Why humans have puzzle-shaped cells
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The asthma diagnosis jigsaw puzzle: an adaptable teaching concept to facilitate the diagnosis of asthma in adults and children presenting to primary care
The asthma diagnosis jigsaw puzzle is a clinical practice and teaching concept conceived in clinical practice and refined through an expert multidisciplinary consensus process by academics and clinicians with an interest in primary respiratory care. The concept incorporates guidance to facilitate the effective diagnosis of adults or children with asthma in primary care where misdiagnosis is common. The jigsaw puzzle metaphor teaches a problem-solving approach to diagnosis, introducing the concept of diagnosis over time and in no particular sequence. Puzzle pieces can be collected from the domains of presentation, history, symptoms and physical examination, as well as objective tests. The clinician’s challenge is to complete the diagnostic jigsaw puzzle testing the likelihood of a picture which can be recognised as asthma. This approach aligns with symptom-based pattern-recognition approaches taught to primary care clinicians which gets easier and more reliable with experience. Relational continuity, or informational continuity through the patient record, is integral to the process of puzzle completion. Where non-fitting puzzle pieces are encountered, alternative or additional diagnoses should be considered and/or referral to secondary care pursued. As a metaphor, ‘puzzle completion’ may be used within clinical communication encounters, addressing the importance of partnership working (‘completing the puzzle together’), uncertainty (deciding ‘which pieces fit’) and changes in symptoms over time (enabling the ‘puzzle picture to become clearer’). Adaptation of this teaching concept has started through translation of educational resources, including puzzle pieces. Supporting case vignettes developed locally will contextualise the jigsaw puzzle teaching concept. The Asthma Diagnosis Jigsaw Puzzle teaching concept has been piloted in North Macedonia and is also developed for educational workshops by primary care health educators in Malaysia, India and Uganda.
A latent Axin2+/Scx+ progenitor pool is the central organizer of tendon healing
A tendon’s ordered extracellular matrix (ECM) is essential for transmitting force but is also highly prone to injury. How tendon cells embedded within and surrounding this dense ECM orchestrate healing is not well understood. Here, we identify a specialized quiescent Scx+/Axin2+ population in mouse and human tendons that initiates healing and is a major functional contributor to repair. Axin2+ cells express stem cell markers, expand in vitro, and have multilineage differentiation potential. Following tendon injury, Axin2+-descendants infiltrate the injury site, proliferate, and differentiate into tenocytes. Transplantation assays of Axin2-labeled cells into injured tendons reveal their dual capacity to significantly proliferate and differentiate yet retain their Axin2+ identity. Specific loss of Wnt secretion in Axin2+ or Scx+ cells disrupts their ability to respond to injury, severely compromising healing. Our work highlights an unusual paradigm, wherein specialized Axin2+/Scx+ cells rely on self-regulation to maintain their identity as key organizers of tissue healing.
Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets
Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.
VDAC2 loss elicits tumour destruction and inflammation for cancer therapy
Tumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies through mechanisms that are largely unclear1,2. Here, using complementary in vivo and in vitro CRISPR–Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS–STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified BAK as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced BAK activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS–STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8+ T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious cancer immunotherapy.
Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy
The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.
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