Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint.

The aminopeptidase, endoplasmic reticulum aminopeptidase 1 (ERAP1), trims peptides for loading into major histocompatibility complex class I (MHC class I), and loss of this activity has broad effects on the MHC class I peptidome. Here, we investigated the impact of targeting ERAP1 in immune checkpoint blockade (ICB), as MHC class I interactions mediate both activating and inhibitory functions in antitumor immunity. Loss of ERAP sensitized mouse tumor models to ICB, and this sensitivity depended on CD8 T cells and natural killer (NK) cells.

Development of compact transcriptional effectors using high-throughput measurements in diverse contexts.

Transcriptional effectors are protein domains known to activate or repress gene expression; however, a systematic understanding of which effector domains regulate transcription across genomic, cell type and DNA-binding domain (DBD) contexts is lacking. Here we develop dCas9-mediated high-throughput recruitment (HT-recruit), a pooled screening method for quantifying effector function at endogenous target genes and test effector function for a library containing 5,092 nuclear protein Pfam domains across varied contexts. We also map context dependencies of effectors drawn from unannotated protein regions using a larger library tiling chromatin regulators and transcription factors.

Risk Factors for Sacroiliac Joint Fusion after Instrumented Spinal Fusion.

Study Design: Retrospective Cohort Study.

Objective: To identify risk factors for sacroiliac (SI) joint fusion after instrumented spinal fusion.

Methods: Patients were identified from the PearlDiver BiscayneBay database.

Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion.

Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogenous tumors may display variability in their aggressiveness, and how immunologic-factors impinge on their aggressiveness remains understudied. Here we studied the mechanisms responsible for the immune-escape of murine tumors with low ITH.

Glioma synapses recruit mechanisms of adaptive plasticity.

The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. The consequent glioma cell membrane depolarization drives tumour proliferation.

Association between cervical fracture patterns and blunt cerebrovascular injury when screened with computed tomographic angiography.

Background Context: Prior studies have demonstrated a close association between cervical spine fractures and blunt cerebrovascular injuries (BCVI). Undiagnosed BCVI is a feared complication because of the potentially catastrophic outcomes in a missed posterior circulation stroke. Computed tomography angiography (CTA) is commonly used to screen BCVI in the trauma setting.

Systematic discovery of recombinases for efficient integration of large DNA sequences into the human genome.

Large serine recombinases (LSRs) are DNA integrases that facilitate the site-specific integration of mobile genetic elements into bacterial genomes. Only a few LSRs, such as Bxb1 and PhiC31, have been characterized to date, with limited efficiency as tools for DNA integration in human cells. In this study, we developed a computational approach to identify thousands of LSRs and their DNA attachment sites, expanding known LSR diversity by >100-fold and enabling the prediction of their insertion site specificities.

In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer.

The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1/HLA-E.

Cervical fracture patterns associated with blunt cerebrovascular injures when utilizing computed tomographic angiography: a systematic review and meta-analysis.

Background Context: Prior studies have demonstrated an association between cervical spine fractures and blunt cerebrovascular injuries (BCVI) due to the intimate anatomic relationship between the cervical spine and the vertebral arteries. Digital subtraction angiography (DSA) has historically been the gold standard, but computed tomography angiography (CTA) is commonly used to screen for BCVI in the trauma setting. However, there is no consensus regarding which fracture patterns mandate screening.

Checkpoint blockade-induced CD8+ T cell differentiation in head and neck cancer responders.

Background: Immune checkpoint blockade (ICB) response in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is limited to 15%-20% of patients and underpinnings of resistance remain undefined.

Methods: Starting with an anti-PD1 sensitive murine HNSCC cell line, we generated an isogenic anti-PD1 resistant model. Mass cytometry was used to delineate tumor microenvironments of both sensitive parental murine oral carcinoma (MOC1) and resistant MOC1esc1 tumors.

Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.

Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape.

Early detection of T-cell lymphoma with T follicular helper phenotype by RHOA mutation analysis.

Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma with T follicular helper phenotype (PTCL-TFH) are a group of complex clinicopathological entities that originate from T follicular helper cells and share a similar mutation profile. Their diagnosis is often a challenge, particularly at an early stage, because of a lack of specific histological and immunophenotypic features, paucity of neoplastic T cells and prominent polymorphous infiltrate. We investigated whether the lymphoma-associated RHOA Gly17Val (c.

In vivo screens using a selective CRISPR antigen removal lentiviral vector system reveal immune dependencies in renal cell carcinoma.

CRISPR-Cas9 genome engineering has increased the pace of discovery for immunology and cancer biology, revealing potential therapeutic targets and providing insight into mechanisms underlying resistance to immunotherapy. However, endogenous immune recognition of Cas9 has limited the applicability of CRISPR technologies in vivo. Here, we characterized immune responses against Cas9 and other expressed CRISPR vector components that cause antigen-specific tumor rejection in several mouse cancer models.

Changes in knee kinematics from applied external Tibial torque: Implications for stabilizing an anterior cruciate ligament deficient knee.

Background: Changes in knee kinematics from internal tibial torque under tibiofemoral compression force have been studied, but the potentially stabilizing effects of external tibial torque have not been reported. We hypothesized that for a given knee flexion angle, 1) external torque would significantly reduce anterior tibial translation, internal tibial rotation, and valgus tibial rotation before and after sectioning the anterior cruciate ligament and 2) changes in kinematics from applied external torque would be significantly greater with the cruciate cut.

Methods: A robotic test system was used to flex intact human knees continuously from 0° to 50° under 200 N compression, without and with 5 Nm external torque.

Research Productivity of Foot and Ankle Fellowship Faculty.

Background: Contribution to literature is critical for progress in the field of orthopaedics. No previous study has yet examined the academic productivity of foot and ankle surgery fellowship faculty.

Purpose: To evaluate the publishing productivity of foot and ankle fellowship faculty.

Website evaluation for shoulder and elbow fellowships in the United States: an evaluation of accessibility and content.

Hypothesis And/or Background: When examining the access and content related to shoulder and elbow fellowship websites, only 64% of programs had individual websites in a query performed 5 years earlier. The purpose of this study was to re-evaluate content about individual programs listed on the American Shoulder and Elbow Surgeons (ASES) website and on individual program websites and compare the results to prior data.

Methods: The ASES website was accessed to determine both the number of ASES-recognized shoulder and elbow fellowships and the number of direct links to fellowship program websites.

An Update on Foot and Ankle Fellowship Website Content and Accessibility.

Background: The content and accessibility of foot and ankle fellowship websites impact applicants and fellowship programs. This study aimed to evaluate the accessibility provided via the American Orthopaedic Foot & Ankle Society (AOFAS) websites and individual websites.

Methods: The AOFAS website was used to identify existing foot and ankle fellowship programs.

Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade.

Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively.

Femoral Contact Forces in the Anterior Cruciate Ligament Deficient Knee: A Robotic Study.

Purpose: To measure contact forces (CFs) at standardized locations representative of clinical articular cartilage defects on the medial and lateral femoral condyles during robotic tests with simulated weightbearing knee flexion.

Methods: Eleven human knees had 20-mm-diameter cylinders of native bone/cartilage cored from both femoral condyles at standardized locations, with each cylinder attached to a custom-built load cell that maintained the plug in its precise anatomic position. A robotic test system was used to flex the knee from 0° to 50° under 200-N tibiofemoral compression without and with a 2 Nm internal tibial torque, 5 Nm external tibial torque, and 45 N anterior tibial force (AF).

Contact force between the tibial spine and medial femoral condyle: A biomechanical study.

Background: Contact between the tibial spine and medial femoral condyle with internal tibial rotation (ITR) has been proposed as a factor for the development of osteochondritis dissecans lesions. We hypothesized that tibial spine contact force (CF) would increase significantly with applied internal tibial torque (IT).

Methods: A 20 mm diameter cylinder of bone encompassing the tibial spine was cored and attached to a load cell.