Search

PDF file - 1496K, Supplementary Methods; Supplementary Figure 1: Production and characterisation of tumor cells dependent on Bcr-Abl for survival; Supplementary Figure 2: HDACi with different isoform specificities induce apoptosis of Bcr-Abl(p210) expressing cells; Supplementary Figure 3: Knockdown of HDAC6 does not induce the acetylation of histones or affect sensitivity to HDAC inhibitors; Supplementary Table 1: HDACi selectively inhibit a range of different HDACs; Supplementary Table 2: Pharmacokinetic analysis of vorinostat and MRLB-223; Supplementary Table 3: FDG uptake was measured at different times in the same animals using region of interest software (ROI) on the PET.

Histone deacetylase inhibitors (HDACi) are anticancer agents that induce hyperacetylation of histones, resulting in chromatin remodeling and transcriptional changes. In addition, nonhistone proteins, such as the chaperone protein Hsp90, are functionally regulated through hyperacetylation mediated by HDACis. Histone acetylation is thought to be primarily regulated by HDACs 1, 2, and 3, whereas the acetylation of Hsp90 has been proposed to be specifically regulated through HDAC6. We compared the molecular and biologic effects induced by an HDACi with broad HDAC specificity (vorinostat) with agents that predominantly inhibited selected class I HDACs (MRLB-223 and romidepsin). MRLB-223, a potent inhibitor of HDACs 1 and 2, killed tumor cells using the same apoptotic pathways as the HDAC 1, 2, 3, 6, and 8 inhibitor vorinostat. However, vorinostat induced histone hyperacetylation and killed tumor cells more rapidly than MRLB-223 and had greater therapeutic efficacy in vivo. FDCP-1 cells dependent on the Hsp90 client protein Bcr-Abl for survival, were killed by all HDACis tested, concomitant with caspase-dependent degradation of Bcr-Abl. These studies provide evidence that inhibition of HDAC6 and degradation of Bcr-Abl following hyperacetylation of Hsp90 is likely not a major mechanism of action of HDACis as had been previously posited. Mol Cancer Ther; 12(12); 2709–21. ©2013 AACR.

PDF file - 29K, Supplementary Figure 7. Tumor-bearing WT mice lacking CD4+, CD8+ and/or NK cells or perforin respond successfully to vorinostat treatment.

PDF file - 23K, Supplementary Figure 2. Rag-2γc-/- mice are not susceptible to drug-mediated toxicity and Eeta-myc cells do not develop resistance to vorinostat.

PDF file - 138K

PDF file - 66K, Supplementary Figure 3. IFN-gammaR-/- mice are resistant to the growth of transplanted lymphoma due to high levels of serum IFN-gamma.

PDF file - 428K, Supplementary Figure 6. Depletion of immune cell subsets with mAb is successful in tumor-bearing WT mice.

PDF file - 52K, Median survival and statistical analysis of the therapeutic efficacy of HDACi in WT and immunocompromised mice.

Cell-intrinsic effects such as induction of apoptosis and/or inhibition of cell proliferation have been proposed as the major antitumor responses to histone deacetylase inhibitors (HDACi). These compounds can also mediate immune-modulatory effects that may contribute to their anticancer effects. However, HDACi can also induce anti-inflammatory, and potentially immunosuppressive, outcomes. We therefore sought to clarify the role of the immune system in mediating the efficacy of HDACi in a physiologic setting, using preclinical, syngeneic murine models of hematologic malignancies and solid tumors. We showed an intact immune system was required for the robust anticancer effects of the HDACi vorinostat and panobinostat against a colon adenocarcinoma and two aggressive models of leukemia/lymphoma. Importantly, although HDACi-treated immunocompromised mice bearing established lymphoma succumbed to disease significantly earlier than tumor bearing, HDACi-treated wild-type (WT) mice, treatment with the conventional chemotherapeutic etoposide equivalently enhanced the survival of both strains. IFN-γ and tumor cell signaling through IFN-γR were particularly important for the anticancer effects of HDACi, and vorinostat and IFN-γ acted in concert to enhance the immunogenicity of tumor cells. Furthermore, we show that a combination of vorinostat with α-galactosylceramide (α-GalCer), an IFN-γ–inducing agent, was significantly more potent against established lymphoma than vorinostat treatment alone. Intriguingly, B cells, but not natural killer cells or CD8+ T cells, were implicated as effectors of the vorinostat antitumor immune response. Together, our data suggest HDACi are immunostimulatory during cancer treatment and that combinatorial therapeutic regimes with immunotherapies should be considered in the clinic. Cancer Res; 73(24); 7265–76. ©2013 AACR.

PDF file - 92K, Supplementary Figure 4. Eμ-myc cells expressing a mutated IFN-gammaR respond to vorinostat by not IFN-gamma, and proliferation of Eμ-myc cells is not effected by IFN-gamma.

PDF file - 164K, Supplementary Figure 5. IFN-gamma and vorinostat act in concert to enhance tumor cell imunogenicity.

PDF file - 25K, Supplementary Figure 1. Vorinostat treatment of MC38 cells induces hallmarks of immunogenic cell death.

BACKGROUND: Optimization of nutritional status is recommended in patients with cystic fibrosis (CF) given the association between lower body mass index (BMI) and poor clinical outcomes. However, higher BMI and body fat correlate with glucose impairment and higher leptin levels in the general population. Differences in body composition and leptin levels between the categories of glucose tolerance were assessed in youth with CF and healthy controls. METHODS: In a cross-sectional study, 59 adolescents and young adults with CF and 15 healthy controls matched by age and gender, underwent body composition analysis using dual energy X-ray absorptiometry (DXA) and a 2-hour oral glucose tolerance test (OGTT). Measures of insulin sensitivity, β-cell insulin secretion and fasting leptin levels were obtained. RESULTS: Of the participants with CF, 62% were classified as abnormal glucose tolerant and 22% with cystic fibrosis related diabetes (CFRD). Patients with CFRD had a lower fat mass index (FMI) z-score, wt z-score and leptin levels compared to the control group (−1.86 vs. - 0.59, p=0.01; −1.86 vs 0.44, p=

Background: To date, no study has been performed on the relationship between depression and perimenopausal symptoms using the Path model in Iran. Objective: This study aims to assess the relationship between depression and menopause symptoms using the PATH model. Methods: A cross-sectional study was conducted for 4 months, in 2019, and 332 menopausal women were enrolled in 14 public health centers. Data collection instruments included questionnaires of demographic characteristics, anxiety instrument, Menopause Rating Scale, and the Beck Depression short Inventory (BDI-S). The hypothesized mediators were assessed using Structural Equation Modeling (SEM). The model included depression symptoms (dependent variable), anxiety (mediators), number of alive children (moderator), and menopausal symptoms (independent variable). Analyses were conducted by SPSS 16 and AMOS 20. Results: There was a significant positive correlation between menopause symptoms with total anxiety (Rs=0.52), state anxiety (Rs=0.47), trait anxiety (Rs=0.46), and depression (Rs=0.54). Depression had a significant positive correlation with total anxiety (Rs=0.64), trait anxiety (Rs=0.58), and state anxiety (Rs=0.59). Also, the total mediating effect of total anxiety and depression and the total moderating effect of the number of alive children were significant on menopause symptoms. Conclusion: According to the results of the present study, there is an association between depression and menopausal symptoms. Therefore, health providers should pay more attention to the psychological health of women during the perimenopausal period. The predictor factors should be considered in both intervention and clinical assessment of menopause women.

The RD53B chip for HL-LHC upgrades of ATLAS and CMS pixel detectors needs to provide reliable operation in a radiation hostile environment with inevitable Single Event Effects (SEE). To answer the challenge, substantial efforts are made to protect and evaluate the critical parts of the digital logic and to characterize the on-chip Clock and Data Recovery (CDR) circuit. The SEE sensitivity of the digital logic is evaluated by testing with both heavy-ions and protons. The on-chip CDR is characterized by measuring the SEE-induced phase shifts of its output clocks and their implication on the high-speed link stability.

BACKGROUND MiR-371a-3p predicts the presence of a macroscopic non-teratomatous germ cell tumour (GCT). We hypothesised that miR-371a-3p can also detect recurrence during active surveillance (AS) of stage I GCT. METHODS We prospectively collected serum samples of 33 men. Relative expression of serum miR-371a-3p levels was determined at each follow-up visit using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS Recurrence was detected using standard follow-up investigations in 10/33 patients (30%) after a median of 7 months. Directly after orchiectomy, miR-371a-3p levels were not elevated in any of the 15 patients with available post-orchiectomy samples. However, all ten recurring patients exhibited increasing miR-371a-3p levels during follow-up, while miR-371a-3p levels remained non-elevated in all but one patient without recurrence. MiR-371a-3p detected recurrences at a median of 2 months (range 0-5) earlier than standard follow-up investigations. CONCLUSIONS MiR-371a-3p levels immediately post orchiectomy are not predictive for recurrences and unfortunately cannot support decision-making for AS vs. adjuvant treatment. However, miR-371a-3p detects recurrences reliably and earlier than standard follow-up investigations. If this can be confirmed in larger cohorts, monitoring miR-371a-3p could replace surveillance imaging in seminomatous GCT and reduce the amount of imaging in non-seminomatous GCT. Earlier detection of disease recurrence may also reduce the overall treatment burden.

Objectives This study sought to establish worldwide and regional diagnostic reference levels (DRLs) and achievable administered activities (AAAs) for single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Background Reference levels serve as radiation dose benchmarks to compare individual laboratories against aggregated data, helping to identify sites in greatest need of dose reduction interventions. DRLs for SPECT MPI have previously been derived from national or regional registries. To date there have been no multiregional reports of DRLs for SPECT MPI from a single standardized dataset. Methods Data were submitted voluntarily to the INCAPS (International Atomic Energy Agency Nuclear Cardiology Protocols Study), a cross-sectional, multinational registry of MPI protocols. A total of 7,103 studies were included. DRLs and AAAs were calculated by protocol for each world region and for aggregated worldwide data. Results The aggregated worldwide DRLs for rest-stress or stress-rest studies employing technetium Tc 99m–labeled radiopharmaceuticals were 11.2 mCi (first dose) and 32.0 mCi (second dose) for 1-day protocols, and 23.0 mCi (first dose) and 24.0 mCi (second dose) for multiday protocols. Corresponding AAAs were 10.1 mCi (first dose) and 28.0 mCi (second dose) for 1-day protocols, and 17.8 mCi (first dose) and 18.7 mCi (second dose) for multiday protocols. For stress-only technetium Tc 99m studies, the worldwide DRL and AAA were 18.0 mCi and 12.5 mCi, respectively. Stress-first imaging was used in 26% to 92% of regional studies except in North America where it was used in just 7% of cases. Significant differences in DRLs and AAAs were observed between regions. Conclusions This study reports reference levels for SPECT MPI for each major world region from one of the largest international registries of clinical MPI studies. Regional DRLs may be useful in establishing or revising guidelines or simply comparing individual laboratory protocols to regional trends. Organizations should continue to focus on establishing standardized reporting methods to improve the validity and comparability of regional DRLs.

Objectives This study sought to describe worldwide variations in the use of myocardial perfusion imaging hardware, software, and imaging protocols and their impact on radiation effective dose (ED). Background Concerns about long-term effects of ionizing radiation have prompted efforts to identify strategies for dose optimization in myocardial perfusion scintigraphy. Studies have increasingly shown opportunities for dose reduction using newer technologies and optimized protocols. Methods Data were submitted voluntarily to the INCAPS (International Atomic Energy Agency Nuclear Cardiology Protocols Study) registry, a multinational, cross-sectional study comprising 7,911 imaging studies from 308 labs in 65 countries. The study compared regional use of camera technologies, advanced post-processing software, and protocol characteristics and analyzed the influence of each factor on ED. Results Cadmium-zinc-telluride and positron emission tomography (PET) cameras were used in 10% (regional range 0% to 26%) and 6% (regional range 0% to 17%) of studies worldwide. Attenuation correction was used in 26% of cases (range 10% to 57%), and advanced post-processing software was used in 38% of cases (range 26% to 64%). Stress-first single-photon emission computed tomography (SPECT) imaging comprised nearly 20% of cases from all world regions, except North America, where it was used in just 7% of cases. Factors associated with lower ED and odds ratio for achieving radiation dose ≤9 mSv included use of cadmium-zinc-telluride, PET, advanced post-processing software, and stress- or rest-only imaging. Overall, 39% of all studies (97% PET and 35% SPECT) were ≤9 mSv, while just 6% of all studies (32% PET and 4% SPECT) achieved a dose ≤3 mSv. Conclusions Newer-technology cameras, advanced software, and stress-only protocols were associated with reduced ED, but worldwide adoption of these practices was generally low and varied significantly between regions. The implementation of dose-optimizing technologies and protocols offers an opportunity to reduce patient radiation exposure across all world regions.

Peer counseling programs are increasingly popular, and intervention trials have established efficacy. However, pragmatic, real-world effectiveness of peer counseling programs are limited, but necessary, to justify funding. This study examined the effectiveness of the Loving Support Peer Counseling (LSPC) program to increase breastfeeding duration and reasons for cessation among Women, Infants, and Children (WIC) participants. In a sample of 178 WIC participants, new mothers who received LSPC breastfed for an average of 8.6 weeks longer relative to mothers who did not receive LSPC (p < .001). Although all mothers cited concerns about infants'’ nutritional uptake, WIC mothers who did not receive LSPC reported frustration as the reason for breastfeeding cessation. This study supports the pragmatic, real-world effectiveness of LSPC among WIC mothers.

OBJECTIVE: To determine prevalence, incidence proportion, and changes of urinary incontinence (UI) 10-13 years after hysterectomy compared to two control groups.STUDY DESIGN: A longitudinal cohort study of 661 women with follow-up for ten years. Originally, 866 women answered a questionnaire on continence status preoperatively. Ten years postoperatively the queries were repeated in 371 with a hysterectomy, 89 with laparoscopic cholecystectomy (LC), and 201 with transcervical endometrial resection (TCRE). Significant incontinence was UI at least once a week. The main outcome measures were prevalence and incidence proportions of UI.RESULTS: The overall prevalence of stress UI ten years after surgery was 23% compared to 12% preoperatively. Urge UI was prevalent in 12% compared to 5% preoperatively. Incidence proportions of stress UI were in hysterectomies 21%, in LC 15%, and in TCRE 18%. Similarly, incidence proportions of urge UI were in hysterectomies 11%, in LC 11%, and in TCRE 8%. No significant differences between surgical procedures were found; however, we found substantial amount of changes in continence status from continent to incontinent and vice versa in all three groups.CONCLUSIONS: No significant difference was found after hysterectomy compared to controls in the prevalence or incidence proportions of UI after 10 years follow-up. Hysterectomy is not a risk factor of UI.

Background. Strictures are a common complication in Crohn’s disease (CD), found in more than 50% of patients. They are characterized by the excessive deposition of extracellular proteins in the tissue as a result of the chronic inflammatory process. The effect of anti-tumor necrosis factor alpha (TNF-α) therapy on the development of fibrosis is not yet fully understood. Aim. To investigate whether the degree of intestinal inflammation and fibrosis is correlated with preoperative anti-TNF-α therapy in patients with CD who are undergoing bowel resection. Methods. This unblinded, prospective, single tertiary center, pilot cohort study included all adult patients with CD who underwent elective, laparoscopic, or open intestinal resection. Preoperative investigations included measurement of blood TNF-α concentration, specific antidrug antibodies, and the concentration of selected inflammatory cytokines. Three pathologists independently examined the specimens and assessed the degree of inflammation and fibrosis. Results. Histopathological specimens from 10 patients with CD who underwent ileocecal or ileocolic resections were retrieved. Four of those patients were on anti-TNF-α treatment prior to surgery. The last dose of the anti-TNF-α agent was administered 1–9 weeks prior to bowel resection. Patients on anti-TNF-α treatment had a higher fibrosis score than controls (p=0.01). Anti-TNF-α treatment was not associated with an increase in CD68- or CD163-positive macrophages. There was no significant relationship between the time from the final preoperative anti-TNF-α dose to surgery and the fibrosis score. No significant association was found between the concentration of major inflammatory cytokines, including TNF-α, and the fibrosis score or degree of inflammation. Conclusions. Patients who underwent preoperative anti-TNF-α treatment had a higher fibrosis score than controls.

The Model-Based Archaeology of Socionatural Systems. T. A. Kohler, & S. Van der Leeuw (eds.), Santa Fe: School of Advanced Research, 2007: 175-208

The paper describes the basic principles and considerations used in modeling for evaluation and scale-up of steam reforming technology. The complicated interaction between catalyst, heat transfer and pressure drop is necessary to know and fully understand when reactors are designed. Although formulated more than 50 years ago, the two-dimensional heterogeneous reactor model forms the basis. But today’s highly integrated reactor designs and optimization of catalyst shapes require a detailed understanding of the complicated flow patterns in steam reforming reactors and this requires use of computational fluid dynamics. This challenges the correctness of the basic key correlations for kinetics, heat and mass transfer and pressure drop. Model evaluation requires fitting of parameters to reconciled process data, but discrimination among different rigorous reactor models is difficult due to the limited number of measurements in the reactor.

Vascular endothelial growth factor-C (VEGF-C)-induced lymphangiogenesis and increased tissue drainage have been reported to inhibit acute and chronic inflammation, and an activated lymphatic endothelium might mediate peripheral tolerance. Using transgenic mice overexpressing VEGF-C in the skin, we found that under inflammatory conditions, VEGF-C-mediated expansion of the cutaneous lymphatic network establishes an immune-inhibitory microenvironment characterised by increased regulatory T (Treg) cells, immature CD11c+CD11b+ dendritic cells (DCs) and CD8+ cells exhibiting decreased effector function. Strikingly, lymphatic endothelial cell (LEC)-conditioned media (CM) potently suppress DC maturation with reduced expression of MHCII, CD40, and IL-6, and increased IL-10 and CCL2 expression. We identify an imbalance in prostaglandin synthase expression after LEC activation, favoring anti-inflammatory prostacyclin synthesis. Importantly, blockade of LEC prostaglandin synthesis partially restores DC maturity. LECs also produce TGF-ß1, contributing to the immune-inhibitory microenvironment. This study identifies novel mechanisms by which the lymphatic endothelium modulates cellular immune responses to limit inflammation., Oncotarget, 7 (26), ISSN:1949-2553

Objectives The aim of this study was to investigate gender-based differences in nuclear cardiology practice globally, with a particular focus on laboratory volume, radiation dose, protocols, and best practices. Background It is unclear whether gender-based differences exist in radiation exposure for nuclear cardiology procedures. Methods In a large, multicenter, observational, cross-sectional study encompassing 7,911 patients in 65 countries, radiation effective dose was estimated for each examination. Patient-level best practices relating to radiation exposure were compared between genders. Analysis of covariance was used to determine any difference in radiation exposure according to gender, region, and the interaction between gender and region. Linear, logistic, and hierarchical regression models were developed to evaluate gender-based differences in radiation exposure and laboratory adherence to best practices. The study also included the United Nations Gender Inequality Index and Human Development Index as covariates in multivariable models. Results The proportion of myocardial perfusion imaging studies performed in women varied among countries; however, there was no significant correlation with the Gender Inequality Index. Globally, mean effective dose for nuclear cardiology procedures was only slightly lower in women (9.6 ± 4.5 mSv) than in men (10.3 ± 4.5 mSv; p Conclusions Despite significant worldwide variation in best practice use and radiation doses from nuclear cardiology procedures, only small differences were observed between genders worldwide. Regional variations noted in myocardial perfusion imaging use and radiation dose offer potential opportunities to address gender-related differences in delivery of nuclear cardiology care.

Thirty five patients were transferred to Royal Perth Hospital (RPH) after the Bali bombings. The patients had severe burn injuries and were considered to be at high-risk of both the carriage and acquisition of multi-resistant organisms (MROs). Whilst seeking to protect the Bali patients with a comprehensive infection control response, we also sought to protect other high-risk patients from nosocomial acquisition of MROs. MROs were detected from 25 (82%) of the 29 Bali patients admitted to RPH. Bali patients were colonised, or infected, with one or more of the following MROs: multi-resistant Acinetobacter baumannii (MRAB) (19 patients), extended-spectrum s-lactamase (ESBL) producing Gram-negative bacteria (15 patients), vancomycin-resistant enterococci (VRE) (nine patients), multi-resistant Pseudomonas aeruginosa (MRPA) (six patients), multi-resistant Chryseobacterium sp. (four patients), and methicillin-resistant Staphylococcus aureus (MRSA) (three patients). Five Bali patients developed a total of eight bacteraemic episodes, with MRPA sepsis contributing to death in two patients. Since the Bali bombings horizontal transmission of Bali MROs has occurred in 41 non-Bali patients in RPH. MRPA has had the greatest clinical impact. Eight non-Bali patients developed a total of 11 bacteraemic episodes, with MRPA sepsis contributing to death in four patients. However, apart from MRPA, we have now controlled transmission of the other MROs in RPH. The emergency response to the Bali disaster required strong leadership, good communication and multi-disciplinary teamwork. The infection control strategy contributed to good outcomes for most Bali bombing patients. However, many patients within the Bali cohort were heavily colonised with MROs, and some developed invasive infection. Subsequent nosocomial transmission of these MROs to non-Bali patients has been a legacy of the Bali tragedy.

Background Strictures are a common complication in Crohn’s disease (CD), which are found in more than 50% of the patients. They are characterised by excessive deposition of extracellular proteins in the tissue as a result of the chronic inflammatory process. The effect of anti- TNF-α therapy on the development of fibrosis is not yet fully understood. The aim of the study was to investigate whether the degree of intestinal inflammation and fibrosis correlates with pre-operative anti-TNF-α therapy in patients with Crohn’s disease undergoing bowel resection. Methods This is an unblinded, prospective, multicentre cohort pilot study. All adult patients with Crohn’s disease, who underwent elective, laparoscopic or open intestinal resection were included. Pre-operative blood investigations included measurement of TNF- α concentration and specific drug antibodies in addition to the concentration of selected inflammatory cytokines. Three pathologists examined the specimens independently and assessed the degree of inflammation and fibrosis. Results Histopathological specimens from 10 patients with CD who underwent ileocecal or ileocolic resections were retrieved. Four of those patients were on anti-TNF-α treatment pre-operatively. The last dose of anti-TNF-α agents was administered within 1–9 weeks prior to bowel resection. Patients on anti-TNF-α treatment had higher fibrosis score than the controls (p = 0.01). Anti-TNF-α treatment was not associated with an increase in either CD68 or CD163-positive macrophages. There was no significant relationship between time from last anti-TNF-α dose to surgery, and fibrosis score. No significant association between the concentration of major inflammatory cytokines including TNF-α and fibrosis score or degree of inflammation was found. Conclusion Patients on anti-TNF-α treatment had higher fibrosis score than the controls.

Anisamide is a small benzamide previously suggested as a tumor-targeting ligand for nanocarriers and it has been shown to enhance tumor uptake in vitro as well as in vivo when grafted on the nanoparticle surface. Anisamide has been hypothesized to interact with the Sigma-1 receptor, based on the binding of larger benzamides, which contain anisamide in their structure, to this receptor. However, the interaction between anisamide and Sigma-1 receptor has never been thoroughly studied. We developed fluorescent PEGylated particles decorated with anisamide, which were preferentially taken up in vitro by melanoma cells compared to macrophages. The anisamide-decorated particles were used to study their interaction with the Sigma-1 receptor. The absence of competition of Sigma-1 receptor ligands for the particle uptake was a first indication that the receptor might not be involved in the uptake process. In addition, the extent of particle uptake did not correlate with the levels of cellular expression of Sigma-1 receptor in the cell models tested. Immunostaining of the receptor on melanoma cells revealed intracellular localization, indirectly excluding the possibility of anisamide binding to the receptor when grafted on the particles. All these data question the previously suggested Sigma-1 receptor-mediated uptake of the anisamide-decorated particles, a finding which may have an impact on the use of anisamide as a targeting ligand.