Areas of strength and opportunities for growth in translational science education and training: Results of a scoping review from the NCATS Education Branch.

Translational science education and training (E&T) aims to prepare the translational workforce to accelerate progress along the translational pipeline toward solutions that improve human health. In 2020-2021, the National Center for Advancing Translational Sciences (NCATS) Education Branch conducted a scoping review of the E&T literature with this focus. The review used the methodological framework proposed by Arksey and O'Malley.

DEIA is essential to advance the goals of translational science: Perspectives from NCATS.

The National Center for Advancing Translational Science (NCATS) seeks to improve upon the translational process to advance research and treatment across all diseases and conditions and bring these interventions to all who need them. Addressing the racial/ethnic health disparities and health inequities that persist in screening, diagnosis, treatment, and health outcomes (e.g.

RAD6 inhibition enhances paclitaxel sensitivity of triple negative breast cancer cells by aggravating mitotic spindle damage.

Background: Paclitaxel (PTX), a first-line therapy for triple negative breast cancers (TNBC) induces anti-tumor activity by microtubule stabilization and inhibition of cell division. Its dose-limiting toxicity and short half-life, however, pose clinical challenges underscoring the need for strategies that increase its efficiency. RAD6, a E2 ubiquitin conjugating enzyme, is associated with centrosomes at all phases of cell cycle.

The National Center for Advancing Translational Sciences' Intramural Training Program and Fellow Career Outcomes.

The National Center for Advancing Translational Sciences (NCATS) defines translational science as "the field of investigation focused on understanding the scientific and operational principles underlying each step of the translational process." A major goal of translational science is to determine commonalities across projects to identify principles for addressing persistent bottlenecks in this process. To meet this goal, translational scientists must be conversant in multiple disciplines, work in teams, and understand the larger translational science ecosystem.

Resistance to the CHK1 inhibitor prexasertib involves functionally distinct CHK1 activities in BRCA wild-type ovarian cancer.

High grade serous ovarian cancer (HGSOC) is a fatal gynecologic malignancy in the U.S. with limited treatment options.

COPD and lung cancer incidence in the Women's Health Initiative Observational Study: A brief report.

Objectives: Lung cancer is the leading cause of cancer mortality in both men and women in the United States. COPD is associated with lung cancer independently of cigarette smoking, but remains understudied in women. Utilizing data from the Women's Health Initiative Observational Study (WHI-OS), this report investigates the association between COPD and development of lung cancer, with a focus on ethnicity and cancer subtype.

RAD6B is a major mediator of triple negative breast cancer cisplatin resistance: Regulation of translesion synthesis/Fanconi anemia crosstalk and BRCA1 independence.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with few therapy options besides chemotherapy. Although platinum-based drugs have shown initial activity in BRCA1-mutated TNBCs, chemoresistance remains a challenge. Here we show that RAD6B (UBE2B), a principal mediator of translesion synthesis (TLS), is overexpressed in BRCA1 wild-type and mutant TNBCs, and RAD6B overexpression correlates with poor survival.

Restored replication fork stabilization, a mechanism of PARP inhibitor resistance, can be overcome by cell cycle checkpoint inhibition.

Poly(ADP-ribose) polymerase (PARP) inhibition serves as a potent therapeutic option eliciting synthetic lethality in cancers harboring homologous recombination (HR) repair defects, such as BRCA mutations. However, the development of resistance to PARP inhibitors (PARPis) poses a clinical challenge. Restoration of HR competency is one of the many molecular factors contributing to PARPi resistance.

Nano-delivery of /Translesion Synthesis Inhibitor SMI#9 for Triple-negative Breast Cancer Therapy.

The triple-negative breast cancer (TNBC) subtype, regardless of their BRCA1 status, has the poorest outcome compared with other breast cancer subtypes, and currently there are no approved targeted therapies for TNBC. We have previously demonstrated the importance of -mediated translesion synthesis pathway in TNBC development/progression and chemoresistance, and the potential therapeutic benefit of targeting with a -selective small-molecule inhibitor, SMI#9. To overcome SMI#9 solubility limitations, we recently developed a gold nanoparticle (GNP)-based platform for conjugation and intracellular release of SMI#9, and demonstrated its cytotoxic activity toward TNBC cells.

Breast cancer complexity: implications of intratumoral heterogeneity in clinical management.

Generation of intratumoral phenotypic and genetic heterogeneity has been attributed to clonal evolution and cancer stem cells that together give rise to a tumor with complex ecosystems. Each ecosystem contains various tumor cell subpopulations and stromal entities, which, depending upon their composition, can influence survival, therapy responses, and global growth of the tumor. Despite recent advances in breast cancer management, the disease has not been completely eradicated as tumors recur despite initial response to treatment.

Pharmacological targeting of RAD6 enzyme-mediated translesion synthesis overcomes resistance to platinum-based drugs.

Platinum drug-induced cross-link repair requires the concerted activities of translesion synthesis (TLS), Fanconi anemia (FA), and homologous recombination repair pathways. The E2 ubiquitin-conjugating enzyme RAD6 is essential for TLS. Here, we show that RAD6 plays a universal role in platinum-based drug tolerance.

Gold nanoparticle conjugated Rad6 inhibitor induces cell death in triple negative breast cancer cells by inducing mitochondrial dysfunction and PARP-1 hyperactivation: Synthesis and characterization.

Unlabelled: We recently developed a small molecule inhibitor SMI#9 for Rad6, a protein overexpressed in aggressive breast cancers and involved in DNA damage tolerance. SMI#9 induces cytotoxicity in cancerous cells but spares normal breast cells; however, its therapeutic efficacy is limited by poor solubility. Here we chemically modified SMI#9 to enable its conjugation and hydrolysis from gold nanoparticle (GNP).

Ultrasound-guided thoracic paravertebral block catheter experience in 2 neonates.

The study objective is to describe our experience with placement and management of thoracic paravertebral block catheters in 2 neonates. The design is retrospective chart review of 2 consecutive newborns undergoing repair of tracheoesophageal fistula. Ultrasound-guided oblique intercostal approach for catheter placement and infusions of dilute ropivicaine for 4-5 days.

Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance.

Bifunctional alkylating and platinum based drugs are chemotherapeutic agents used to treat cancer. These agents induce DNA adducts via formation of intrastrand or interstrand (ICL) DNA crosslinks, and DNA lesions of the ICL type are particularly toxic as they block DNA replication and/or DNA transcription. However, the therapeutic efficacies of these drugs are frequently limited due to the cancer cell's enhanced ability to repair and tolerate these toxic DNA lesions.

Melanoma Development and Progression Are Associated with Rad6 Upregulation and β -Catenin Relocation to the Cell Membrane.

We have previously demonstrated that Rad6 and β -catenin enhance each other's expression through a positive feedback loop to promote breast cancer development/progression. While β -catenin has been implicated in melanoma pathogenesis, Rad6 function has not been investigated. Here, we examined the relationship between Rad6 and β -catenin in melanoma development and progression.

Rad6 is a Potential Early Marker of Melanoma Development.

Melanoma is the leading cause of death from skin cancer in industrialized countries. Several melanoma-related biomarkers and signaling pathways have been identified; however, their relevance to melanoma development/progression or to clinical outcome remains to be established. Aberrant activation of Wnt/β-catenin pathway is implicated in various cancers including melanoma.

The Escherichia coli CydX protein is a member of the CydAB cytochrome bd oxidase complex and is required for cytochrome bd oxidase activity.

Cytochrome bd oxidase operons from more than 50 species of bacteria contain a short gene encoding a small protein that ranges from ∼30 to 50 amino acids and is predicted to localize to the cell membrane. Although cytochrome bd oxidases have been studied for more than 70 years, little is known about the role of this small protein, denoted CydX, in oxidase activity. Here we report that Escherichia coli mutants lacking CydX exhibit phenotypes associated with reduced oxidase activity.