Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation.

Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56bright or CD56dim mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18-activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies.

Examining the relationship between head trauma and opioid use disorder: A systematic review.

OBJECTIVE: To examine recent literature and determine common clinical risk factors between antecedent traumatic brain injury (TBI) and the following development of opioid misuse and provide a framework for clinical identification of at-risk subjects and evaluate potential treatment implications within this association. DESIGN: A comprehensive systematic literature search of PubMed was conducted for articles between 2000 and December 2022. Studies were included if the human participant had any head trauma exposure and any chronic opioid use or dependence. After eligibility criteria were applied, 16 studies were assessed for thematic trends. RESULTS: Opioid use disorder (OUD) risks are heightened in cohorts with head trauma exposed to opioids while in the hospital, specifically with tramadol and oxycodone. Chronic pain was the most common predictor of long-term OUD, and continuous somatic symptoms associated with the TBI can lead to long-term opioid usage. Individuals who present with coexisting psychiatric conditions pose significantly more risk associated with a higher risk of long-term opioid use. CONCLUSION: Findings indicate that therapists and clinicians must consider a risk profile for persons with TBI and follow an integrated care approach to account for mental health, prior substance misuse, presenting somatic symptoms, and current medication regimen during evaluation.

Exploring the link between ACEs and opioid use: A systematic review.

OBJECTIVE: To review the current literature surrounding the relationship between adverse childhood experiences (ACEs) and opioid use disorder (OUD) to guide clinical identification of high-risk individuals and assess treatment implications. DESIGN: A PubMed search was conducted from the year 2000 to 2022 using a series of primary and secondary search terms. A total of 21,524 unique results were screened for relevancy to ACEs and OUDs. After excluding unrelated articles, a total of 48 articles were included in this systematic review. RESULTS: Increased frequency of ACEs was directly related to increased risk of OUD and lower onset age. ACEs were also associated with OUD severity. ACEs linked to OUD included childhood neglect, emotional abuse, physical abuse, and sexual abuse. Additionally, dysfunctional childhood home environment, female gender, and psychiatric/behavioral comorbidities increased the risk of OUD, while resilience was found to be a protective factor. Multiple biochemical markers were associated with both ACEs and OUD. CONCLUSIONS: Children experiencing multiple ACEs should be the target of preventative intervention by medical professionals. Clinicians should include ACEs in their opioid misuse risk assessment. High incidence of co-occurring psychiatric/behavioral disorders provides multiple treatment avenues for patients with OUD. Resilience, along with being therapy target, should be fostered early in the life course. Incorporation of family members may improve opioid abuse treatment outcomes. Future research should focus on interventions interrupting the progression of ACEs to OUD along with proposed biochemical pathways.

An Etiological Investigation of Paraneoplastic Cerebellar Degeneration in Ovarian Cancer Patients: A Systematic Review.

Paraneoplastic syndromes (PNS) are uncommon, distinct clinical complications of a primary tumor. Paraneoplastic cerebellar degeneration (PCD) is a PNS that is described as an autoimmune response targeting Purkinje cells in the cerebellum. Ovarian cancer (OC) is one of the most prevalent causes of cancer-related deaths in women. Anti-Yo is the most common onconeural antibody produced in the PCD immune response and is most typically found in ovarian and breast cancer patients. While the current literature highlights the predisposing genetic factors, diagnostic workflows, and treatment options, the pathophysiology of PCD, among other considerations, remains largely unestablished. This review aimed to systematically observe procedural solutions to facilitate an early diagnosis and improve the prognosis of patients with OC-associated PCD. To that end, we examined literature published from 01/01/2015-11/10/2022 indexed in PubMed by using the keywords "paraneoplastic, cerebellar degeneration" combined with "ovarian cancer." Inclusion criteria were met if PCD and OC diagnoses were made and if studies provided adequate patient information. After screening and assessing records for eligibility using the inclusion and exclusion criteria, 18 articles involving 102 patients were included. The typical patient observed in this sample was diagnosed with International Federation of Gynecology and Obstetrics (FIGO) Stage III, high-grade serous carcinoma. The diagnostic workup typically included a clinical evaluation for dysarthria (50%), ataxia (60%), and gait abnormalities (50%), along with multiple imaging modalities and serological findings (90%). Genetic screening for human leukocyte antigen (HLA) haplotype susceptibility for PCD and immune tolerance modulators regulation may also be recommended prior to starting treatment. Findings support the use of corticosteroids (35%) and intravenous immunoglobulin (IVIg) (40%) as viable treatment options for managing PCD in conjunction with systemic therapy for the primary malignancy. A diagnosis of PCD should be considered if a patient has had a malignancy in the past five years with the presence of explicit cerebellar symptoms. This clinical diagnosis can be further supplemented by serologic and radiologic findings. Recognizing PCD symptoms and scheduling genetic and proteomic testing may help with early diagnosis and better prognosis.

Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis.

Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on skin and arteries of healthy mice versus those with psoriasis, which carries cardiovascular risk in man. Our findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to home to distal skin and later to arteries. There, these cells mediate thickening of the collagenous matrix, such that larger molecules including lipoproteins become entrapped. HDL transit was rescued by depleting CD4+ T cells, neutralizing interleukin-17, or inhibiting lysyl oxidase that crosslinks collagen. Experimental psoriasis also increased vascular stiffness and atherosclerosis via this common pathway. Thus, interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen.