Assessment of TROP2, CEACAM5 and DLL3 in metastatic prostate cancer: Expression landscape and molecular correlates.

Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity.

Multilevel Intervention Stepped Wedge Designs (MLI-SWDs).

Multilevel interventions (MLIs) hold promise for reducing health inequities by intervening at multiple types of social determinants of health consistent with the socioecological model of health. In spite of their potential, methodological challenges related to study design compounded by a lack of tools for sample size calculation inhibit their development. We help address this gap by proposing the Multilevel Intervention Stepped Wedge Design (MLI-SWD), a hybrid experimental design which combines cluster-level (CL) randomization using a Stepped Wedge design (SWD) with independent individual-level (IL) randomization.

ASSESSMENT OF CELL SURFACE TARGETS IN METASTATIC PROSTATE CANCER: EXPRESSION LANDSCAPE AND MOLECULAR CORRELATES.

Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To fully capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity.

Fragmentomic analysis of circulating tumor DNA-targeted cancer panels.

Background: The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA), and multiple cfDNA-targeted sequencing panels are now commercially available for Food and Drug Administration (FDA)-approved biomarker indications to guide treatment. More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner.

Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer.

Purpose: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC).

Limiting adverse birth outcomes in resource-limited settings (LABOR): protocol of a prospective intrapartum cohort study.

Each year, nearly 300,000 women and 5 million fetuses or neonates die during childbirth or shortly thereafter, a burden concentrated disproportionately in low- and middle-income countries. Identifying women and their fetuses at risk for intrapartum-related morbidity and death could facilitate early intervention. The Limiting Adverse Birth Outcomes in Resource-Limited Settings (LABOR) Study is a multi-country, prospective, observational cohort designed to exhaustively document the course and outcomes of labor, delivery, and the immediate postpartum period in settings where adverse outcomes are frequent.

Individualized interventions and precision health: Lessons learned from a systematic review and implications for analytics-driven geriatric research.

Older adults are characterized by profound clinical heterogeneity. When designing and delivering interventions, there exist multiple approaches to account for heterogeneity. We present the results of a systematic review of data-driven, personalized interventions in older adults, which serves as a use case to distinguish the conceptual and methodologic differences between individualized intervention delivery and precision health-derived interventions.

A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer.

BackgroundNeuroendocrine prostate cancer (NEPC) is an aggressive subtype, the presence of which changes the prognosis and management of metastatic prostate cancer.MethodsWe performed analytical validation of a Circulating Tumor Cell (CTC) multiplex RNA qPCR assay to identify the limit of quantification (LOQ) in cell lines, synthetic cDNA, and patient samples. We next profiled 116 longitudinal samples from a prospectively collected institutional cohort of 17 patients with metastatic prostate cancer (7 NEPC, 10 adenocarcinoma) as well as 265 samples from 139 patients enrolled in 3 adenocarcinoma phase II trials of androgen receptor signaling inhibitors (ARSIs).

SEEMLIS: a flexible semi-automated method for enrichment of methylated DNA from low-input samples.

Background: DNA methylation alterations have emerged as hallmarks of cancer and have been proposed as screening, prognostic, and predictive biomarkers. Traditional approaches for methylation analysis have relied on bisulfite conversion of DNA, which can damage DNA and is not suitable for targeted gene analysis in low-input samples. Here, we have adapted methyl-CpG-binding domain protein 2 (MBD2)-based DNA enrichment for use on a semi-automated exclusion-based sample preparation (ESP) platform for robust and scalable enrichment of methylated DNA from low-input samples, called SEEMLIS.

Beyond Two Cultures: Cultural Infrastructure for Data-driven Decision Support.

In the twenty years since Dr. Leo Breiman's incendiary paper was first published, algorithmic modeling techniques have gone from controversial to commonplace in the statistical community. While the widespread adoption of these methods as part of the contemporary statistician's toolkit is a testament to Dr.

Development and validation of multivariable prediction models for adverse COVID-19 outcomes in patients with IBD.

Objectives: Develop an individualised prognostic risk prediction tool for predicting the probability of adverse COVID-19 outcomes in patients with inflammatory bowel disease (IBD).

Design And Setting: This study developed and validated prognostic penalised logistic regression models using reports to the international Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease voluntary registry from March to October 2020. Model development was done using a training data set (85% of cases reported 13 March-15 September 2020), and model validation was conducted using a test data set (the remaining 15% of cases plus all cases reported 16 September-20 October 2020).

The Society for Vascular Surgery Objective Performance Goals for Critical Limb Ischemia are attainable in select patients with ischemic wounds managed with wound care alone.

Background: To set therapeutic benchmarks, in 2009 the Society for Vascular Surgery defined objective performance goals (OPG) for treatment of patients with chronic limb threatening ischemia (CLTI) with either open surgical bypass or endovascular intervention. The goal of these OPGs are to set standards of care from a revascularization standpoint and to provide performance benchmarks for 1 year patency rates for new endovascular therapies. While OPGs are useful in this regard, a critical decision point in the treatment of patients with CLTI is determining when revascularization is necessary.

AR gene rearrangement analysis in liquid biopsies reveals heterogeneity in lethal prostate cancer.

Castration-resistant prostate cancer (CRPC) is driven by AR gene aberrations that arise during androgen receptor (AR)-targeted therapy. AR amplification and mutations have been profiled in circulating tumor cells (CTCs), but whether AR gene rearrangements can be assessed in CTCs is unknown. In this study, we leveraged CRPC cell lines with defined AR gene rearrangements to develop and validate a CTC DNA analysis approach that utilized whole genome amplification and targeted DNA-sequencing of AR and other genes important in CRPC.

Prospective Evaluation of Clinical Outcomes Using a Multiplex Liquid Biopsy Targeting Diverse Resistance Mechanisms in Metastatic Prostate Cancer.

Purpose: Nearly all men with prostate cancer treated with androgen receptor (AR) signaling inhibitors (ARSIs) develop resistance via diverse mechanisms including constitutive activation of the AR pathway, driven by AR genomic structural alterations, expression of AR splice variants (AR-Vs), or loss of AR dependence and lineage plasticity termed neuroendocrine prostate cancer. Understanding these de novo acquired ARSI resistance mechanisms is critical for optimizing therapy.

Materials And Methods: A novel liquid biopsy technology was used to collect mRNA from circulating tumor cells (CTCs) to measure expression of AR-Vs, AR targets, and neuroendocrine prostate cancer markers.

Phase II Multicenter Study of Enzalutamide in Metastatic Castration-Resistant Prostate Cancer to Identify Mechanisms Driving Resistance.

Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance.

Development and initial clinical testing of a multiplexed circulating tumor cell assay in patients with clear cell renal cell carcinoma.

Although therapeutic options for patients with advanced renal cell carcinoma (RCC) have increased in the past decade, no biomarkers are yet available for patient stratification or evaluation of therapy resistance. Given the dynamic and heterogeneous nature of clear cell RCC (ccRCC), tumor biopsies provide limited clinical utility, but liquid biopsies could overcome these limitations. Prior liquid biopsy approaches have lacked clinically relevant detection rates for patients with ccRCC.

Development and validation of multivariable prediction models for adverse COVID-19 outcomes in IBD patients.

Importance: Risk calculators can facilitate shared medical decision-making . Demographics, comorbidities, medication use, geographic region, and other factors may increase the risk for COVID-19-related complications among patients with IBD .

Objectives: Develop an individualized prognostic risk prediction tool for predicting the probability of adverse COVID-19 outcomes in patients with IBD.

Centrosome amplification is a frequent event in circulating tumor cells from subjects with metastatic breast cancer.

Centrosome amplification (CA) is a common phenomenon in cancer, promotes genomic stability and cancer evolution, and has been reported to promote metastasis. CA promotes a stochastic gain/loss of chromosomes during cell division, known as chromosomal instability (CIN). However, it is unclear whether CA is present in circulating tumor cells (CTCs), the seeds for metastasis.

Pairing Microwell Arrays with an Affordable, Semiautomated Single-Cell Aspirator for the Interrogation of Circulating Tumor Cell Heterogeneity.

Comprehensive analysis of tumor heterogeneity requires robust methods for the isolation and analysis of single cells from patient samples. An ideal approach would be fully compatible with downstream analytic methods, such as advanced genomic testing. These endpoints necessitate the use of live cells at high purity.

Versatile exclusion-based sample preparation platform for integrated rare cell isolation and analyte extraction.

Rare cell populations provide a patient-centric tool to monitor disease treatment, response, and resistance. However, understanding rare cells is a complex problem, which requires cell isolation/purification and downstream molecular interrogation - processes challenged by non-target populations, which vary patient-to-patient and change with disease. As such, cell isolation platforms must be amenable to a range of sample types while maintaining high efficiency and purity.

Regulation of inside-out β1-integrin activation by CDCP1.

Tumor metastasis depends on the dynamic regulation of cell adhesion through β1-integrin. The Cub-Domain Containing Protein-1, CDCP1, is a transmembrane glycoprotein which regulates cell adhesion. Overexpression and loss of CDCP1 have been observed in the same cancer types to promote metastatic progression.