The geography of the European potash industry

Thesis (M.A.)--University of Illinois at Urbana-Champaign, 1927.Includes bibliographical references

HLA-DR15-derived self-peptides are involved in increased autologous T cell proliferation in multiple sclerosis

The HLA-DR15 haplotype confers the largest part of the genetic risk to develop multiple sclerosis, a prototypic CD4+ T cell-mediated autoimmune disease. The mechanisms how certain HLA-class II molecules functionally contribute to autoimmune diseases are still poorly understood, but probably involve shaping an autoimmune-prone T cell repertoire during central tolerance in the thymus and subsequently maintaining or even expanding it in the peripheral immune system. Self-peptides that are presented by disease-associated HLA-class II molecules most likely play important roles during both processes. Here, we examined the functional involvement of the HLA-DR15 haplotype in autologous proliferation in multiple sclerosis and the contribution of HLA-DR15 haplotype-derived self-peptides in an in vitro system. We observe increased autologous T cell proliferation in patients with multiple sclerosis in relation to the multiple sclerosis risk-associated HLA-DR15 haplotype. Assuming that the spectrum of self-peptides that is presented by the two HLA-DR15 allelic products is important for sustaining autologous proliferation we performed peptide elution and identification experiments from the multiple sclerosis-associated DR15 molecules and a systematic analysis of a DR15 haplotype-derived self-peptide library. We identify HLA-derived self-peptides as potential mediators of altered autologous proliferation. Our data provide novel insights about perturbed T cell repertoire dynamics and the functional involvement of the major genetic risk factor, the HLA-DR15 haplotype, in multiple sclerosi

Clonality of circulating tumor cells in breast cancer brain metastasis patients

BACKGROUND: The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options. METHODS: Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs). RESULTS: CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status (p = 0.029) of the primary tumor as well as with the prevalence of bone metastases (p = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time (p < 0.05). Combining the results of both enrichment methods, 63.6% of the patients were classified as CTC positive. In three patients, the matched tumor tissue and single CTCs were analyzed by NGS showing chromosomal aberrations with a high genomic clonality and mutations in pathways potentially important in brain metastasis formation. CONCLUSION: The detection of CTCs, regardless of the enrichment method, is of prognostic relevance in BCBM patients and in combination with molecular analysis of CTCs can help defining patients with higher risk of early relapse and suitability for targeted treatment

Human leukocyte antigen (HLA)-DRB1*15:01 and HLA-DRB5*01:01 present complementary peptide repertoires

Human leukocyte antigen (HLA)-DR15 is a haplotype associated with multiple sclerosis. It contains the two DRB* genes DRB1*1501 (DR2b) and DRB5*0101 (DR2a). The reported anchor motif of the corresponding HLA-DR molecules was determined in 1994 based on a small number of peptide ligands and binding assays. DR2a could display a set of peptides complementary to that presented by DR2b or, alternatively, a similar peptide repertoire but recognized in a different manner by T cells. It is known that DR2a and DR2b share some peptide ligands, although the degree of similarity of their associated peptidomes remains unclear. In addition, the contribution of each molecule to the global peptide repertoire presented by the HLA-DR15 haplotype has not been evaluated. We used mass spectrometry to analyze the peptide pools bound to DR2a and DR2b, identifying 169 and 555 unique peptide ligands of DR2a and DR2b, respectively. The analysis of these sets of peptides allowed the refinement of the corresponding binding motifs revealing novel anchor residues that had been overlooked in previous analyses. Moreover, the number of shared ligands between both molecules was low, indicating that DR2a and DR2b present complementary peptide repertoires to T cells. Finally, our analysis suggests that, quantitatively, both molecules contribute to the peptide repertoire presented by cells expressing the HLA-DR15 haplotype

What they fill in today, may not be useful tomorrow: Lessons learned from studying Medical Records at the Women hospital in Tabriz, Iran

<p>Abstract</p> <p>Background</p> <p>The medical record is used to document patient's medical history, illnesses and treatment procedures. The information inside is useful when all needed information is documented properly. Medical care providers in Iran have complained of low quality of Medical Records. This study was designed to evaluate the quality of the Medical Records at the university hospital in Tabriz, Iran.</p> <p>Methods</p> <p>In order to get a background of the quality of documentation, 300 Medical Records were randomly selected among all hospitalized patient during September 23, 2003 and September 22, 2004. Documentation of all records was evaluated using checklists. Then, in order to combine objective data with subjective, 10 physicians and 10 nurses who were involved in documentation of Medical Records were randomly selected and interviewed using two semi structured guidelines.</p> <p>Results</p> <p>Almost all 300 Medical Records had problems in terms of quality of documentation. There was no record in which all information was documented correctly and compatible with the official format in Medical Records provided by Ministry of Health and Medical Education. Interviewees believed that poor handwriting, missing of sheets and imperfect documentation are major problems of the Paper-based Medical Records, and the main reason was believed to be high workload of both physicians and nurses.</p> <p>Conclusion</p> <p>The Medical Records are expected to be complete and accurate. Our study has unveiled that the Medical Records are not documented properly in the university hospital where the Medical Records are also used for educational purposes. Such incomplete Medical Records are not reliable resources for medical care too. Some influencing factors external to the structure of the Medical Records (i.e. human factors and work conditions) are involved.</p

Exploring health stakeholders' perceptions on moving towards comprehensive primary health care to address childhood malnutrition in Iran: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Due to the multifaceted aspect of child malnutrition, a comprehensive approach, taking social factors into account, has been frequently recommended in health literature. The Alma-Ata declaration explicitly outlined comprehensive primary health care as an approach that addresses the social, economic and political causes of poor health and nutrition.</p> <p>Iran as a signatory country to the Alma Ata Declaration has established primary health care since 1979 with significant progress on many health indicators during the last three decades. However, the primary health care system is still challenged to reduce inequity in conditions such as child malnutrition which trace back to social factors. This study aimed to explore the perceptions of the Iranian health stakeholders with respect to the Iranian primary health care performance and actions to move towards a comprehensive approach in addressing childhood malnutrition. Health stakeholders are defined as those who affect or can be affected by health system, for example health policy-makers, health providers or health service recipients.</p> <p>Methods</p> <p>Stakeholder analysis approach was undertaken using a qualitative research method. Different levels of stakeholders, including health policy-makers, health providers and community members were interviewed as either individuals or focus groups. Qualitative content analysis was used to interpret and compare/contrast the viewpoints of the study participants.</p> <p>Results</p> <p>The results demonstrated that fundamental differences exist in the perceptions of different health stakeholders in the understanding of comprehensive notion and action. Health policy-makers mainly believed in the need for a secure health management environment and the necessity for a whole of the government approach to enhance collaborative action. Community health workers, on the other hand, indicated that staff motivation, advocacy and involvement are the main challenges need to be addressed. Turning to community stakeholders, greater emphasis has been placed on community capabilities, informal link with other social sectors based on trust and local initiatives.</p> <p>Conclusion</p> <p>This research provided a picture of the differences in the perceptions and values of different stakeholders with respect to primary health care concepts. The study suggests that a top-down approach, which still exists among health policy-makers, is a key obstacle that delays, and possibly worse, undermines the implementation of the comprehensive strategy codified by the Alma-Ata Declaration. A need to revitalise primary health care to use its full potential and to combine top-down and bottom-up approaches by narrowing the gap between perceptions of policy makers and those who provide and receive health-related services is crucial.</p

A prognostic neural epigenetic signature in high-grade glioma

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stemcell-like cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural-progenitor-cell-like, astrocyte-like and oligodendrocyte-progenitor-like, alongside oligodendrocytes and excitatory neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients' plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes

Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which current immunotherapy approaches have been unsuccessful. Here, we explore the mechanisms underlying immune evasion in GBM. By serially transplanting GBM stem cells (GSCs) into immunocompetent hosts, we uncover an acquired capability of GSCs to escape immune clearance by establishing an enhanced immunosuppressive tumor microenvironment. Mechanistically, this is not elicited via genetic selection of tumor subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in GSCs are enforced following immune attack. These changes launch a myeloid-affiliated transcriptional program, which leads to increased recruitment of tumor-associated macrophages. Furthermore, we identify similar epigenetic and transcriptional signatures in human mesenchymal subtype GSCs. We conclude that epigenetic immunoediting may drive an acquired immune evasion program in the most aggressive mesenchymal GBM subtype by reshaping the tumor immune microenvironment