Phase I/II Trial of Perioperative Avelumab in Combination With Chemoradiation in the Treatment of Stage II/III Resectable Esophageal and Gastroesophageal Junction Cancer.

Background And Objectives: Standard treatment of patients with stage II/III esophageal or gastroesophageal junction (E/GEJ) cancer involves neoadjuvant chemoradiation (nCRT), resection, and immunotherapy. Our trial evaluated the addition of perioperative avelumab to standard treatments.

Methods: Patients with resectable E/GEJ cancers received avelumab with nCRT and adjuvant avelumab after resection.

Infections and antibiotic resistance in Malawian children under five years old hospitalized with severe acute malnutrition.

This prospective cohort study from Malawi updates our understanding of the burden of bacterial infections and drug resistance in children <5 years hospitalized with severe acute malnutrition. Urinary tract infection was diagnosed in 20% and bacteremia in 10%. Resistance to first and second-line antibiotics occurred in >1/3 of bacteria isolated.

Development of a live cell assay for real-time monitoring the interactions between the Hippo pathway components 14-3-3 and TAZ.

The Hippo pathway plays an important role in organ size control and tissue homeostasis. Dysregulation is involved in many pathologies, including cancer, which has attracted interest in targeting the Hippo pathway. Since the upstream components are bona fide tumor suppressors, it is feasible to target oncogenic downstream targets such as TAZ, a key downstream effector in the Hippo pathway.

Evidence-Based Infant Assessment for Cerebral Palsy: Diagnosis Timelines and Intervention Access in a Newborn Follow-up Setting.

Evidence-based assessment pathways inform early detection of cerebral palsy and access to intervention. This study investigated the relationships between early evidence-based assessments, diagnosis timeline, and rehabilitation intervention access in a population of children with cerebral palsy who were seen between 2010 and 2022 at the University of Wisconsin Waisman Center Newborn Follow Up Clinic. Cerebral palsy-specific assessments were increasingly integrated after the publication of early detection guidelines by Novak et al.

Using an in-office passive leg raise to identify older adults with suboptimal blood pressure control.

Introduction: Passive leg raise (PLR) is a simple, dynamic maneuver that has been used to increase preload to the heart. We hypothesize that PLR may offer a new and efficient office-based tool for assessing blood pressure (BP) control in older adults.

Methods: One hundred and three veterans (≥60 years old) without known cardiovascular disease and varying degrees of blood pressure control were included in this cross-sectional cohort study.

School Perceptions and Attendance for Children With Medical Complexity During COVID-19 Over Time.

Background: Disparities in school attendance exist for children with medical complexity (CMC) due to COVID-19. Longitudinal changes in family-reported school safety perceptions and predictors of full-time, in-person school attendance are unknown.

Methods: This was a prospective, longitudinal cohort study with 3 survey waves (June 2021-June 2022) among English- and Spanish-speaking families of CMC aged 5 to 17 years and pre-pandemic school attendance.

Long-term follow up of patients treated with a DNA vaccine (pTVG-hp) for PSA-recurrent prostate cancer.

We have previously reported two single-agent phase I trials, evaluating the dose or schedule, of a DNA vaccine (pTVG-HP) encoding prostatic acid phosphatase (PAP) administered with GM-CSF as the adjuvant. These were in patients with PSA-recurrent, radiographically non-metastatic, prostate cancer (PCa). We report here the long-term safety and overall survival of these patients.

Fragment-Based Interrogation of the 14-3-3/TAZ Protein-Protein Interaction.

The identification of chemical starting points for the development of molecular glues is challenging. Here, we employed fragment screening and identified an allosteric stabilizer of the complex between 14-3-3 and a TAZ-derived peptide. The fragment binds preferentially to the 14-3-3/TAZ peptide complex and shows moderate stabilization in differential scanning fluorimetry and microscale thermophoresis.

Performance characteristics of "lollipop" swabs for the diagnosis of infection with SARS-CoV-2.

Background: Common biologic samples used to diagnose COVID-19 include nasopharyngeal, nasal, or oropharyngeal swabs, and salivary samples. The performance characteristics of a sucked "lollipop" swab to detect SARS-CoV-2 virus is assessed in four small sub-studies.

Methods: In each sub-study, a flocked swab was sucked for 20 s and submitted for PCR detection of SARS-CoV-2 virus.

Long non-coding RNA MALAT 1 and PHOX2B expression in olfactory neuroblastomas and sympathetic neuroblastomas.

Long noncoding RNAs (lncRNAs) participate in transcriptional, epigenetic, and post-transcriptional regulation of gene expression and may influence carcinogenesis. MALAT1 is a lncRNA that is expressed in endocrine and many other neoplasms and it has been shown to have oncogenic and/or tumor suppressor effects in tumor development. Olfactory neuroblastomas arise in the nasal cavity while sympathetic neuroblastomas are present mainly in the adrenal and periadrenal regions.

A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints.

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release.

Quantitative evaluation of lesion response heterogeneity for superior prognostication of clinical outcome.

Purpose: Standardized reporting of treatment response in oncology patients has traditionally relied on methods like RECIST, PERCIST and Deauville score. These endpoints assess only a few lesions, potentially overlooking the response heterogeneity of all disease. This study hypothesizes that comprehensive spatial-temporal evaluation of all individual lesions is necessary for superior prognostication of clinical outcome.

Administration of intratumoral GD2-directed interleukin-2 immunocytokine and local radiation therapy to activate immune rejection of spontaneous canine melanoma.

Canine malignant melanoma provides a clinically relevant, large animal parallel patient population to study the GD2-reactive hu14.18-IL-2 immunocytokine as it is similar to human melanoma and expresses GD2. The objectives of this study were to evaluate safety, radiation fractionation, and identify informative biomarkers of an in-situ tumor vaccine involving local radiation therapy plus intratumoral-immunocytokine in melanoma tumor-bearing dogs.

TrkB-mediated neuroprotection in female hippocampal neurons is autonomous, estrogen receptor alpha-dependent, and eliminated by testosterone: a proposed model for sex differences in neonatal hippocampal neuronal injury.

Background: Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of learning disabilities and memory deficits in children. In both human and animal studies, female neonate brains are less susceptible to HI than male brains. Phosphorylation of the nerve growth factor receptor TrkB has been shown to provide sex-specific neuroprotection following in vivo HI in female mice in an estrogen receptor alpha (ERα)-dependent manner.

An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity.

The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include cases of the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), human immunodeficiency virus type 1 (HIV-1 or AIDS), and the pregnancy- and posttransplant-relevant human cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term applications, is often limited by the induction of viral drug resistance or side effects.

Comparative Study of the Effect of Radiation Delivered by Lutetium-177 or Actinium-225 on Anti-GD2 Chimeric Antigen Receptor T Cell Viability and Functions.

Chimeric antigen receptor (CAR) T cells have been relatively ineffective against solid tumors. Low-dose radiation which can be delivered to multiple sites of metastases by targeted radionuclide therapy (TRT) can elicit immunostimulatory effects. However, TRT has never been combined with CAR T cells against solid tumors in a clinical setting.

TrkB-mediated sustained neuroprotection is sex-specific and Erα-dependent in adult mice following neonatal hypoxia ischemia.

Background: Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of life-long neurological morbidities that result in learning and memory impairments. Evidence suggests that male neonates are more susceptible to the detrimental effects of HI, yet the mechanisms mediating these sex-specific responses to neural injury in neonates remain poorly understood. We previously tested the effects of treatment with a small molecule agonist of the tyrosine kinase B receptor (TrkB), 7,8-dihydroxyflavone (DHF) following neonatal HI and determined that females, but not males exhibit increased phosphorylation of TrkB and reduced apoptosis in their hippocampi.

Pyrrolopyrimidine based CSF1R inhibitors: Attempted departure from Flatland.

The colony-stimulating factor 1 receptor (CSF1R) is an attractive target for inflammation disorders and cancers. Based on a series of pyrrolo[2,3-d]pyrimidine containing two carbo-aromatic rings, we have searched for new CSF1R inhibitors having a higher fraction of sp-atoms. The phenyl unit in the 4-amino group could efficiently be replaced by tetrahydropyran (THP) retaining inhibitor potency.

Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers.

Despite the availability of currently approved antiviral drugs, infections with human cytomegalovirus (HCMV) still cause clinically challenging, sometimes life-threatening situations. There is an urgent need for enhanced anti-HCMV drugs that offer improved efficacy, reduced dosages and options for long-term treatment without risk of the development of viral drug resistance. Recently, we reported the pronounced anti-HCMV efficacy of pharmacological inhibitors of cyclin-dependent kinases (CDKs), in particular, the potential of utilizing drug synergies upon combination treatment with inhibitors of host CDKs and the viral CDK-like kinase pUL97 (vCDK/pUL97).

Phase 2 trial of a DNA vaccine (pTVG-HP) and nivolumab in patients with castration-sensitive non-metastatic (M0) prostate cancer.

Purpose: We have previously reported that a plasmid DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) had greater clinical activity when given in combination with pembrolizumab to patients with metastatic, castration-resistant prostate cancer. The current trial was conducted to evaluate vaccination with PD-1 blockade, using nivolumab, in patients with early, recurrent (M0) prostate cancer.

Methods: Patients with M0 prostate cancer were treated with pTVG-HP (100 µg administered intradermally) and nivolumab (240 mg intravenous infusion) every 2 weeks for 3 months, and then every 4 weeks for 1 year of total treatment.

Parent Perceptions of Trainees in Pediatric Care: Cross-Sectional Study.

Background: Clinical experience and progressive autonomy are essential components of medical education and must be balanced with patient comfort. While previous studies have suggested that most patients accept trainee involvement in their care, few studies have focused specifically on the views of parents of pediatric patients or examined groups who may not report acceptance.

Objective: This study aims to understand parental profiles of resident and medical student involvement in pediatric care and to use latent class analysis (LCA) methodology to identify classes of responses associated with parent demographic characteristics.

Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Toxicity and Efficacy Results of a Phase 1b Trial.

Purpose: Ablative local treatment of all radiographically detected metastatic sites in patients with oligometastatic non-small cell lung cancer (NSCLC) increases progression-free survival (PFS) and overall survival (OS). Prior studies demonstrated the safety of combining stereotactic body radiation therapy (SBRT) with single-agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy for patients with oligometastatic NSCLC.

Design of a randomized, placebo-controlled study evaluating efficacy and safety of a cancer preventative vaccine in dogs.

Preventative anti-cancer vaccination strategies have long been hampered by the challenge of targeting the diverse array of potential tumor antigens, with successes to date limited to cancers with viral etiologies. Identification and vaccination against frameshift neoantigens conserved across multiple species and tumor histologies is a potential cancer preventative strategy currently being investigated. Companion dogs spontaneously develop cancers at a similar incidence to those in people and are a complementary comparative patient population for the development of novel anti-cancer therapeutics.

Control of maternal Zika virus infection during pregnancy is associated with lower antibody titers in a macaque model.

Introduction: Zika virus (ZIKV) infection during pregnancy results in a spectrum of birth defects and neurodevelopmental deficits in prenatally exposed infants, with no clear understanding of why some pregnancies are more severely affected. Differential control of maternal ZIKV infection may explain the spectrum of adverse outcomes.

Methods: Here, we investigated whether the magnitude and breadth of the maternal ZIKV-specific antibody response is associated with better virologic control using a rhesus macaque model of prenatal ZIKV infection.