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

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

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

Evaluation of Meropenem, Imipenem and Ertapenem Impregnated MacConkey Agar Plates for the Detection of Carbapenem Resistant Enterobacteriaceae

Background: Rapid detection of carbapenem resistant bacteria, in particular, members of the Enterobacteriaceae family (CRE), is of utmost importance for the management of infected or colonized patients. Methods: Three carbapenems; meropenem, imipenem and ertapenem, with two different concentrations (0.5 mg/ml and 1.0 mg/ml), were impregnated in MacConkey agar. The carbapenem impregnated MacConkey agar plates; ([Mac-Mem], [Mac-Imp] and [Mac-Ert]), were then evaluated for the detection of carbapenem resistant Gram-negative bacteria in particular the blaKPC producing Enterobacteriaceae. The Limit of Detection (LOD) of the plates was determined after counting the colonies that grew on the plates after serial logarithmic dilutions of ten. Carbapenem resistant Gram-negative bacteria were prepared in normal saline, inoculated on the different plates and incubated at 35oC for 18-24 hours. The specificity and the shelf-life of the plates were determined by challenging the plates with six ESBL positive members of the Enterobacteriaceae family (K. pneumoniae, Salmonella species, Shigella species, E. coli, Proteus species and Citrobacter species) and one Enterobacter species with the blaAmpC phenotype. Finally, the MacConkey agar plates impregnated with 0.5 mg/ml meropenem were further challenged by incorporating them in the routine Caritas Baby Hospital active surveillance program for the detection of carbapenem resistant bacteria. Results: Of the three carbapenems impregnated plates, Mac-Ert plates gave the lowest number of colony forming units (CFU’s) detected regardless of the concentration of the antibiotic used. This was followed by the Mac-Mem plates which showed an LOD of less than 200 CFU’s for most of the blaKPC positive bacteria tested at both antibiotic concentrations. The worst performance was noted for the Mac-Imp plate regardless of the antibiotic concentration used as a number of carbapenem resistant bacterial strains failed to grow on the plate. The Mac-Mem plates showed the best specificity as none of the ESBL and blaAmpC positive isolates grew on the plates at either antibiotic concentration tested after 18-24hours incubation in ambient air at 35oC. On the other hand, the Mac-Ert plates failed to inhibit the growth of the Citrobacter species tested at both antibiotic concentrations and the Proteus species tested at the 0.5µg/ml antibiotic concentration. The Mac-Imp plates showed poor specificity as both concentrations failed to inhibit the growth of the Proteus, Enterobacter and Citrobacter species evaluated after 18-24 hours incubation in ambient air at 35oC. Of all the plates tested, the 0.5 µg/ml Mac-Mem agar had the best shelf-life of up to one month at 4-8oC. Conclusions: The high specificity and the good selectivity, in addition to the long shelf-life allowed the 0.5µg/ml Mac-Mem agar to be used as a cost effective selective medium for the isolation of carbapenem resistant Gram-negative bacteria, in particular the blaKPC producing members of the Enterobacteriaceae family

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

Cancer stem cell metabolism

Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Determining the role of cancer stem cell metabolism in carcinogenesis has become a major focus in cancer research, and substantial efforts are conducted towards discovering clinical targets

Arab Protestant women in theological education: a contribution to ecclesial understanding of Christianity in the Middle East

This thesis offers a contribution to the wider study of theological education (TE) through exploring the TE of Arab Protestant Women (APW) in the Middle East (ME). Historical and qualitative research is combined to present an account of APW in TE. Despite the deeply historic and complex ecclesial character of Christianity in the region, ecclesiology is rarely given due consideration in modern history of Protestantism for the ME. In this thesis the contemporary state of APW is explored in the context of dialogue with the Eastern Christian traditions which are the dominant ecclesial of the Christian tradition in the Middle East. I propose a reorientation away from the ecclesial perspectives traditionally offered by Protestant missions. This ecclesial proposition for Protestant mission and presence in the Middle East is a central aspect of the originality and contribution of this research. Hence, my work develops a Protestant ecclesiology which allows itself to be situated within this complex ecclesial context. My research on women is posited within this ecclesial context for Protestant presence and mission in the Middle East. My work makes an original contribution, not just developing ideas on Protestant ecclesiology and TE, but how women are situated in a religious and ecclesial context of unique diversity and plurality. The thesis also examines how religious education (RE) with a comparative awareness that also in the majority Muslim culture there has also been a reconsidering of questions about religious education and the transmission of religious identity. In analysing the current situation of the TE of APW, the thesis addresses outcomes from first-hand ethnographic experience, observations from field research and ethnographic interviews. A triangulation method is used to understand the experiences of APW in TE. The autoethnographic voice contributes further triangulation enabling the researcher to express her own voice and experience as an Arab Protestant woman in TE. This use of the ‘own voices’ (‘emic’) insider approach has enabled APW to speak with great candour about their roles in, perceptions of and experiences in TE. Their historical and contemporary context has meant that APW have not been able to make the contribution to which they naturally aspire. However, we are now at an ecclesial turning point which has been able to resource women to make a contribution to theology within this distinct ecclesial context. I call this the Third Nahda, following the historical First and Second Nahdas in the ME. In so naming I am suggesting that this ecclesial term be used to indicate a distinct contribution to Protestant thought and practice. Hence my work has at its heart the question of ecumenical intent and reciprocity. My research thus makes a contribution to the development of Protestant thought in relation to APW within the complex ecclesial world of the ME