The Multifaceted Role of Osteopontin in Modulating the Tumor Microenvironment.

Osteopontin, a key structural protein in the extracellular matrix, plays a pivotal role in regulating the local tumor microenvironment and systemic immunity during cancer progression. Recognizing that tumor cells do not exist in isolation but rather interact with a multitude of stromal components that significantly influence patient outcomes and therapy responses, this review focuses on the role of osteopontin in non-tumor cells in the context of solid cancers and the associated phenotypic and mechanistic insights. We explore how osteopontin influences the behavior of various innate and adaptive immune cells, including natural killer cells, neutrophils, macrophages, dendritic cells, myeloid-derived suppressor cells, B cells, T cells, as well as structural stromal cells such as fibroblasts, endothelial cells, and adipocytes.

Increased ErbB2 signaling is an early adaptation to androgen signaling inhibition and persists in castration resistant prostate cancer.

Purpose: ErbB2 activity is increased in a subset of prostate cancer (PCa), but the gene is rarely amplified. This study sought to identify mechanisms driving increased ErbB2 activity and their role in progression to castration resistant prostate cancer (CRPC).

Experimental Design: ErbB2 signaling was interrogated with a combination of immunohistochemistry (IHC), reverse-phase protein array, and RNA sequencing in cell lines, xenografts, and clinical tumors at various stages of castration resistance.

Miniaturized scalable arrayed CRISPR screening in primary cells enables discovery at the single donor resolution.

High-efficiency gene editing in primary human cells is critical for advancing therapeutic development and functional genomics, yet conventional electroporation platforms often require high cell input and are poorly suited to parallelized experiments. Here we introduce a next-generation digital microfluidics (DMF) electroporation platform that enables high-throughput, low-input genome engineering using discrete droplets manipulated on a planar electrode array. The system supports 48 independently programmable reaction sites and integrates seamlessly with laboratory automation, allowing efficient delivery of CRISPR-Cas9 RNPs and mRNA cargo into as few as 3,000 primary human cells per condition.

Buenos Aires Breast Cancer Symposium 2024: bridging basic and clinical research in breast cancer.

The second edition of the Buenos Aires Breast Cancer Symposium (BA-BCS), the first to be held in person, took place from September 3rd to 6th, 2024, in Buenos Aires, Argentina. Nineteen scientists from Brazil, Canada, the United States, the United Kingdom, Denmark, Germany, and Spain, along with six Argentine experts, shared and discussed their recent findings with the audience. Young researchers had the opportunity to present their results through either mini-oral presentations or posters, facilitating oneon-one interactions and the potential for new collaborations.

Physiologically Based and Population Pharmacokinetic Modeling of Midazolam in Children With Obesity Using Real-World Data.

Children represent a highly complex and variable population for treatment, including interindividual differences in drug dose-exposure. Midazolam has been used as a sedative for hospitalized children on- and off-label; however, factors affecting interindividual variability (IIV) in observed clearance for this population are not fully understood and can result in extreme under- or overexposure. Obesity has been described as a significant influence on midazolam in adolescents, which could potentially alter drug exposure.

Expansion of a Pharmacokinetic Model for Diazepam to Characterize Real-World IV and Oral Data in Children With and Without Obesity.

Diazepam is a benzodiazepine approved for use in adults and children. The label incorporates recommended dosing for status epilepticus in children. Published population pharmacokinetic (PK) modeling recommends an intravenous bolus dose of 0.

Bacteremia in Pediatric Solid Organ Transplant Recipients within 1 Year of Transplant.

Background: Bacteremia is a major cause of morbidity and mortality in immunocompromised children, yet there are limited data in children who have undergone solid organ transplantation (SOT).

Methods: We retrospectively reviewed bloodstream infections (BSI) in 581 recipients of heart, liver, or kidney transplants over a 14-year period.

Results: Overall 1-year incidence in this population was 8.

Transition to Enteral Triazole Antifungal Therapy for Pediatric Invasive Candidiasis: Secondary Analysis of a Multicenter Cohort Study Conducted by the Pediatric Fungal Network.

Of 319 children with invasive candidiasis, 67 (21%) transitioned from intravenous to enteral antifungal therapy. Eight (12%) transitioned back to intravenous antifungal therapy, one due to perceived treatment failure defined by clinical progression or worsening. Global treatment response at study completion was successful in 66 participants who transitioned to enteral therapy.

Osteopontin is a therapeutic target that drives breast cancer recurrence.

Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence.

Pharmacokinetics of Dexamethasone in Children and Adolescents with Obesity.

Dexamethasone is a synthetic glucocorticoid approved for treating disorders of various organ systems in both adult and pediatric populations. Currently, approved pediatric dosing recommendations are weight-based, but it is unknown whether differences in dexamethasone drug disposition and exposure exist for children with obesity. This study aimed to develop a population pharmacokinetic (PopPK) model for dexamethasone with data collected from children with obesity.

Targeting fatty acid oxidation enhances response to HER2-targeted therapy.

Metabolic reprogramming, a hallmark of tumorigenesis, involves alterations in glucose and fatty acid metabolism. Here, we investigate the role of Carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in long-chain fatty acid (LCFA) oxidation, in ErbB2-driven breast cancers. In ErbB2+ breast cancer models, ablation of Cpt1a delays tumor onset, growth, and metastasis.

Multicenter Analysis of Valganciclovir Prophylaxis in Pediatric Solid Organ Transplant Recipients.

Background: Valganciclovir is the only approved antiviral for cytomegalovirus (CMV) prevention in pediatric solid organ transplantation (SOT). Additional approaches may be needed to improve outcomes.

Methods: A multicenter retrospective study from 2016 to 2019 was conducted of pediatric SOT recipients in whom at least 3 months of valganciclovir prophylaxis was planned.

Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population.

Background: Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity.

Objective: This study aimed to address the gap by leveraging PK data from two prospective standard-of-care pediatric trials (n = 88) covering an age range from 1 month to 19 years, including those with obesity (64%), and applying a physiologically based PK (PBPK) modeling framework.

Methods: A published PBPK model of levetiracetam for children aged 2 years and older was extended to pediatric patients younger than 2 years of age and patients older than 2 years of age with obesity by accounting for the obesity and age-related changes in PK using PK-Sim software.

Elevated expression of wildtype RhoC promotes ErbB2- and Pik3ca-induced mammary tumor formation.

Copy number gains in genes coding for Rho activating exchange factors as well as losses affecting genes coding for RhoGAP proteins are common in breast cancer (BC), suggesting that elevated Rho signaling may play an important role. Extra copies and overexpression of RHOC also occur, although a role for RhoC overexpression in driving tumor formation has not been assessed in vivo. To this end, we report on the development of a Rosa26 (R26)-targeted Cre-conditional RhoC overexpression mouse (R26).

Approach for defining human adenovirus infection and disease for central review adjudication in clinical studies.

Background: Pediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk for morbidity and mortality from human adenovirus (HAdV). HAdV can be detected in an asymptomatic state, referred to as infection or with signs or symptoms of illness, referred to as disease. Standardized case definitions are needed to distinguish infection from disease and allow for consistent reporting in both observational cohort studies and therapeutic clinical trials.

BK virus-associated hemorrhagic cystitis in pediatric stem cell transplantation: a case report and scoping review.

Introduction: BK virus-associated hemorrhagic cystitis (BK-HC) is a debilitating and poorly understood complication of hematopoietic stem cell transplantation (SCT). Hematuria, dysuria, and other symptoms associated with BK-HC are common in the immediate post-SCT period, making BK-HC difficult to distinguish from other conditions presenting with these symptoms. Despite published criteria for diagnosis, the degree to which these criteria are consistently applied to either clinical diagnosis or to studies informing BK-HC management is unclear.

Remdesivir for COVID-19 in Hospitalized Children: A Phase 2/3 Study.

Objectives: Remdesivir decreases the risk of SARS-CoV-2 infection progressing to severe disease in adults. This study evaluated remdesivir safety and pharmacokinetics in infants and children.

Methods: This was a phase 2/3, open-label trial in children aged 28 days to 17 years hospitalized for polymerase chain reaction-confirmed SARS-CoV-2 infection.

Invasive growth of brain metastases is linked to CHI3L1 release from pSTAT3-positive astrocytes.

Background: Compared to minimally invasive brain metastases (MI BrM), highly invasive (HI) lesions form abundant contacts with cells in the peritumoral brain parenchyma and are associated with poor prognosis. Reactive astrocytes (RAs) labeled by phosphorylated STAT3 (pSTAT3) have recently emerged as a promising therapeutic target for BrM. Here, we explore whether the BrM invasion pattern is influenced by pSTAT3+ RAs and may serve as a predictive biomarker for STAT3 inhibition.

USP22 overexpression fails to augment tumor formation in MMTV-ERBB2 mice but loss of function impacts MMTV promoter activity.

The Ubiquitin Specific Peptidase 22 (USP22), a component of the Spt-Ada-Gcn5 Acetyltransferase (SAGA) histone modifying complex, is overexpressed in multiple human cancers, but how USP22 impacts tumorigenesis is not clear. We reported previously that Usp22 loss in mice impacts execution of several signaling pathways driven by growth factor receptors such as erythroblastic oncogene B b2 (ERBB2). To determine whether changes in USP22 expression affects ERBB2-driven tumorigenesis, we introduced conditional overexpression or deletion alleles of Usp22 into mice bearing the Mouse mammary tumor virus-Neu-Ires-Cre (MMTV-NIC) transgene, which drives both rat ERBB2/NEU expression and Cre recombinase activity from the MMTV promoter resulting in mammary tumor formation.

A pilot recruitment strategy to enhance ethical and equitable access to Covid-19 pediatric vaccine trials.

Background/aims: The SARS-CoV-2 pandemic disproportionately impacted communities with lower access to health care in the United States, particularly before vaccines were widely available. These same communities are often underrepresented in clinical trials. Efforts to ensure equitable enrollment of participants in trials related to treatment and prevention of Covid-19 can raise concerns about exploitation if communities with lower access to health care are targeted for recruitment.