Conformational Dynamics of an Amyloidogenic Intermediate of Transthyretin: Implications for Structural Remodeling and Amyloid Formation.

The aggregation pathway of transthyretin (TTR) proceeds through rate-limiting dissociation of the tetramer (a dimer of dimers) and partial misfolding of the resulting monomer, which assembles into amyloid structures through a downhill polymerization mechanism. The structural features of the aggregation-prone monomeric intermediate are poorly understood. NMR relaxation dispersion offers a unique opportunity to characterize amyloidogenic intermediates when they exchange on favorable timescales with NMR-visible ground states.

Stress and Anxiety Among Correctional Health Care Professionals in a U.S. State Prison System During COVID-19.

Since prisons were an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, the experience of correctional health care professionals (HCPs) may differ from HCPs in other settings. This cross-sectional descriptive study assessed stress, anxiety, and burnout levels in home and work environments among HCPs employed by one U.S.

Probing the Dissociation Pathway of a Kinetically Labile Transthyretin Mutant.

Aggregation of transthyretin (TTR) is associated with devastating amyloid diseases. Amyloidosis begins with the dissociation of the native homotetramer (a dimer of dimers) to form a monomeric intermediate that assembles into pathogenic aggregates. This process is accelerated at low pH, but the process by which TTR dissociates and reassembles at neutral pH remains poorly characterized due to the low population of intermediates.

Mental Health Treatment-Seeking Appraisal, Afrocentric Cultural Norms, and Mental Health Functioning: Buffering Factors of Young Black Men's Externalizing Behavior.

Background: Depression rates are disproportionately high among Black American Men. This disparity--compounded by low mental healthcare seeking rates and high incorrect diagnosis rates in men--could be related to masculine norms, including self-reliance, restrictive emotionality, and stoicism. Furthermore, men are more likely to engage in externalized behavior, such as aggression, to cope with mental health challenges; this pattern is influenced by cultural and environmental factors.

Method for estimation of apoptotic cell fraction of cytotherapy using in vivo fluorine-19 magnetic resonance: pilot study in a patient with head and neck carcinoma receiving tumor-infiltrating lymphocytes labeled with perfluorocarbon nanoemulsion.

Background: Adoptive transfer of T cells is a burgeoning cancer therapeutic approach. However, the fate of the cells, once transferred, is most often unknown. We describe the first clinical experience with a non-invasive biomarker to assay the apoptotic cell fraction (ACF) after cell therapy infusion, tested in the setting of head and neck squamous cell carcinoma (HNSCC).

Addressing Drug Resistance in Cancer: A Team Medicine Approach.

Drug resistance remains one of the major impediments to treating cancer. Although many patients respond well initially, resistance to therapy typically ensues. Several confounding factors appear to contribute to this challenge.

Molecular insights into the multifaceted functions and therapeutic targeting of high mobility group box 1 in metabolic diseases.

HMGB1 is a ubiquitously expressed protein localized in nucleus, cytoplasm, as well as secreted into extracellular space. Nuclear HMGB1 binds to DNAs and RNAs, regulating genomic stability and transcription. Cytoplasmic HMGB1 regulates autophagy through binding to core autophagy regulators.

Click-Ready Perfluorocarbon Nanoemulsion for F MRI and Multimodal Cellular Detection.

We describe an imaging probe platform that is readily modifiable to accommodate binding of different molecular targeting moieties and payloads for multimodal image generation. In this work, we demonstrate the utility of perfluorocarbon (PFC) nanoemulsions incorporating dibenzocyclooctyne (DBCO) by enabling postemulsification functionalization via a click reaction with azide-containing ligands. The addition of DBCO-lipid to the surfactant in PFC nanoemulsions did not affect nanoemulsion size or nanoemulsion stability.

Assessing Oximetry Response to Chimeric Antigen Receptor T-cell Therapy against Glioma with F MRI in a Murine Model.

Purpose: To assess the cell-specific, intracellular partial pressure of oxygen (Po) dynamics of both tumor and chimeric antigen receptor (CAR) T cells in a murine immunotherapy model.

Materials And Methods: Human glioblastoma cells or human T cells were intracellularly labeled with perfluorocarbon nanoemulsion droplet sensors prior to in vivo injection in severe combined immunodeficient mice to measure Po in the two cell types in response to treatment. Two main sets of experiments were performed: mice were injected in the flank with perfluorocarbon-labeled human glioblastoma cells and were then inoculated with either CAR T cells or untransduced T cells or were untreated 5 days after tumor inoculation; and mice with unlabeled glioblastoma tumors were inoculated with perfluorocarbon-labeled CAR T cells or untransduced T cells 5 days after tumor inoculation.

Metallofluorocarbon Nanoemulsion for Inflammatory Macrophage Detection via PET and MRI.

Inflammation is associated with a range of serious human conditions, including autoimmune and cardiovascular diseases and cancer. The ability to image active inflammatory processes greatly enhances our ability to diagnose and treat these diseases at an early stage. We describe molecular compositions enabling sensitive and precise imaging of inflammatory hotspots in vivo.

BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity.

MLL is a target of chromosomal translocations in acute leukemias with poor prognosis. The common MLL fusion partner AF9 (MLLT3) can directly bind to AF4, DOT1L, BCOR, and CBX8. To delineate the relevance of BCOR and CBX8 binding to MLL-AF9 for leukemogenesis, here we determine protein structures of AF9 complexes with CBX8 and BCOR, and show that binding of all four partners to AF9 is mutually exclusive.

Non-Small Cell Lung Cancer from Genomics to Therapeutics: A Framework for Community Practice Integration to Arrive at Personalized Therapy Strategies.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, and therapeutic management has advanced with the identification of various key oncogenic mutations that promote lung cancer tumorigenesis. Subsequent studies have developed targeted therapies against these oncogenes in the hope of personalizing therapy based on the molecular genomics of the tumor. This review presents approved treatments against actionable mutations in NSCLC as well as promising targets and therapies.

Implementing Lung Cancer Screening and Prevention in Academic Centers, Affiliated Network Offices and Collaborating Care Sites.

Lung cancer is one of the deadliest and yet largely preventable neoplasms. Smoking cessation and lung cancer screening are effective yet underutilized lung cancer interventions. City of Hope Medical Center, a National Cancer Institute (NCI)- designated comprehensive cancer center, has 27 community cancer centers and has prioritized tobacco control and lung cancer screening throughout its network.

Tankyrase inhibition sensitizes cells to CDK4 blockade.

Tankyrase (TNKS) 1/2 are positive regulators of WNT signaling by controlling the activity of the ß-catenin destruction complex. TNKS inhibitors provide an opportunity to suppress hyperactive WNT signaling in tumors, however, they have shown limited anti-proliferative activity as a monotherapy in human cancer cell lines. Here we perform a kinome-focused CRISPR screen to identify potential effective drug combinations with TNKS inhibition.

An examination of Latino advanced cancer patients' and their informal caregivers' preferences for communication about advance care planning: A qualitative study.

Objectives: Latino-advanced cancer patients engage in advance care planning (ACP) at lower rates than non-Latino patients. The goal of the present study was to understand patients' and caregivers' preferred methods of communicating about ACP.

Methods: Patients and caregivers were interviewed about cultural, religious, and familial beliefs that influence engagement in ACP and preferences for ACP communication.

Paramagnetic Fluorinated Nanoemulsions for in vivo F-19 MRI.

Purpose: We aim to develop perfluorocarbon-based nanoemulsions with improved sensitivity for detection of inflammatory macrophages in situ using F-19 MRI. Towards this goal, we evaluate the feasibility of nanoemulsion formulation incorporating a metal chelate in the fluorous phase which shortens the F-19 longitudinal relaxation rate and image acquisition time.

Procedures: Perfluorinated linear polymers were conjugated to metal-binding tris-diketonate, blended with unconjugated polymers, and emulsified in water.

Distinct Colorectal Cancer-Associated APC Mutations Dictate Response to Tankyrase Inhibition.

The majority of colorectal cancers show hyperactivated WNT signaling due to inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor. Genetically restoring APC suppresses WNT and induces rapid and sustained tumor regression, implying that reengaging this endogenous tumor-suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and organoid cultures, we show that tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control , but that effective responses are critically dependent on how APC is disrupted.