Project description:Aldehyde dehydrogenase (ALDH1) activity has long been established as a pro-tumorigenic feature of many cancers, yet the identification of specific isoforms that are enriched in cancer, the mechanism of action of this isoform(s), and viable therapeutic strategies to target this pathway have long remained absent. Whereas one of the well-established functions of the ALDH1a family is the conversion of retinaldehyde into retinoic acid to activate nuclear retinoid signaling, the retinoid pathway is paradoxically hypothesized as a cell-intrinsic tumor suppressor pathway. Here we resolve this long-standing conflict by showing that while ALDH1a3 is broadly overexpressed across diverse cancer types, ALDH1a3 expressing tumor cells often lose the sensitivity to retinoid signaling. Instead, all-trans retinoic acid produced by ALDH1a3 acts in a paracrine fashion to suppress anti-tumor immunity and promote tumor growth. We further used structure-based high throughput screening to develop a series of first-in-class, therapeutically viable antagonists of ALDH1a3 with potent anti-tumor immunotherapeutic activity, an excellent pharmacological profile and no evidence of toxicity. Findings of this study resolve prior contradictions in the retinoid pathway through the development of highly specific and potent ALDH1a3 inhibitors.
Project description:iTRAQ-based quantitative proteomics and phosphoproteomics analyses of induced pluripotent stem cells (iPSC) from patients with longstanding type 1 diabetes. "Preserved DNA Damage Checkpoint Pathway Protects From Complications in Long-standing Type 1 Diabetes", Cell Metabolism, in press.
2015-07-08 | MSV000079185 | MassIVE
Project description:Phylogenomic analyses of ciliates
| PRJNA428772 | ENA
Project description:A phylogenomic study of Steganinae fruit flies (Diptera: Drosophilidae)
Project description:The immune system faces a task that approximates cognition in its complexity as it processes a multitude of intrinsic and extrinsic signals and integrates these into responses of the appropriate class, specificity, magnitude, and duration for a given threat, with the host’s life often depending on the outcome. CD4+ T lymphocytes occupy a unique role in the generation and regulation of immunity within this context and influence multiple innate and adaptive cell types. With respect to CD8+ cytotoxic T lymphocytes (CTL), CD4+ T cells function early in the response as ‘helpers’ (TH) to increase its magnitude and functionality, and later as regulatory cells (Treg) to restore homeostasis and avoid immune pathology. Using a Listeria monocytogenes (Lm) infection model, we probed whether the conditions of initial pathogen encounter could influence the generation of TH versus Treg. Infection induces rapid polyclonal conversion to functional FoxP3+CD25+ Treg within 24 hours. These findings resolve long-standing questions regarding the requirement for TH and reveal a remarkable degree of plasticity in the function of CD4+ T cells, which can be quickly converted to Treg in vivo in response to acute inflammation.