Circulating cytokine associations with clinical outcomes in melanoma patients treated with combination nivolumab plus ipilimumab.

Nivolumab plus ipilimumab (aCTLA-4/aPD-1) combination therapy has significantly improved clinical outcomes in patients with metastatic melanoma, with 50%-60% of patients responding to treatment, but predictors of response are poorly characterized. We hypothesized that circulating cytokines and peripheral white blood cells may predict response to therapy and evaluated 15 cytokines and complete blood counts (CBC with differentials) from 89 patients with advanced melanoma treated with combination therapy from three points in time: pre-treatment, one month and approximately three months after starting therapy. Clinical endpoints evaluated included durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS).

Percutaneous Transcatheter Approach to Partial Anomalous Pulmonary Venous Return: A Case Series.

Our study presents cases demonstrating the technique and safety of percutaneous occlusion of adult patients with partial anomalous pulmonary venous return (PAPVR). PAPVR is a rare condition that is traditionally treated surgically. Percutaneous interventions are rarely reported.

The dynamics of hematopoiesis over the human lifespan.

Over a lifetime, hematopoietic stem cells (HSCs) adjust their lineage output to support age-aligned physiology. In model organisms, stereotypic waves of hematopoiesis have been observed corresponding to defined age-biased HSC hallmarks. However, how the properties of hematopoietic stem and progenitor cells change over the human lifespan remains unclear.

Overcoming Resistance Mechanisms to Melanoma Immunotherapy.

The advent of immune checkpoint inhibition has revolutionized treatment of advanced melanoma. While most patients derive survival benefit from established immunotherapies, notably monoclonal antibodies blocking cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1, a subset does not optimally respond due to the manifestation of innate or acquired resistance to these therapies. Combination regimens have proven efficacious relative to single-agent blockade, but also yield high-grade treatment toxicities that are often dose-limiting for patients.

Safer and efficient base editing and prime editing via ribonucleoproteins delivered through optimized lipid-nanoparticle formulations.

Delivering ribonucleoproteins (RNPs) for in vivo genome editing is safer than using viruses encoding for Cas9 and its respective guide RNA. However, transient RNP activity does not typically lead to optimal editing outcomes. Here we show that the efficiency of delivering RNPs can be enhanced by cell-penetrating peptides (covalently fused to the protein or as excipients) and that lipid nanoparticles (LNPs) encapsulating RNPs can be optimized for enhanced RNP stability, delivery efficiency and editing potency.

Nurse Care Management of Opioid Use Disorder Treatment After 3 Years: A Secondary Analysis of the PROUD Cluster Randomized Clinical Trial.

Importance: The Primary Care Opioid Use Disorders (PROUD) treatment trial was a 2-year implementation trial that demonstrated the Massachusetts office-based addiction treatment (OBAT) model of nurse care management for opioid use disorder (OUD) increased OUD treatment in the 2 years after implementation began (8.2 more patient-years of OUD treatment per 10 000 primary care patients). The intervention was continued for a third year, permitting evaluation of 3-year outcomes.

In vivo photoreceptor base editing ameliorates rhodopsin-E150K autosomal-recessive retinitis pigmentosa in mice.

Rhodopsin, the prototypical class-A G-protein coupled receptor, is a highly sensitive receptor for light that enables phototransduction in rod photoreceptors. Rhodopsin plays not only a sensory role but also a structural role as a major component of the rod outer segment disc, comprising over 90% of the protein content of the disc membrane. Mutations in which lead to structural or functional abnormalities, including the autosomal recessive E150K mutation, result in rod dysfunction and death.

Directed evolution of engineered virus-like particles with improved production and transduction efficiencies.

Engineered virus-like particles (eVLPs) are promising vehicles for transient delivery of proteins and RNAs, including gene editing agents. We report a system for the laboratory evolution of eVLPs that enables the discovery of eVLP variants with improved properties. The system uses barcoded guide RNAs loaded within DNA-free eVLP-packaged cargos to uniquely label each eVLP variant in a library, enabling the identification of desired variants following selections for desired properties.

EvoAI enables extreme compression and reconstruction of the protein sequence space.

Designing proteins with improved functions requires a deep understanding of how sequence and function are related, a vast space that is hard to explore. The ability to efficiently compress this space by identifying functionally important features is extremely valuable. Here we establish a method called EvoScan to comprehensively segment and scan the high-fitness sequence space to obtain anchor points that capture its essential features, especially in high dimensions.

Tumor-Associated Tractography Derived from High-Angular-Resolution Q-Space MRI May Predict Patterns of Cellular Invasion in Glioblastoma.

Background: The invasion of glioblastoma cells beyond the visible tumor margin depicted by conventional neuroimaging is believed to mediate recurrence and predict poor survival. Radiomic biomarkers that are associated with the direction and extent of tumor infiltration are, however, non-existent.

Methods: Patients from a single center with newly diagnosed glioblastoma ( = 7) underwent preoperative Q-space magnetic resonance imaging (QSI; 3T, 64 gradient directions, b = 1000 s/mm) between 2018 and 2019.

Targeting RAF1 gene fusions with MEK inhibition in metastatic melanoma.

The biological and clinical relevance of gene fusions in melanoma is unknown. Reports and preclinical data have suggested that tumor cells with specific rearrangements such as RAF1 gene fusions could be therapeutically targeted. To investigate the relevance of targeted therapy in patients with melanoma harboring RAF1 gene fusions, we reviewed records of 1268 melanoma patients with targeted sequencing data at the Dana-Farber Cancer Institute.

Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.

Precise repair of the pathogenic mutation in hematopoietic stem cells (HSCs) represents an ideal cure for patients with sickle cell disease (SCD). Here, we demonstrate correction of the SCD phenotype by converting the sickle mutation codon (GTG) into a benign G-Makassar variant (GCG) using in vivo base editing in HSCs. We show successful production of helper-dependent adenoviral vectors expressing an all-in-one base editor mapping to the sickle mutation site.

Comprehensive Dynamic 3-Dimensional Analysis of the Tricuspid Valve in Functional Tricuspid Regurgitation: Implications for Prophylactic Tricuspid Valve Intervention.

Objectives: To track and measure changes in the tricuspid annulus (TA) using 3-dimensional (3D) echocardiography during a complete cardiac cycle in patients with functional tricuspid regurgitation (TR) compared to patients without TR, and to compare tricuspid annular plane systolic excursion (TAPSE) derived from 2-dimensional (2D) and 3D coordinates as a measure of right ventricular (RV) function to the standard method of 2D fractional area change (FAC).

Design: Intraoperative 3D echocardiography data were collected prospectively, followed by postprocessing software analysis to track and reconstruct changes throughout the cardiac cycle.

Setting: Data were collected from 108 patients undergoing left-sided heart surgery at 2 large academic centers-Beth Israel Deaconess Medical Center in Boston, MA and Rhode Island Hospital, Providence, RI-between November 2018 and April 2020.

Beyond seizure freedom: Reduction in anti-seizure medication after epilepsy surgery.

Introduction: Patients considering therapeutic epilepsy surgery often seek to decrease the number of anti-seizure medications (ASMs) they need. Predicting such reductions remains challenging. Although predictors of seizure freedom after epilepsy surgery are well-established, long-term outcomes remain modest and factors associated with ASM reduction, even in the absence of seizure freedom, may improve surgical planning to align with patient goals.

Odontoid fractures in the pediatric population: a systematic review and management algorithm.

Purpose: The management of odontoid fractures in adult patients has been widely described. However, there is sparse literature about this injury in the pediatric population. This study aimed to review published literature regarding the management and outcomes of pediatric odontoid fractures to develop a stepwise treatment algorithm.