Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence

Endothelial nitric oxide synthase gene polymorphisms in recurrent spontaneous abortions

Objective: The risk of miscarriage is enhanced by a variety of genetic and environmental factors. Previous studies indicated an association between endothelial nitric oxide synthase (eNOS) activity, and implantation and maintenance of pregnancy, but it is rather controversial whether polymorphisms of the gene encoding for eNOS are associated with recurrent spontaneous abortions (RSA). The aim of our study was to determine whether the 27 bp intron 4 repeat polymorphism (4VNTR) and a Glu298Asp missense mutation encoded by exon 7 of the eNOS gene are associated with an increased risk for recurrent spontaneous abortions (RSA), in the Greek population. Methods: A total of 126 women who had at least three unexplained spontaneous abortions before 20 weeks of gestation, with the same partner, were included in the study group. The control group consistent of 130 women with at least two live childbirths and without history of abortions. All patients and controls were investigated for the two polymorphisms. To genotype the cohorts we used the PCR-RFLPs method. Results: The observed frequencies of bb, ba, aa genotypes of the VNTR, in intron 4, polymorphism were 0.75, 0.24, 0.01, respectively, for the patient group and 0.73, 0.24, 0.03, respectively, for the control group. The observed frequencies of GG, GT, TT of the Glu298Asp polymorphism were 0.42, 0.45, 0.13, respectively, for the patient group and 0.47, 0.45, 0.08, respectively, for the control group. Statistical analysis of the results indicates no significant difference between the two groups, for both the two studied polymorphisms. Conclusion: Our results do not show any influence of the two polymorphisms, VNTR in intron 4 and Glu298Asp of the eNOS gene, on early pregnancy. © 2008 Springer-Verlag

Lymphomatous renal involvement

Leonard de Bona was a businessman, possibly of Italian descent, in Eagle Pass, Texas, who ran a hardware and supply store in that area for nearly 20 years. He served as a point of contact for customers throughout South Texas and nearby Mexico, providing not only hardware but food, clothing, and sundries. He had business contacts in San Antonio, Chicago, and abroad (Central Mexico, Italy, and other locations.)Archive of Correspondence relating to L. de Bona's Eagle Pass Hardware and Supply Store from 1887-1903 and undated. Approximately 500 letters, varying states of condition, some browning. An important archive for a businessman on the border in Eagle Pass, Texas with nearly 500 letters, most from neighboring Texas communities, order supplies.Organized by the following series: Correspondence and ChronologicalBona, L. de, Papers, 1887-1903 and undated, Southwest Collection/Special Collections Library, Texas Tech University, Lubbock, TexasOrder filled 1888-12-20

Cytology of Pericardial Effusion due to Malignancy

Background. Malignant pericardial effusion occurs in one tenth of all cancers. It is a very serious disorder that is mainly a secondary process due to metastasis because primary neoplasms of the pericardium such as mesotheliomas, sarcomas being exceedingly rare