrating long term photostability. Here, we investigate the cytotoxic effects of <it>in vitro </it>QD labeling on MSC proliferation and differentiation and use as a cell label in a cardiomyocyte co-culture.</p> <p>Results</p> <p>A dose-response to QDs in rat bone marrow MSCs was assessed in Control (no-QDs), Low concentration (LC, 5 nmol/L) and High concentration (HC, 20 nmol/L) groups. QD yield and retention, MSC survival, proinflammatory cytokines, proliferation and DNA damage were evaluated in MSCs, 24 -120 hrs post QD labeling. In addition, functional integration of QD labeled MSCs in an <it>in vitro </it>cardiomyocyte co-culture was assessed. A dose-dependent effect was measured with increased yield in HC vs. LC labeled MSCs (93 ± 3% vs. 50% ± 15%, p < 0.05), with a larger number of QD aggregates per cell in HC vs. LC MSCs at each time point (p < 0.05). At 24 hrs >90% of QD labeled cells were viable in all groups, however, at 120 hrs increased apoptosis was measured in HC vs. Control MSCs (7.2% ± 2.7% vs. 0.5% ± 0.4%, p < 0.05). MCP-1 and IL-6 levels doubled in HC MSCs when measured 24 hrs after QD labeling. No change in MSC proliferation or DNA damage was observed in QD labeled MSCs at 24, 72 and 120 hrs post labeling. Finally, in a cardiomyocyte co-culture QD labeled MSCs were easy to locate and formed functional cell-to-cell couplings, assessed by dye diffusion.</p> <p>Conclusion</p> <p>Fluorescent QDs label MSC effectively in an <it>in vitro </it>co-culture model. QDs are easy to use, show a high yield and survival rate with minimal cytotoxic effects. Dose-dependent effects suggest limiting MSC QD exposure.</p

Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli

PURPOSE: Recent in vitro studies suggested that the autocrine leptin loop might contribute to breast cancer development by enhancing cell growth and survival. To evaluate whether the leptin system could become a target in breast cancer therapy, we examined the expression of leptin and its receptor (ObR) in primary and metastatic breast cancer and noncancer mammary epithelium. We also studied whether the expression of leptin/ObR in breast cancer can be induced by obesity-related stimuli, such as elevated levels of insulin, insulin-like growth factor-I (IGF-I), estradiol, or hypoxic conditions. EXPERIMENTAL DESIGN: The expression of leptin and ObR was examined by immunohistochemistry in 148 primary breast cancers and 66 breast cancer metastases as well as in 90 benign mammary lesions. The effects of insulin, IGF-I, estradiol, and hypoxia on leptin and ObR mRNA expression were assessed by reverse transcription-PCR in MCF-7 and MDA-MB-231 breast cancer cell lines. RESULTS: Leptin and ObR were significantly overexpressed in primary and metastatic breast cancer relative to noncancer tissues. In primary tumors, leptin positively correlated with ObR, and both biomarkers were most abundant in G3 tumors. The expression of leptin mRNA was enhanced by insulin and hypoxia in MCF-7 and MDA-MB-231 cells, whereas IGF-I and estradiol stimulated leptin mRNA only in MCF-7 cells. ObR mRNA was induced by insulin, IGF-I, and estradiol in MCF-7 cells and by insulin and hypoxia in MDA-MB-231 cells. CONCLUSIONS: Leptin and ObR are overexpressed in breast cancer, possibly due to hypoxia and/or overexposure of cells to insulin, IGF-I, and/or estradiol

Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans

Rationale: Air pollution has been associated with increased prevalence of type 2 diabetes; however, the mechanisms remain unknown. We have shown that acute ozone exposure in rats induces release of stress hormones, hyperglycemia, leptinemia, and glucose intolerance that are associated with global changes in peripheral glucose, lipid, and amino acid metabolism

Vibrotactile adaptation fails to enhance spatial localization in adults with autism

A recent study (Tannan et al., 2006) showed that pre-exposure of a skin region to a 5 sec 25 Hz flutter stimulus (“adaptation”) results in an approximately 2-fold improvement in the ability of neurologically healthy human adults to localize mechanical stimulation delivered to the same skin region that received the adapting stimulation. Tannan et al. (Tannan et al., 2006) proposed that tactile spatial discriminative performance is improved following adaptation because adaptation is accompanied by an increase in the spatial contrast in the response of contralateral primary somatosensory cortex (SI) to mechanical skin stimulation – an effect identified in previous imaging studies of SI cortex in anesthetized non-human primates (e.g., Simons et al., 2005; Tommerdahl et al., 2002; Whitsel et al., 1989)

Pediatric Visceral Leishmaniasis in Albania: A Retrospective Analysis of 1,210 Consecutive Hospitalized Patients (1995–2009)

Albania is a developing country that is rapidly improving in social, economic and sanitary conditions. The health care system in still in progress and the impact of some infectious diseases remains poorly understood. In particular, little information is available on incidence, clinical features and response to treatment of visceral leishmaniasis (VL) in childhood. We performed a retrospective analysis of data recorded from 1995 to 2009 at the national pediatric reference hospital of Tirana where any child suspected for VL is referred for specific diagnosis and treatment. Epidemiology, clinical features and management of the disease were considered. The main findings can be summarized as follows: i) The incidence of the disease in Albanian children (25/100,000 in the age group 0–6 years) is much higher than in developed Mediterranean countries endemic for VL; ii) The disease is associated with poor sanitary conditions as suggested by the high rate of severe clinical features and frequency of co-morbidities; iii) The cheapest drug available for Mediterranean VL treatment (meglumine antimoniate) is highly effective (99% full cure rate) and well tolerated. Limitations were identified in the low standard laboratory diagnostic capability and unsatisfactory medical surveillance in less urbanized areas. An improvement is warranted of a disease-specific surveillance system in Albania

Epidemiology and pattern of resistance of gram-negative bacteria isolated from blood samples in hospitalized patients: A single center retrospective analysis from southern italy

Background: Blood culturing remains the mainstream tool to inform an appropriate treatment in hospital-acquired bloodstream infections and to diagnose any bacteremia. Methods: A retrospective investigation on the prevalence of Gram-negative bacteria (GNB) and their resistance in hospitalized patients by age, sex, and units from blood cultures (BCs) was conducted from January 2018 to April 2020 at Sant’Elia hospital, Caltanissetta, southern Italy. We divided the patient age range into four equal intervals. Results: Multivariate demographic and microbiological variables did not show an association between bacteria distributions and gender and age. The distribution by units showed a higher prevalence of Klebsiella pneumoniae and Acinetobacter baumannii in the intensive care unit (ICU) and Escherichia coli in the non-intensive care units (non-ICUs). The analysis of antibiotic resistance showed that E. coli was susceptible to a large class of antibiotics such as carbapenem and trimethoprim-sulfamethoxazole. K. pneumoniae showed a significant susceptibility to colistin, tigecycline, and trimethoprim-sulfamethoxazole. From the survival analysis, patients with E. coli had a higher survival rate. Conclusions: The authors stress the importance of the implementation of large community-level programs to prevent E. coli bacteremia. K. pneumoniae and E. coli susceptibility patterns to antibiotics, including in the prescription patterns of general practitioners, suggest that the local surveillance and implementation of educational programs remain essential measures to slow down the spread of resistance and, consequently, increase the antibiotic lifespan

Potential Added Value of Psychological Capital in Predicting Work Attitudes

Meeting the challenge of effectively managing human resources requires new thinking and approaches. To extend the traditional perspective of economic capital, increasing recognition is being given to human capital and more recently social capital, this article proposes and empirically tests the potential added value that psychological capital may have for employee attitudes of satisfaction and commitment. After first providing the background and theory of PsyCap, this article reports a study of manufacturing employees (N = 74) that found a significant relationship between PsyCap and job satisfaction (r=.373) and organization commitment (r=.313). Importantly, the employees’ PsyCap had a significant added impact over human and social capital on these work attitudes. Future research and practical implications conclude the article

The effects of user characteristics on query performance in the presence of information request ambiguity

This paper investigates the effects of personality characteristics on individuals' abilities to compose queries from information requests containing various types of ambiguity. In particular, this research examines the effects of user personality characteristics on query performance in the presence of information requests that contained no extraneous, syntactic, or both extraneous and syntactic ambiguities. The results indicate that personality characteristics significantly affect users' abilities to compose accurate queries. Neuroticism, agreeableness, openness to experience, and conscientiousness significantly affected the number of errors made in the query formulations. Conscientiousness affected the length of time taken to compose the queries and neuroticism affected the confidence users had in the accuracy of their queries. Although several personality dimensions affected query performance, no significant interactions between personality dimensions and ambiguity were detected. Furthermore, both query complexity and information request ambiguity exhibited greater impacts on query performance than personality characteristics. Hence, organizations should attempt to train users to deal with query complexity and information request ambiguity before modifying their training programs for personality characteristics