Rational Design of Novel Allosteric EYA2 Inhibitors as Potential Therapeutics for Multiple Brain Cancers.

The Eyes Absent (EYA) family of developmental proteins, often in partnership with the sine oculis (SIX) homeobox proteins, promote cancer metastasis and recurrence in numerous tumor types. In addition to being a transcriptional coactivator, EYA2 is a Tyr phosphatase that dephosphorylates H2AX which leads to repair instead of apoptosis upon DNA damage and ERβ which inhibits the anti-tumor transcriptional activity of ERβ. The SIX members of the EYA-SIX complex are difficult to target, therefore, we targeted the EYA2 to promote cell death and prevent cancer progression.

The time required to achieve endotracheal intubation in dogs: a comparison of veterinary students and qualified veterinary surgeons.

Objective: To determine whether final year veterinary students take longer to perform endotracheal intubation than qualified veterinary surgeons.

Study Design: Observational cohort study.

Animals: A total of 38 healthy mesocephalic dogs undergoing general anaesthesia for a clinical purpose unrelated to this study.

Inhibition of CtBP-Regulated Proinflammatory Gene Transcription Attenuates Psoriatic Skin Inflammation.

Psoriasis is a chronic immune-mediated disease characterized by excessive proliferation of epidermal keratinocytes and increased immune cell infiltration to the skin. Although it is well-known that psoriasis pathogenesis is driven by aberrant production of proinflammatory cytokines, the mechanisms underlying the imbalance between proinflammatory and anti-inflammatory cytokine expression are incompletely understood. In this study, we report that the transcriptional coregulators CtBP1 and 2 can transactivate a common set of proinflammatory genes both in the skin of imiquimod-induced mouse psoriasis model and in human keratinocytes and macrophages stimulated by imiquimod.

An Entrustable Professional Activities Model for Assessment of Undergraduate Competence in Anesthesia and Surgery: Performance of the Assessment Scheme and the Impact of Assessment Timing and Variation in Structure of Teaching Activities on Student Outcomes.

An entrustable professional activity (EPA) model was used to assess the anesthesia and surgery competence of year 4 students during elective neutering procedures over 3 academic years (cohort A, cohort B, and cohort C). Two competence thresholds were defined by an expert panel, the minimum acceptable standard (MAS) and the standard expected at the start of final-year rotations (SFR). The assessment scheme performed as expected, and the median level of supervision achieved by students either matched or exceeded the SFR for all EPAs except one, which matched the MAS.

C-terminal binding proteins 1 and 2 in traumatic brain injury-induced inflammation and their inhibition as an approach for anti-inflammatory treatment.

Traumatic brain injury (TBI) induces an acute inflammatory response in the central nervous system that involves both resident and peripheral immune cells. The ensuing chronic neuroinflammation causes cell death and tissue damage and may contribute to neurodegeneration. The molecular mechanisms involved in the maintenance of this chronic inflammation state remain underexplored.

Smad7 Promotes Healing of Radiotherapy-Induced Oral Mucositis without Compromising Oral Cancer Therapy in a Xenograft Mouse Model.

Purpose: We previously reported preventive and therapeutic effects of Smad7, a multifunctional protein, on radiotherapy (RT)-induced mucositis in mice without promoting human oral cancer cell survival or migration . The current study aims to determine whether a Smad7-based biologic can treat existing oral mucositis during radiotherapy for oral cancer and whether this treatment compromises RT-induced cancer cell killing in neighboring oral cancer. We transplanted human oral cancer cells into the tongues of mice and applied craniofacial irradiation to simultaneously kill tumor cells and induce oral mucositis, thus modeling RT and mucositis in oral cancer patients.

CPP-E1A fusion peptides inhibit CtBP-mediated transcriptional repression.

The carboxyl-terminal binding proteins (CtBP) are transcriptional corepressors that regulate the expression of multiple epithelial-specific and pro-apoptotic genes. Overexpression of CtBP occurs in many human cancers where they promote the epithelial-to-mesenchymal transition, stem cell-like features, and cell survival, while knockdown of CtBP in tumor cells results in p53-independent apoptosis. CtBPs are recruited to their target genes by binding to a conserved PXDLS peptide motif present in multiple DNA-binding transcription factors.

The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target.

Transcriptional corepressor proteins have emerged as an important facet of cancer etiology. These corepressor proteins are often altered by loss- or gain-of-function mutations, leading to transcriptional imbalance. Thus, research directed at expanding our current understanding of transcriptional corepressors could impact the future development of new cancer diagnostics, prognostics, and therapies.

The SIX1-EYA transcriptional complex as a therapeutic target in cancer.

Introduction: The SIX homeodomain proteins and the eyes absent (EYA) family of co-activators form a bipartite transcription factor complex that promotes the proliferation and survival of progenitor cells during organogenesis and is down-regulated in most adult tissues. Abnormal over-expression of SIX1 and EYA in adult tissue is associated with the initiation and progression of diverse tumor types. Importantly, SIX1 and EYA are often co-overexpressed in tumors, and the SIX1-EYA2 interaction has been shown to be critical for metastasis in a breast cancer model.

Small Molecule, NSC95397, Inhibits the CtBP1-Protein Partner Interaction and CtBP1-Mediated Transcriptional Repression.

Carboxyl-terminal binding protein (CtBP) is a transcriptional corepressor that suppresses multiple proapoptotic and epithelial genes. CtBP is overexpressed in many human cancers, and its overexpression increases stem cell-like features, epithelial-mesenchymal transition, and cancer cell survival. Knockdown of CtBP also increases apoptosis independent of p53 in cell culture.

Allosteric inhibitors of the Eya2 phosphatase are selective and inhibit Eya2-mediated cell migration.

Eya proteins are essential co-activators of the Six family of transcription factors and contain a unique tyrosine phosphatase domain belonging to the haloacid dehalogenase family of phosphatases. The phosphatase activity of Eya is important for the transcription of a subset of Six1-target genes, and also directs cells to the repair rather than apoptosis pathway upon DNA damage. Furthermore, Eya phosphatase activity has been shown to mediate transformation, invasion, migration, and metastasis of breast cancer cells, making it a potential new drug target for breast cancer.

Complex formation among the RNA export proteins Nup98, Rae1/Gle2, and TAP.

Most nucleocytoplasmic traffic through the nuclear pore complex is mediated by soluble receptors of the importin/exportin or karyopherin family. mRNA export is unique in that no receptor of this family has been implicated in trafficking of the bulk of mRNAs. Instead, many diverse proteins have been linked to mRNA export, but an all-encompassing model remains elusive.