The PPARα agonist fenofibrate suppresses B-cell lymphoma in mice by modulating lipid metabolism

AbstractObesity is associated with an increased risk for malignant lymphoma development. We used Bcr/Abl transformed B cells to determine the impact of aggressive lymphoma formation on systemic lipid mobilization and turnover. In wild-type mice, tumor size significantly correlated with depletion of white adipose tissues (WAT), resulting in increased serum free fatty acid (FFA) concentrations which promote B-cell proliferation in vitro. Moreover, B-cell tumor development induced hepatic lipid accumulation due to enhanced hepatic fatty acid (FA) uptake and impaired FA oxidation. Serum triglyceride, FFA, phospholipid and cholesterol levels were significantly elevated. Consistently, serum VLDL/LDL-cholesterol and apolipoprotein B levels were drastically increased. These findings suggest that B-cell tumors trigger systemic lipid mobilization from WAT to the liver and increase VLDL/LDL release from the liver to promote tumor growth. Further support for this concept stems from experiments where we used the peroxisome proliferator-activated receptor α (PPARα) agonist and lipid-lowering drug fenofibrate that significantly suppressed tumor growth independent of angiogenesis and inflammation. In addition to WAT depletion, fenofibrate further stimulated FFA uptake by the liver and restored hepatic FA oxidation capacity, thereby accelerating the clearance of lipids released from WAT. Furthermore, fenofibrate blocked hepatic lipid release induced by the tumors. In contrast, lipid utilization in the tumor tissue itself was not increased by fenofibrate which correlates with extremely low expression levels of PPARα in B-cells. Our data show that fenofibrate associated effects on hepatic lipid metabolism and deprivation of serum lipids are capable to suppress B-cell lymphoma growth which may direct novel treatment strategies. This article is part of a Special Issue entitled Lipid Metabolism in Cancer

Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer

Background: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Previous findings from small-scale studies revealed conflicting results about its independent prognostic significance with regard to different clinical end points in pancreatic cancer (PC) patients. Therefore, the aim of our study was the external validation of the prognostic significance of NLR in a large cohort of PC patients. Methods: Data from 371 consecutive PC patients, treated between 2004 and 2010 at a single centre, were evaluated retrospectively. The whole cohort was stratified into two groups according to the treatment modality. Group 1 comprised 261 patients with inoperable PC at diagnosis and group 2 comprised 110 patients with surgically resected PC. Cancer-specific survival (CSS) was assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of the NLR, the modified Glasgow prognostic score (mGPS) and the platelet-lymphocyte ratio univariate and multivariate Cox regression models were applied. Results: Multivariate analysis identified increased NLR as an independent prognostic factor for inoperable PC patients (hazard ratio (HR)=2.53, confidence interval (CI)=1.64–3.91, P<0.001) and surgically resected PC patients (HR=1.61, CI=1.02–2.53, P=0.039). In inoperable PC patients, the mGPS was associated with poor CSS only in univariate analysis (HR=1.44, CI=1.04–1.98). Conclusion: Risk prediction for cancer-related end points using NLR does add independent prognostic information to other well-established prognostic factors in patients with PC, regardless of the undergoing therapeutic modality. Thus, the NLR should be considered for future individual risk assessment in patients with PC

Whole-genome characterization of myoepithelial carcinomas of the soft tissue

Myoepithelial carcinomas (MECs) of soft tissue are rare and aggressive tumors affecting young adults and children, but their molecular landscape has not been comprehensively explored through genome sequencing. Here, we present the whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing findings of two MECs. Patients 1 and 2 (P1, P2), both male, were diagnosed at 27 and 37 yr of age, respectively, with shoulder (P1) and inguinal (P2) soft tissue tumors. Both patients developed metastatic disease, and P2 died of disease. P1 tumor showed a rhabdoid cytomorphology and a complete loss of INI1 (SMARCB1) expression, associated with a homozygous SMARCB1 deletion. The tumor from P2 showed a clear cell/small cell morphology, retained INI1 expression and strong S100 positivity. By WES and WGS, tumors from both patients displayed low tumor mutation burdens, and no targetable alterations in cancer genes were detected. P2's tumor harbored an EWSR1::KLF15 rearrangement, whereas the tumor from P1 showed a novel ASCC2::GGNBP2 fusion. WGS evidenced a complex genomic event involving mainly Chromosomes 17 and 22 in the tumor from P1, which was consistent with chromoplexy. These findings are consistent with previous reports of EWSR1 rearrangements (50% of cases) in MECs and provide a genetic basis for the loss of SMARCB1 protein expression observed through immunohistochemistry in 10% of 40% of MEC cases. The lack of additional driver mutations in these tumors supports the hypothesis that these alterations are the key molecular events in MEC evolution. Furthermore, the presence of complex structural variant patterns, invisible to WES, highlights the novel biological insights that can be gained through the application of WGS to rare cancers

Loss of adipose triglyceride lipase is associated with human cancer and induces mouse pulmonary neoplasia

Metabolic reprogramming is a hallmark of cancer. Understanding cancer metabolism is instrumental to devise innovative therapeutic approaches. Anabolic metabolism, including the induction of lipogenic enzymes, is a key feature of proliferating cells. Here, we report a novel tumor suppressive function for adipose triglyceride lipase (ATGL), the rate limiting enzyme in the triglyceride hydrolysis cascade. In immunohistochemical analysis, non-small cell lung cancers, pancreatic adenocarcinoma as well as leiomyosarcoma showed significantly reduced levels of ATGL protein compared to corresponding normal tissues. The ATGL gene was frequently deleted in various forms of cancers. Low levels of ATGL mRNA correlated with significantly reduced survival in patients with ovarian, breast, gastric and non-small cell lung cancers. Remarkably, pulmonary neoplasia including invasive adenocarcinoma developed spontaneously in mice lacking ATGL pointing to an important role for this lipase in controlling tumor development. Loss of ATGL, as detected in several forms of human cancer, induces spontaneous development of pulmonary neoplasia in a mouse model. Our results, therefore, suggest a novel tumor suppressor function for ATGL and contribute to the understanding of cancer metabolism. We propose to evaluate loss of ATGL protein expression for the diagnosis of malignant tumors. Finally, modulation of the lipolytic pathway may represent a novel therapeutic approach in the treatment of human cancer

Serotype Distribution and Drug Resistance in Streptococcus pneumoniae, Palestinian Territories

To determine antimicrobial drug resistance of Streptococcus pneumoniae serotypes, we analyzed isolates from blood cultures of sick children residing in the West Bank before initiation of pneumococcal vaccination. Of 120 serotypes isolated, 50.8%, 73.3%, and 80.8% of the bacteremia cases could have been prevented by pneumococcal conjugate vaccines. Serotype 14 was the most drug-resistant serotype isolated

Model-based specification of safety compliance needs for critical systems : A holistic generic metamodel

Abstract Context: Many critical systems must comply with safety standards as a way of providing assurance that they do not pose undue risks to people, property, or the environment. Safety compliance is a very demanding activity, as the standards can consist of hundreds of pages and practitioners typically have to show the fulfilment of thousands of safety-related criteria. Furthermore, the text of the standards can be ambiguous, inconsistent, and hard to understand, making it difficult to determine how to effectively structure and manage safety compliance information. These issues become even more challenging when a system is intended to be reused in another application domain with different applicable standards. Objective: This paper aims to resolve these issues by providing a metamodel for the specification of safety compliance needs for critical systems. Method: The metamodel is holistic and generic, and abstracts common concepts for demonstrating safety compliance from different standards and application domains. Its application results in the specification of “reference assurance frameworks” for safety-critical systems, which correspond to a model of the safety criteria of a given standard. For validating the metamodel with safety standards, parts of several standards have been modelled by both academic and industry personnel, and other standards have been analysed. We further augment this with feedback from practitioners, including feedback during a workshop. Results: The results from the validation show that the metamodel can be used to specify safety compliance needs for aerospace, automotive, avionics, defence, healthcare, machinery, maritime, oil and gas, process industry, railway, and robotics. Practitioners consider that the metamodel can meet their needs and find benefits in its use. Conclusion: The metamodel supports the specification of safety compliance needs for most critical computer-based and software-intensive systems. The resulting models can provide an effective means of structuring and managing safety compliance information

Emergence of Klebsiella pneumoniae Carbapenemase (blaKPC-2) in members of the Enterobacteriaceae family in Palestine

Abstract Background: The global spread of carbapenem resistant Enterobacteriaceae (CRE) has limited the physicians’ antimicrobial treatment options of infected patients. CRE’s which carry the Klebsiella pneumonia Carbapenemase (blaKPC) resistance mechanism have been rapidly spreading in many parts of the world, and have been responsible for high patients’ morbidity and mortality. Methods: Two protocols recommended by the Center for Disease Control and Prevention (CDC) were followed to detect CRE’s in Palestine. In addition, the antimicrobial sensitivity patterns for several antibiotic classes were determined for the isolated CRE’s by the disc diffusion method according to the clinical and laboratory standard institute (CLSI) M100-S22 guidelines. The Minimal Inhibitory Concentrations (MICs) of the carbapenem, ertapenem, imipenem and meropenem were determined for all the CRE’s by E-test. The isolates β-lactam resistance mechanisms were further investigated by analyzing 31 different types of β–lactamase genes by polymerase chain reaction (PCR). Results: Four bacterial isolates, 3 Enterobacter cloacae and 1 Klebsiella pneumoniae, were determined to be non-susceptible to one or all of the carbapenems (ertapenem, imipenem and meropenem) tested. All isolates which carried the blaKPC-2 gene showed an extreme drug resistance profile. These isolates were resistant to all β-lactam antibiotics, co-trimoxazole and gentamicin, while susceptible to only amikacin and colistin sulfate. Different combination of plasmid encoded b–lactamase genes (blaTEM, blaSHV, blaOXA-1, blaMIR-1, blaGES-23 and blaKPC-2) were present in these isolates. Of interest, was the isolation of the first E. cloacae strains co-producing the blaKPC-2 and a novel blaGES-23 β-lactamase. Conclusions: The presence of all these plasmid encoded b-lactamase in Palestine is alarming and mandates actions to be taken to control antibiotics usage and the activation of hospital infection control programs in order to prevent the spread of these extremely drug resistant bacteria