This longitudinal study among Registered Nurses has four purposes: (1) to investigate whether emotional, quantitative and physical demands, and family-work conflict have a negative impact on nurses' ...perceived effort; (2) to investigate whether quality of leadership, developmental opportunities, and social support from supervisors and colleagues have a positive impact on meaning of work; (3) to investigate whether burnout from the combined impact of perceived effort and meaning of work mediates the relationship with occupational turnover intention; and (4) whether the relationships in our overall hypothesized framework are moderated by age (nurses categorized under 40 years versus ≥ 40 years old). In line with our expectations, emotional, quantitative, and physical demands, plus family-work conflict appeared to increase levels of perceived effort. Quality of leadership, developmental opportunities, and social support from supervisors and colleagues increased the meaning of work levels. In addition, increased perceived stress resulted in higher burnout levels, while increased meaning of work resulted in decreased burnout levels. Finally, higher burnout levels appeared to lead to a higher occupational turnover intention. Obviously, a nursing workforce that is in good physical and psychological condition is only conceivable when health care managers protect the employability of their nursing staff, and when there is a dual responsibility for a sustainable workforce. Additionally, thorough attention for the character of job demands and job resources according to nurses' age category is necessary in creating meaningful management interventions.
Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists. Here we report ...the rational design and optimization of bispecific CAR-T cells with robust activity against heterogeneous multiple myeloma (MM) that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit superior CAR expression and function compared to T cells that co-express individual BCMA and CS1 CARs. Combination therapy with anti-PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, while CAR-T cell treatment alone achieves durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.
CAR T cells ignite antitumor immunity Alizadeh, Darya; Brown, Christine E.
Trends in immunology,
October 2023, 2023-10-00, 20231001, Volume:
44, Issue:
10
Journal Article
Peer reviewed
Broadening immune responses through antigen spreading remains the ‘Holy Grail’ of cancer immunotherapy. A study by Ma and colleagues reveals that vaccine boosting of chimeric antigen receptor (CAR)-T ...cells in mice promotes endogenous immunity and elicits antigen spread to eliminate antigenically heterogenous solid tumors through a mechanism crucially dependent on interferon (IFN)γ.
Broadening immune responses through antigen spreading remains the ‘Holy Grail’ of cancer immunotherapy. A study by Ma and colleagues reveals that vaccine boosting of chimeric antigen receptor (CAR)-T cells in mice promotes endogenous immunity and elicits antigen spread to eliminate antigenically heterogenous solid tumors through a mechanism crucially dependent on interferon (IFN)γ.
Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, ...provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.
No tabular summary of potentially life-threatening, kidney-toxic dietary supplements (DS; includes herbs) based on PubMed case reports is currently available online and continually updated to ...forewarn United States consumers, clinicians, and companies manufacturing DS. The purpose of this review was to create an online research summary table of kidney toxicity case reports related to DS.
Documented PubMed case reports (1966 to May 2016, and cross-referencing) of DS appearing to contribute to kidney toxicity were listed in “DS Toxic Tables.” Keywords included “herb” or “dietary supplement” combined with “kidney” to generate an overview list, and possibly “toxicity” to narrow the selection. Case reports were excluded if they involved herb combinations (some exceptions), Chinese herb mixtures, teas of mixed herb contents, mushrooms, poisonous plants, self-harm, excessive doses (except vitamins/minerals), legal or illegal drugs, drug-herbal interactions, and confounders of drugs or diseases. Since commercial DS often include a combination of ingredients, they were treated separately; so were foods. A few foods with kidney-toxic effects were listed in a fourth table. The spectrum of herbal or DS-induced kidney injuries included kidney stones, nephritis, nephrotic syndrome, necrosis, acute kidney injury (AKI; previously known as acute renal failure ARF), chronic kidney disease, kidney transplant, and death.
Approximately 7 herbs (minus 4 no longer for sale) and 10 dietary supplements (minus 3 excluded due to excessive doses + germanium that is no longer sold) have been related to kidney injury case reports published in PubMed (+crosslisting) in the last 50 + years (1966 to May 2016). The implicated herbs include Chinese yew (Taxus celbica) extract, impila (Callilepis laureola), morning cypress (Cupressus funebris Endl), St. John's wort (Hypericum perforatum), thundergod vine (Tripterygium wilfordii hook F), tribulus (Tribulus terrestris) and wormwood (Artemisia herba-alba). No longer sold in the United States are chocolate vine or mu tong (Caulis aristolochiae), guang fang ji (Aristolochia fangchi), ma huang (Ephedra sinica), and Tenshin Tokishigyaku-ka-goshuyu-shokyo-to. The DS include bile (sheep), chlorella, chromium (Cr), CKLS, creatine, gallbladder (fish), glucosamine, hydrazine, N.O.-Xplode, Spanish fly, and excess intakes of vitamins A, C, and D. Germanium (Ge) is not available for sale. The top two DS with the largest number of reported publications, but not always case reports, in descending order, were the aristolochic acid-containing herbs guang fang ji (mistaken identity) and chocolate vine or mu tong. The remaining DS featured one to three publications over a 50+ year period. Numerous case reports were reported for kidney-toxic foods: djenkol bean, gallbladders (carp fish, pufferfish, & snake), and star fruit (only in chronic kidney disease patients), and uncooked yam powder or juice.
This online “DS Toxic Table” provides clinicians, consumers, and manufacturers with a list of herbs that could potentially contribute to kidney injuries.
The global impact of dementia is a key healthcare priority, and although it is possible to live well with dementia, public perception is often negative. Serious digital games are becoming a credible ...delivery method to educate/train individuals in the business and health sectors and to challenge perceptions. The main objective of the study was to evaluate the effectiveness of a digital game prototype on individual attitudes towards dementia. A digital game to improve public knowledge and understanding about dementia (www.dementiagame.com) was co-designed with people living with dementia and student nurses. The Game was evaluated using a pretest-posttest design. Participants for the evaluation were recruited via social media in one UK university and completed the Approaches to Dementia Questionnaire (ADQ) before and after playing the game. Overall, 457 individuals completed both pre and post test questionnaires. The total ADQ score demonstrated a significant improvement in positive attitudes (p < 0.001), and both subscales of Hope and Recognition of Personhood also saw significant improvements (p < 0.001). The use of a serious digital game has demonstrated a significant effect on the respondents' perceptions of dementia. Overall, there was a more positive view of the abilities of people with dementia and what their capabilities were. They were also more likely to be recognised as unique individuals with the same values as any other person. The benefit of using digital gaming to improve perceptions of dementia has been demonstrated, nonetheless further research is required to reach a more diverse population and test as a Randomised Control Trial to provide definitive evidence for use in policy and practice.
Adoptive cellular immunotherapy (ACT) employing engineered T lymphocytes expressing chimeric antigen receptors (CARs) has demonstrated promising antitumor effects in advanced hematologic cancers, ...such as relapsed or refractory acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, supporting the translation of ACT to non-hematological malignancies. Although CAR T cell therapy has made remarkable strides in the treatment of patients with certain hematological cancers, in solid tumors success has been limited likely due to heterogeneous antigen expression, immunosuppressive networks in the tumor microenvironment limiting CAR T cell function and persistence, and suboptimal trafficking to solid tumors. Here, we outline specific approaches to overcome barriers to CAR T cell effectiveness in the context of the tumor microenvironment and offer our perspective on how expanding the use of CAR T cells in solid tumors may require modifications in CAR T cell design. We anticipate these modifications will further expand CAR T cell therapy in clinical practice.
No online current list of potentially life-threatening, hepatotoxic herbs and dietary supplements based on PubMed case reports exists in a summarized tabular form.
Documented case reports of herbs or ...dietary supplements (DS; includes herbs) appearing to contribute to liver injury were used to create an online “DS Toxic Table” of potentially hepatotoxic herbs and dietary supplements (PubMed, 1966 to June, 2016, and cross-referencing). The spectrum of DS induced liver injuries (DSILI) included elevated liver enzymes, hepatitis, steatosis, cholestasis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, veno-occlusive disease, acute liver failure requiring a liver transplant, and death.
Over the past 50 years, approximately 21 herbs (minus germander and usnic acid that are no longer sold) and 12 dietary supplements (minus the nine no longer sold and vitamin A & niacin due to excess intake) posed a possible risk for liver injures in certain individuals. The herbs with the most number of reported publications (but not cases studies) in descending order, were germander, black cohosh, kava extract, and green tea extract.
These online DS Toxic Tables will contribute to continued Phase IV post marketing surveillance to detect possible liver toxicity cases and serve to forewarn consumers, clinicians, and corporations.
Unlimited generation of chimeric antigen receptor (CAR) T cells from human-induced pluripotent stem cells (iPSCs) is an attractive approach for “off-the-shelf” CAR T cell immunotherapy. Approaches to ...efficiently differentiate iPSCs into canonical αβ T cell lineages, while maintaining CAR expression and functionality, however, have been challenging. We report that iPSCs reprogramed from CD62L+ naive and memory T cells followed by CD19-CAR engineering and 3D-organoid system differentiation confers products with conventional CD8αβ-positive CAR T cell characteristics. Expanded iPSC CD19-CAR T cells showed comparable antigen-specific activation, degranulation, cytotoxicity, and cytokine secretion compared with conventional CD19-CAR T cells and maintained homogeneous expression of the TCR derived from the initial clone. iPSC CD19-CAR T cells also mediated potent antitumor activity in vivo, prolonging survival of mice with CD19+ human tumor xenografts. Our study establishes feasible methodologies to generate highly functional CAR T cells from iPSCs to support the development of “off-the-shelf” manufacturing strategies.
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•3D-organoid culture supports differentiation of CAR+ iPSCs into functional CAR T cells•iPSC-derived CAR T cells demonstrate conventional αβ T cell phenotypes•iPSC-derived CAR T cells show lower CAR expression and a homogeneous TCR repertoire•iPSC-derived CAR T cells demonstrate potent antitumor activity in vitro and in vivo
Wang et al. establish feasible methodologies to generate highly functional CAR T cells from T-cell-derived iPSCs using 3D-organoid cultures, thereby supporting the development of “off-the-shelf” manufacturing strategies.
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