KT-253, A Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy Than MDM2 Small Molecule Inhibitors.

Murine double minute 2 (MDM2) is an E3 ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors (SMIs) have demonstrated limited activity, underscoring an unmet need for a better approach to target MDM2. KT 253 is a highly potent and selective heterobifunctional degrader that overcomes the MDM2 feedback loop seen with SMIs and induces apoptosis in a range of hematologic and solid tumor lines.

Association between urinary biomarkers MMP-7/TIMP-2 and reduced renal function in children with ureteropelvic junction obstruction.

Importance: Extracellular matrix proteins and enzymes involved in degradation have been found to be associated with tissue fibrosis and ureteropelvic junction obstruction (UPJO). In this study we developed a promising urinary biomarker model which can identify reduced renal function in UPJ obstruction patients. This can potentially serve as a non-invasive way to enhance surgical decision making for patients and urologists.

Engineered RBCs Encapsulating Antigen Induce Multi-Modal Antigen-Specific Tolerance and Protect Against Type 1 Diabetes.

Antigen-specific therapies that suppress autoreactive T cells without inducing systemic immunosuppression are a much-needed treatment for autoimmune diseases, yet effective strategies remain elusive. We describe a microfluidic Cell Squeeze technology to engineer red blood cells (RBCs) encapsulating antigens to generate tolerizing antigen carriers (TACs). TACs exploit the natural route of RBC clearance enabling tolerogenic presentation of antigens.

Clinical outcome of pediatric and young adult subclinical varicoceles: a single-institution experience.

Subclinical varicocele represents an abnormality of veins of the pampiniform plexus on scrotal ultrasound (US) without a clinically palpable varicocele. Its significance remains unclear. While guidelines do not recommend surgical intervention, clinical management is variable.

DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody-Drug Conjugate Modality.

A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1-pyrrol-3-yl)benzene ("MPB") payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the "MPB" binding component and guided structure-activity relationship generation. This hybrid series of payloads exhibited excellent activity when tested against a panel of various cancer cell lines.

3D Culture Models with CRISPR Screens Reveal Hyperactive NRF2 as a Prerequisite for Spheroid Formation via Regulation of Proliferation and Ferroptosis.

Cancer-associated mutations that stabilize NRF2, an oxidant defense transcription factor, are predicted to promote tumor development. Here, utilizing 3D cancer spheroid models coupled with CRISPR-Cas9 screens, we investigate the molecular pathogenesis mediated by NRF2 hyperactivation. NRF2 hyperactivation was necessary for proliferation and survival in lung tumor spheroids.

Innate Immune Responses and Gut Microbiomes Distinguish HIV-Exposed from HIV-Unexposed Children in a Population-Specific Manner.

In both high- and low-income countries, HIV-negative children born to HIV-positive mothers (HIV exposed, uninfected [HEU]) are more susceptible to severe infection than HIV-unexposed, uninfected (HUU) children, with altered innate immunity hypothesized to be a cause. Both the gut microbiome and systemic innate immunity differ across biogeographically distinct settings, and the two are known to influence each other. And although the gut microbiome is influenced by HIV infection and may contribute to altered immunity, the biogeography of immune-microbiome correlations among HEU children have not been investigated.

Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome.

Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage.

Dynamic mitigation of EDFA power excursions with machine learning.

Dynamic optical networking has promising potential to support the rapidly changing traffic demands in metro and long-haul networks. However, the improvement in dynamicity is hindered by wavelength-dependent power excursions in gain-controlled erbium doped fiber amplifiers (EDFA) when channels change rapidly. We introduce a general approach that leverages machine learning (ML) to characterize and mitigate the power excursions of EDFA systems with different equipment and scales.

Collaborating with our adult colleagues: A case series of robotic surgery for suspicious and cancerous lesions in children and young adults performed in a free-standing children's hospital.

Background: In adult urologic oncology the use of robotics has become commonplace; in pediatric urology it is rare. Herein, we describe a collaboration between an adult and a pediatric urologist performing robotic surgery for children and young adults with suspicious or cancerous genitourinary (GU) lesions.

Objectives: To evaluate clinical and oncologic outcomes in children and young adults undergoing robotic surgery for suspicious or cancerous lesions of the GU tract; to describe our collaborative model between an adult and pediatric surgeon at a free-standing children's hospital.

Robot-assisted laparoscopic lower pole partial nephrectomy in the pediatric patient.

Introduction: In pediatric urology, partial nephrectomy is used primarily to remove a non-functioning renal moiety in a duplicated system. There are few data on infants undergoing this procedure. As such, we present a robot-assisted laparoscopic lower pole partial nephrectomy in an infant.

Pediatric Robot-Assisted Laparoscopic Pyeloplasty.

The laparoscopic approach to the pyeloplasty procedure has proven to be safe and effective in the pediatric population. Multiple studies have revealed outcomes comparable to the open approach. However, a major drawback to laparoscopy is the technical challenge of precise suturing in the small working space in children.

Urinary Proteomics Yield Pathological Insights for Ureteropelvic Junction Obstruction.

Prenatal hydronephrosis is a common condition that may spontaneously resolve after birth. However, this condition can result in renal damage and requires surgical correction in a number of cases. Preventing renal damage is paramount, but existing diagnostic technology is invasive, exposes infants to radiation, is costly, and is often indeterminate.

A Cyclic Peptide Mimic of the β-Amyloid Binding Domain on Transthyretin.

Self-association of β-amyloid (Aβ) into oligomers and fibrils is associated with Alzheimer's disease (AD), motivating the search for compounds that bind to and inhibit Aβ oligomerization and/or neurotoxicity. Peptides are an attractive class of such compounds, with potential advantages over small molecules in affinity and specificity. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to Aβ.

The surgical management of male epispadias in the new millennium.

Male epispadias is a rare and challenging urologic condition. As part of the epispadias-exstrophy complex of genitourinary anomalies, it covers a broad spectrum with the mildest forms being the rarest. The anatomic classification into glanular, penile, and penopubic is based on the location of the urethral meatus.

Transthyretin-derived peptides as β-amyloid inhibitors.

Self-association of β-amyloid (Aβ) into soluble oligomers and fibrillar aggregates is associated with Alzheimer's disease pathology, motivating the search for compounds that selectively bind to and inhibit Aβ oligomerization and/or neurotoxicity. Numerous small-molecule inhibitors of Aβ aggregation or toxicity have been reported in the literature. However, because of their greater size and complexity, peptides and peptidomimetics may afford improved specificity and affinity as Aβ aggregation modulators compared to small molecules.

Elevated inflammatory mediators in adults with oculorespiratory syndrome following influenza immunization: a public health agency of Canada/Canadian Institutes of Health Research Influenza Research Network Study.

Oculorespiratory syndrome (ORS) is an infrequent adverse event following influenza vaccination. Its clinical presentation suggests that ORS is an immune-mediated phenomenon, but studies of symptomatic individuals have been few. This study measured cytokine levels in peripheral blood samples following influenza vaccination in those with and without current ORS symptoms.

Transthyretin as both a sensor and a scavenger of β-amyloid oligomers.

Transthyretin (TTR) is a homotetrameric transport protein, assembled from monomers that each contain two four-stranded β-sheets and a short α-helix and loop. In the tetramer, the "inner" β-sheet forms a hydrophobic pocket while the helix and loop are solvent-exposed. β-Amyloid (Aβ) aggregates bind to TTR, and the level of binding is significantly reduced in mutants L82A (on the loop) and L110A (on the inner β-sheet).

Identification of beta-amyloid-binding sites on transthyretin.

Transthyretin (TTR) binds to the Alzheimer-related peptide beta-amyloid (Aβ), and may protect against Aβ-induced neurotoxicity. In this work, the specific domains on TTR involved with binding to Aβ were probed. An array was constructed of peptides derived from overlapping sequences from TTR.

The role of the Src family kinase Lyn in the immunomodulatory activities of cathelicidin peptide LL-37 on monocytic cells.

Cathelicidin LL-37 is a multifunctional, immunomodulatory and antimicrobial host-defense peptide of the human immune system. Here, we identified the role of SFKs in mediating the chemokine induction activity of LL-37 in monocytic cells. LL-37 induced SFK phosphorylation; and chemical inhibitors of SFKs suppressed chemokine production in response to LL-37 stimulation.

Approaches to avoid immune responses induced by repeated subcutaneous injections of allogeneic umbilical cord tissue-derived cells.

Background: Cellular treatments for repairing diseased tissues represent a promising clinical strategy. Umbilical cord tissue-derived cells (UTC) are a unique source of cells with a low immunogenic profile and potential for tissue repair. By using UTC from miniature swine, we previously demonstrated that despite their low immunogenic phenotype, UTC could induce an immune response under certain inflammatory conditions and after multiple subcutaneous (SC) injections.

Variables to be controlled in the assessment of blood innate immune responses to Toll-like receptor stimulation.

Variability in TLR function influences susceptibility to infectious as well as immune-mediated diseases. Given the outbred nature of humans, identifying functional Toll-like receptor variability and its role in clinical disease requires such analysis to be conducted in large, often multi-centered cohorts. Yet the technically complex measurements involved in innate immune analysis benefit from centralized processing of samples.

Myelogenous leukemia in adult inbred MHC-defined miniature swine: a model for human myeloid leukemias.

This manuscript reports on five cases of spontaneous myelogenous leukemia, similar to human disease, occurring within highly inbred, histocompatible sublines of Massachusetts General Hospital (MGH) MHC-defined miniature swine. In cases where a neoplasm was suspected based on clinical observations, samples were obtained for complete blood count, peripheral blood smear, and flow cytometric analysis. Animals confirmed to have neoplasms were euthanized and underwent necropsy.

Immunogenicity of umbilical cord tissue derived cells.

Umbilical cord tissue provides a unique source of cells with potential for tissue repair. Umbilical cord tissue-derived cells (UTCs) are MHC class I (MHCI) dull and negative for MHC class II (MHCII), but can be activated to increase MHCI and to express MHCII with IFN-gamma stimulation. Mesenchymal stem cells with similar characteristics have been inferred to be nonimmunogenic; however, in most cases, immunogenicity was not directly assessed.