An examination of the relationship between epithelial to mesenchymal transition and cancer stem cells in solid tumors

Thesis (M.A.)--Boston UniversityThis thesis examines the connection between epithelial to mesenchymal transition (EMT) and cancer stem cells (CSC) in solid tumors. Epithelial to mesenchymal transition describes the conversion of cancer cells from an adherent, differentiated, and polar phenotype (epithelial) to a motile, plastic, and apolar phenotype (mesenchymal). EMT is correlated with metastasis; EMT is usually measured by QRT-PCR or immunohistochemistry. Cancer stem cells are thought to be responsible for metastasis and recurrence. They have been found in almost all solid tumors and cancer stem cell-enriched populations are detectable using flow cytometry. EMT and cancer stem cells have many jeans, transcription factors, and signaling pathways in common. Both have been clinically correlated with patient outcomes and disease-free survival. There's currently no consensus on mechanistic connection between the two phenomena. The current data on critical signaling pathways as well as the effect of the tumor stroma and cytotoxic therapy is examined. The current body of research points to the conclusion that EMT may be responsible for the cancer stem cell-enriched populations in solid tumors

Intravenous doxycycline, azithromycin, or both for severe scrub typhus

BACKGROUND: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. METHODS: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. RESULTS: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of −13.3 percentage points (95% confidence interval [CI], (21.6 to −5.1; P=0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of −14.8 percentage points (95% CI, −23.1 to −6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, −7.0 to 10.0; P=0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups. CONCLUSIONS: Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry–India number, CTRI/2018/08/015159.

Lipid-Coated Biodegradable Particles as "Synthetic Pathogens" for Vaccine Engineering

The physicochemical context in which molecules are presented at the surfaces of microbes has tremendous implications for the immune response to vaccination. The spacing and mobility of molecules may control interactions of their receptors, influencing immune cell activation, pathogen uptake, and antigen processing. The chemical environment of antigens also influences the specificity of the humoral immune response, because antibodies recognize antigen in its three-dimensional shape and context. Finally, physical properties of antigen, such as diameter, impact immune response on both a cellular and tissue level. We have constructed ldquosynthetic pathogensrdquo consisting of a biodegradable core polymer coated by a lipid shell to mimic a bilayer-enveloped pathogen. Synthesized in an oil-in-water emulsion, these particles have an average diameter on the order of either 100 nm, mimicking a lipid-enveloped viral pathogen, or 1 micron, mimicking a bacterial pathogen. CryoEM reveals self-assembled lipid layers at the particle surface. With tunable chemical and physical properties, these particles can be used to study the importance of specific properties of biomaterials when used in vaccination. Because all components are biodegradable, the particles may provide a clinically applicable way of implementing structural features of microbes in synthetic vaccines.Paul & Daisy Soros Fellowships for New Americans (New York, N.Y.)Hertz FoundationHuman Frontier Science Program (Strasbourg, France)Massachusetts Institute of Technology. Undergraduate Research Opportunities ProgramUnited States. Defense Advanced Research Projects AgencyNational Science Foundation (U.S.)National Institutes of Health (U.S.)National Science Foundation (U.S.). Graduate Research Fellowshi