Showing papers by "Agilent Technologies published in 2022"

A Standardized Investigational Ki-67 Immunohistochemistry Assay Used to Assess High-Risk Early Breast Cancer Patients in the monarchE Phase 3 Clinical Study Identifies a Population With Greater Risk of Disease Recurrence When Treated With Endocrine Therapy Alone

Abstract: The objectives were to develop a standardized Ki-67 immunohistochemistry (IHC) method for precise, robust, and reproducible assessment of patients with early breast cancer, and utilize this assay to evaluate patients participating in the monarchE study (NCT03155997). The Ki-67 assay was developed and validated for sensitivity, specificity, repeatability, precision, and robustness using a predefined ≥20% cutoff. Reproducibility studies (intersite and intrasite, interobserver and intraobserver) were conducted at 3 external laboratories using detailed scoring instructions designed for monarchE. Using the assay, patient tumors were classified as displaying high (≥20%) or low (<20%) Ki-67 expression; Kaplan-Meier methods evaluated 2-year invasive disease-free survival rates for these 2 groups among patients treated with endocrine therapy (ET) alone. All analytical validation and reproducibility studies achieved point estimates of >90% for negative, positive, and overall percent agreement. Intersite reproducibility produced point estimate values of 94.7%, 100.0%, and 97.3%. External interobserver reproducibility produced point estimate values of 98.9%, 97.8%, and 98.3%. Among 1954 patients receiving ET alone, 986 (50.5%) had high and 968 (49.5%) had low Ki-67 expression. Patients with high Ki-67 had a clinically meaningful increased risk of developing invasive disease within 2 years compared with those with low Ki-67 [2-y invasive disease-free survival rate: 86.1% (95% confidence interval: 83.1%-88.7%) vs. 92.0% (95% confidence interval: 89.7%-93.9%), respectively]. This standardized Ki-67 methodology resulted in high concordance across multiple laboratories, and its use in the monarchE study prospectively demonstrated the prognostic value of Ki-67 IHC in HR+, HER2- early breast cancer with high-risk clinicopathologic features.

Using Feedback Control Principles as Guiding Metaphors for Business Processes

Abstract: This paper asks: how do we apply the fundamental principles of feedback in physical systems to business processes? This is a tempting idea because feedback is clearly present in business/decision processes, but as in the case of feedback of biological systems, getting beyond the qualitative and phenomenological descriptions to models with structure for which parameters can be determined from measurements is difficult.In this context, what can feedback principles, so often based on rigid mathematical analysis, provide to such systems for which any mathematical rigor is hard to find? Our approach in this section will be inspired by the words of Captain Barbosa in Pirates of the Caribbean [1], as to think of fundamental feedback principles as guidelines, rather than actual rules. That being said, we believe those guidelines provide a rich source of correction for business processes. In the end our feedback-fundamentals inspired guidelines may not guarantee us only correct decisions, but they can keep us away from practices we would never try in engineering systems.

Enhanced epithelial to mesenchymal transition and chemoresistance in advanced Retinoblastoma tumors is driven by miR-181a

Abstract: Abstract Advanced retinoblastoma (Rb) tumors can infiltrate distant tissues and cause a potent threat to vision and life. Through transcriptomic profiling, we discovered key epithelial to mesenchymal transition (EMT) and chemotherapy resistance genes at higher expression levels in advanced Rb tumors. Rb-/- tumor cells acquire metastasis-like phenotype through the EMT program that critically contributes to chemoresistance. We demonstrate that prolonged chemo-drug exposure in Rb cells elicits an EMT program through ZEB1 and SNAI2 that further acquires therapeutic resistance through cathepsin L and MDR1 mediated drug efflux mechanisms. Further, 16 significantly differentially expressed miRNAs were identified in patient tumors, of which miR-181a-5p was significantly reduced in advanced Rb tumors and associated with altered EMT and drug resistance genes. Enhancing miR-181a-5p levels in Rb-/- cells and Rb-/- chemo-resistant sublines controls EMT transcription factors ZEB1 and SNAI2 and halts the transition switch, thereby reversing drug resistance. We thus identify miR-181a-5p as a potential therapeutic target for EMT triggered drug-resistant cancers that can halt their invasion and sensitize them to low dose chemotherapy drugs. Graphical Abstract