Liver Transplantation for Polycystic Disease: Experience and Results of a Single-Center Series.

Polycystic liver disease (PLD) is a hereditary condition, and its symptoms are due to the growth of cysts. Liver transplantation (LT) is the only curative treatment. A retrospective single-center analysis was conducted on the 10 LTs performed for PLD between 2004 and 2023.

Preservation of Liver Graft Using the Hypothermic Oxygenated Perfusion (HOPE) System: A single-center experience.

Introduction: The hypothermic oxygenated perfusion (HOPE) system has been developed to improve the quality of previously considered suboptimal liver grafts, reduce complications, and increase the number of available donors. The aim of this study is to evaluate the results since its implementation in the liver transplant (LT) program at our center.

Materials And Methods: We conducted a retrospective descriptive analysis of all LTs with HOPE from August 2022 to November 2023 with a minimum follow-up of 3 months.

Definition and assessment of psychological frailty in older adults: A scoping review.

Objectives: The confusion surrounding psychological frailty and its components prompts the need for a standardized conceptual definition. To address this, we aimed to (1) identify the psychological variables included in multicomponent frailty assessment instruments used with older adults and examine their operationalization; and (2) formulate a thorough conceptualization of psychological frailty based on the variables identified.

Methods: This study followed the most recent recommendations for conducting scoping reviews and is reported in accordance with PRISMA-ScR guidelines.

Regional and intratumoral adoptive T-cell therapy.

Adoptive T-cell therapies (ACTs) including tumor-infiltrating lymphocytes and engineered T cells (transgenic T-cell receptor and chimeric antigen receptor T cells), have made an important impact in the field of cancer treatment over the past years. Most of these therapies are typically administered systemically in approaches that facilitate the elimination of hematologic malignancies. Therapeutical efficacy against solid tumors, however, with the exception of tumor-infiltrating lymphocytes against melanoma, remains limited due to several barriers preventing lymphocyte access to the tumor bed.

CAR-engineered lymphocyte persistence is governed by a FAS ligand/FAS auto-regulatory circuit.

Chimeric antigen receptor (CAR)-engineered T and NK cells can cause durable remission of B-cell malignancies; however, limited persistence restrains the full potential of these therapies in many patients. The FAS ligand (FAS-L)/FAS pathway governs naturally-occurring lymphocyte homeostasis, yet knowledge of which cells express FAS-L in patients and whether these sources compromise CAR persistence remains incomplete. Here, we constructed a single-cell atlas of diverse cancer types to identify cellular subsets expressing , the gene encoding FAS-L.

Defining and assessing psychological frailty in older adults: a scoping review protocol.

Introduction: Frailty is widely acknowledged as a multidimensional construct encompassing physical, psychological and social aspects. However, the lack of consensus in defining and operationalising psychological frailty challenges the holistic approach to frailty advocated by health professionals. Consequently, there is a need to develop a comprehensive definition of psychological frailty based on contributions made by experts in the field, primarily existing frailty assessment tools.

Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens.

T-cell-mediated immunotherapies are limited by the extent to which cancer-specific antigens are homogenously expressed throughout a tumor. We reasoned that recurrent splicing aberrations in cancer represent a potential source of tumor-wide and public neoantigens, and to test this possibility, we developed a novel pipeline for identifying neojunctions expressed uniformly within a tumor across diverse cancer types. Our analyses revealed multiple neojunctions that recur across patients and either exhibited intratumor heterogeneity or, in some cases, were tumor-wide.

Synergistic effects of combined immunotherapy strategies in a model of multifocal hepatocellular carcinoma.

Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular carcinoma (HCC) patients, but improvements in efficacy are needed to improve response rates. We develop a multifocal HCC model to test immunotherapies by introducing c-myc using hydrodynamic gene transfer along with CRISPR-Cas9-mediated disruption of p53 in mouse hepatocytes. Additionally, induced co-expression of luciferase, EGFP, and the melanosomal antigen gp100 facilitates studies on the underlying immunological mechanisms.

mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy.

Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their systemic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engineered with mRNAs to express either single-chain IL-12 (scIL-12) or an IL-18 decoy-resistant variant (DRIL18) that is not functionally hampered by IL-18 binding protein (IL-18BP).

Intracavitary adoptive transfer of IL-12 mRNA-engineered tumor-specific CD8 T cells eradicates peritoneal metastases in mouse models.

Previous studies have shown that local delivery of tumor antigen-specific CD8 T lymphocytes engineered to transiently express single-chain IL-12 mRNA is highly efficacious. Peritoneal dissemination of cancer is a frequent and often fatal patient condition usually diagnosed when the tumor burden is too large and hence uncontrollable with current treatment options. In this study, we have modeled intracavitary adoptive T cell therapy with OVA-specific OT-I T cells electroporated with IL-12 mRNA to treat B16-OVA and PANC02-OVA tumor spread in the peritoneal cavity.

Intratumoral Gene Transfer of mRNAs Encoding IL12 in Combination with Decoy-Resistant IL18 Improves Local and Systemic Antitumor Immunity.

IL12-based local gene therapy of cancer constitutes an active area of clinical research using plasmids, mRNAs, and viral vectors. To improve antitumor effects, we have experimentally tested the combination of mRNA constructs encoding IL12 and IL18. Moreover, we have used a form of IL18 [decoy-resistant IL18 (DR-18)] which has preserved bioactivity but does not bind to the IL18 binding protein decoy receptor.

A Therapeutically Actionable Protumoral Axis of Cytokines Involving IL-8, TNFα, and IL-1β.

Unlabelled: Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL8 mRNA levels correlate with IL1B and TNF transcripts. Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon carcinoma organoids, and fresh human tumor explants.

Primary and Secondary Caregivers of People with Dementia (PwD): Differential Patterns and Implications for Psychological Support.

Very little attention has been paid to identifying the differential characteristics of primary and secondary dementia caregivers. The aims of this study were: to determine whether differences exist between primary and secondary caregivers of people with dementia (PwD) and to explore the profile of primary and secondary caregivers reporting symptoms of anxiety and/or depression. The participants were 146 caregivers of PwD, 73 primary caregivers and 73 secondary caregivers.

Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.

Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele.

Stress self-perception and burnout in chiropractic students in a lockdown situation due to COVID-19: A cross-sectional and comparative study.

Objective: The purpose of this study was to investigate if COVID-19 lockdown affected stress-perception and burnout in chiropractic students from our institution.

Methods: Stress and burnout in students were assessed using the Perceived Stress Scale and the Maslach Burnout Inventory. The surveys were sent out electronically in March 2020 to chiropractic students enrolled at our college.

CD137 (4-1BB) costimulation of CD8 T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation.

CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human.

Antitumor efficacy and reduced toxicity using an anti-CD137 Probody therapeutic.

Costimulation via CD137 (4-1BB) enhances antitumor immunity mediated by cytotoxic T lymphocytes. Anti-CD137 agonist antibodies elicit mild liver inflammation in mice, and the maximum tolerated dose of Urelumab, an anti-human CD137 agonist monoclonal antibody, in the clinic was defined by liver inflammation-related side effects. A protease-activated prodrug form of the anti-mouse CD137 agonist antibody 1D8 (1D8 Probody therapeutic, Pb-Tx) was constructed and found to be selectively activated in the tumor microenvironment.

New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis.

CD137 (4-1BB) is a surface glycoprotein that belongs to the tumour necrosis factor receptor family (TNFRSF9). Its expression is induced on activation on a number of leucocyte types. Interestingly, for cancer immunotherapy, CD137 becomes expressed on primed T and natural killer (NK) cells, which on ligation provides powerful costimulatory signals.

Engineering bionic T cells: signal 1, signal 2, signal 3, reprogramming and the removal of inhibitory mechanisms.

Gene engineering and combinatorial approaches with other cancer immunotherapy agents may confer capabilities enabling full tumor rejection by adoptive T cell therapy (ACT). The provision of proper costimulatory receptor activity and cytokine stimuli, along with the repression of inhibitory mechanisms, will conceivably make the most of these treatment strategies. In this sense, T cells can be genetically manipulated to become refractory to suppressive mechanisms and exhaustion, last longer and differentiate into memory T cells while endowed with the ability to traffic to malignant tissues.

Online support for family caregivers of people with dementia: a systematic review and meta-analysis of RCTs and quasi-experimental studies.

Online interventions focused on mitigating the negative impact of care on family caregivers of people with dementia have become increasingly popular recently. The aim of this systematic review and meta-analysis was to analyze the effectiveness of these online support programs and to assess whether they do indeed enhance participants' wellbeing. A systematic literature search of 5 scientific databases was performed: PubMed, PsycInfo, CINAHL, Web of Science and Cochrane Library.

Human CD8 T cells are susceptible to TNF-mediated activation-induced cell death.

Activation-induced cell death (AICD) is a complex immunoregulatory mechanism that causes the demise of a fraction of T-lymphocytes upon antigen-driven activation. In the present study we investigated the direct role of TNF in AICD of CD8 T lymphocytes. : Human peripheral mononuclear cells were isolated from healthy donors and fresh tumor-infiltrating lymphocytes were obtained from cancer patients undergoing surgery.

CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity.

Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis.

Exploiting TCR Recognition of Shared Hotspot Oncogene-encoded Neoantigens.

T-cell recognizable p53 hotspot mutations offer opportunities for immunotherapy and immune monitoring. Recognition of p53 mutations by peripheral blood CD8 and CD4 T lymphocytes has been revealed..

Intratumor Adoptive Transfer of IL-12 mRNA Transiently Engineered Antitumor CD8 T Cells.

Retroviral gene transfer of interleukin-12 (IL-12) into T cells markedly enhances antitumor efficacy upon adoptive transfer but has clinically shown unacceptable severe side effects. To overcome the toxicity, we engineered tumor-specific CD8 T cells to transiently express IL-12. Engineered T cells injected intratumorally, but not intravenously, led to complete rejections not only of the injected lesion but also of distant concomitant tumors.

Repurposing the yellow fever vaccine for intratumoral immunotherapy.

Live 17D is widely used as a prophylactic vaccine strain for yellow fever virus that induces potent neutralizing humoral and cellular immunity against the wild-type pathogen. 17D replicates and kills mouse and human tumor cell lines but not non-transformed human cells. Intratumoral injections with viable 17D markedly delay transplanted tumor progression in a CD8 T-cell-dependent manner.