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Abstract Primary cilia are antenna-like organelles which sense extracellular cues and act as signalling hubs. Cilia dysfunction causes a heterogeneous group of disorders known as ciliopathy syndromes affecting most organs. Cilia disassembly, the process by which cells lose their cilium, is poorly understood but frequently observed in disease and upon cell transformation. Here, we uncover a role for the PI3Kα signalling enzyme in cilia disassembly. Genetic PI3Kα-hyperactivation, as observed in PIK3CA-related overgrowth spectrum (PROS) and cancer, induced a ciliopathy-like phenotype during mouse development. Mechanistically, PI3Kα and PI3Kβ produce the PIP3 lipid at the cilia transition zone upon disassembly stimulation. PI3Kα activation initiates cilia disassembly through a kinase signalling axis via the PDK1/PKCι kinases, the CEP170 centrosomal protein and the KIF2A microtubule-depolymerising kinesin. Our data suggest diseases caused by PI3Kα-activation may be considered ‘Disorders with Ciliary Contributions’, a recently-defined subset of ciliopathies in which some, but not all, of the clinical manifestations result from cilia dysfunction.

Abstract Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment, serving diverse functions in tumour progression. However, the mechanisms via which CAFs influence the anti-tumour immunity remain poorly understood. Here, using multiple tumour models and biopsies from cancer patients, we report that α-SMA+ CAFs can form immunological synapses with Foxp3+ regulatory T cells (Tregs) in tumours. Notably, α-SMA+ CAFs can phagocytose and process tumour antigens and exhibit a tolerogenic phenotype which instructs movement arrest, activation and proliferation in Tregs in an antigen-specific manner. Moreover, α-SMA+ CAFs display double-membrane structures resembling autophagosomes in their cytoplasm. Single-cell transcriptomic data showed an enrichment in autophagy and antigen processing/presentation pathways in α-SMA-expressing CAF clusters. Conditional knockout of Atg5 in α-SMA+ CAFs promoted inflammatory re-programming in CAFs, reduced Treg cell infiltration and attenuated tumour development. Overall, our findings reveal an immunosuppressive mechanism entailing the formation of synapses between α-SMA+ CAFs and Tregs in an autophagy-dependent manner.

The central component of the complement cascade, C3, is involved in various biological functions, including opsonization of foreign bodies, clearance of waste material, activation of immune cells, and triggering of pathways controlling development. Given its broad role in immune responses, particularly in phagocytosis and the clearance of microbes, a deficiency in complement C3 in humans is often associated with multiple bacterial infections. Interestingly, an increased susceptibility to infections appears to occur mainly in the first two years of life and then wanes throughout adulthood. In view of the well-established connection between C3 deficiency and infections, therapeutic inhibition of complement at the level of C3 is often considered with caution or disregarded. We therefore set out to investigate the immune and biochemical profile of non-human primates under prolonged treatment with the C3 inhibitor compstatin (Cp40 analog). Cynomolgus monkeys were dosed subcutaneously with Cp40, resulting in systemic inhibition of C3, for 1 week, 2 weeks, or 3 months. Plasma concentrations of both C3 and Cp40 were measured periodically and complete saturation of plasma C3 was confirmed. No differences in hematological, biochemical, or immunological parameters were identified in the blood or tissues of animals treated with Cp40 when compared to those injected with vehicle alone. Further, skin wounds showed no signs of infection in those treated with Cp40. In fact, Cp40 treatment was associated with a trend toward accelerated wound healing when compared with the control group. In addition, a biodistribution study in a rhesus monkey indicated that the distribution of Cp40 in the body is associated with the presence of C3, concentrating in organs that accumulate blood and produce C3. Overall, our data suggest that systemic C3 inhibition in healthy adult non-human primates is not associated with a weakened immune system or susceptibility to infections.

It is unclear why C. elegans continues to produce large quantities of yolk after reproduction. Here the authors show that post-reproductive C. elegans mothers vent yolk which supports their offspring’s growth, serving as a form of primitive lactation.

Summary: Introduction: Periprosthetic joint infection (PJI) is a devastating complication occurring in 1–2% of primary and up to 10% of revised total hip and knee arthroplasties (THA and TKA) impairing patient's quality of life. Occult infections are underdiagnosed, sub-treated and sub-clinically experienced by patients. This study aimed to correlate patients' clinical outcomes with early antibiotic treatment based on use or non-use of a sonication technique on explanted prostheses. Methods: 33 patients with revised THA or TKA were retrospectively evaluated. Clinical outcomes were assessed via Oxford hip or knee scores, and correlated with administration or not of antibiotic treatment based on sonication results. Results: According to laboratory findings the patients were divided in the following three groups: 1. Septic loosening (conventional cultures and/or sonication positive), 2. Aseptic loosening (conventional cultures and sonication negative) and 3. Occult loosening (conventional cultures negative, sonication not performed). The average Oxford score was poor (27.9/60) for the septic, excellent (43.8/60) for the aseptic and intermediate (37.7/60) for the occult group. Additionally, conventional cultures were negative, but sonication-positive, in 6 individuals with patient-related risk factors (male gender, BMI > 30 kg/m2, diabetes, hypertension, steroids and rheumatoid arthritis). Conclusions: Sonication represents a valuable diagnostic technique to guide administration of effective antibiotic treatment for patients, especially for detection of persistent post-revision occult infections. We recommend the systematic investigation of revised prostheses with a sonication technique, but especially in cases with risk factors for infection who it is suspected may have occult loosening.

Renal involvement in inflammatory bowel disease is rather uncommon. This study aims to describe the spectrum of renal involvement in pediatric patients with IBD and reduce delay in detection and management. This is a retrospective study of the renal function of all patients, aged <18 years, who have been followed for IBD in our pediatric gastroenterology department from January 2019 till January 2023. From the 75 IBD patients included in this study 16 % had renal manifestations. The urinalysis revealed proteinuria in 7 patients, proteinuria and hematuria in 3 and proteinuria and glycosuria in 2 patients. All 12 patients with abnormal urinalysis underwent further investigation in order to determine the cause of renal damage and the results are as follows: 2 patients had glomerulonephritis and in other 2 patients renal damage was due to medication adverse effect, 1 had pyelonephritis in combination with chronic active tubulointerstitial nephritis and another 1 had thin basement membrane disease. Three patients had IBD-related dependent renal involvement and 1 resulted in chronic renal failure due to amyloidosis. It is important for all clinicians to be aware of the possibility of renal manifestations in IBD patients for the early diagnosis and prevention of these manifestations and complications. [ABSTRACT FROM AUTHOR]

Systemic mastocytosis (SM) comprises a group of rare disorders resulting from tissue infiltration by pathological mast cells. In a percentage ranging from 5 to 40% in various patient series, SM appears to be associated with an accompanying hematologic neoplasm (SM-AHN). The coexistence of SM with chronic myelogenous leukemia (CML) is extremely rare with only 3 cases in the literature. The natural course of CML has changed dramatically over the past 2 decades with the use of tyrosine kinase inhibitors (TKIs). We report a case of diagnosing SM in a patient in complete molecular remission of CML after stopping TKI treatment.

Introduction: Osteosarcoma (OS) is the most common primary osseous malignant tumour, with high propensity to metastasise in lungs. Pulmonary micro-metastases are present in up to 80% of patients at initial diagnosis and they are associated with significantly worse prognosis. Doxycycline (Dox) is a synthetic tetracycline that has been shown to have anti-cancer properties in vitro and in vivo, and inhibit angiogenesis - effects that may prove beneficial for several types of cancer. The aim of the present work was to study how Dox affects OS cell growth in vitro and in vivo and OS-driven pulmonary metastasis in vivo. Methods: In vitro, the effect of Dox was measured in MG-63 and 143B human OS cell viability, apoptosis, invasion and migration. In vivo, highly metastatic 143B cells were orthotopically implanted into the tibia of SCID mice. The tumour growth and pulmonary metastases between Dox treated and untreated, non-amputated and early amputated xenografts were examined. Results: In vitro, Dox decreased viability, inhibited invasion, migration, and induced the apoptosis of OS cells. In vivo, Dox significantly enhanced tumour necrosis at primary OS sites, similarly to its in vitro effect, and downregulated the expression of Ki67, MMP2, MMP9, VEGFA and ezrin. It also decreased circulating VEGFA and MMP9 protein levels, in line with the decreased metastatic burden in Dox-treated mice (non-amputated and early-amputated). Conclusions: Reprofiling of Dox can prevent the evolvement of pulmonary micro-metastases to clinically detectable macro-metastases and suppress the lethal progress of OS by inhibiting the expression of MMPs, VEGFA and ezrin at primary sites.

Insulin/IGF-1 signalling plays an important role in the regulation of metabolism and ageing. Here the authors show that inactivation of the pathway component PI3K p110α in the adipose tissue of mice produces a beneficial metabolic effect by enhancing β-adrenergic signalling thus energy expenditure.

Abstract Background Primary cardiac lymphomas (PCL) represent extremely rare cardiac tumors which are accompanied by poor prognosis, unless they are timely diagnosed and treated. Case presentation Herein we present a 28-year-old, immunocompetent man who presented to our hospital due to progressively worsening symptoms and signs of superior vena cava syndrome. Multi-modality imaging demonstrated a large intracardiac tumor, which was proven, by biopsy, to be a PCL. The patient received targeted chemotherapy which led to total remission of his disease, with no relapse over a 15-month follow-up period. Conclusions Although PCLs are rare, they should always be kept in mind in the differential diagnosis of cardiac tumors. Timely diagnosis of PCLs and appropriate chemotherapy, alone or in combination with radiotherapy, seems to provide the best results.

BackgroundThe combination of JAK/STAT and HDAC inhibitors exerted beneficial effects in haematological malignancies, presenting promising therapeutic CTCL targets. We aim to investigate the efficacy of JAK1/2i ruxolitinib in combination with HDACi resminostat in CTCL in vitro.Material & methodsNon-toxic concentrations of ruxolitinib and/or resminostat were administered to MyLa (MF) and SeAx (SS) cells for 24h. Cytotoxicity, cell proliferation and apoptosis were estimated through MTT, BrdU/7AAD and Annexin V/PI assay. Multi-pathway analysis was performed to investigate the effect of JAK1/2i and/or HDACi on JAK/STAT, Akt/mTOR and MAPK signalling pathways.ResultsBoth drugs and their combination were cytotoxic in MyLa (pConclusionThe JAKi/HDACi combination exhibited substantial anti-tumor effects in CTCL cell lines, and may represent a promising novel therapeutic modality for CTCL patients.

In Greece, during the 1960s a new period began which marked a break with the past and the start of a new approach for the future. After the post-war period, Greek society began to balance the State budget and create the conditions for the country’s accession to the European Common Market. This was the context in which, in 1964, the second meaningful educational reform of the 20th century was attempted. However, in 1965, the educational reform was quickly blocked on account of the unstable political situation and the imminent dictatorship. This paper examines the changes in Education adopted as part of the 1964 educational reform within their historical and political context, and provides an overview of the major political and educational events that led to their early overthrow in 1965.

Tomato (Solanum lycopersicum L.) is considered one of the most valuable and versatile vegetable crops globally and also serves as a significant model species for fruit developmental biology. Despite its significance, a severe genetic bottleneck and intense selection of genotypes with specific qualitative traits have resulted in the prevalence of a restricted number of (geno)types, also causing a lack of diversity across widespread cultivated types. As a result, the re-emergence of landraces as well as traditional and heirloom varieties is largely acknowledged as a countermeasure to restore phenotypic, phytochemical and genetic diversity while enriching the aroma/taste tomato palette. On those grounds, the Cypriot tomato germplasm was assessed and characterized. Ten landrace accessions were evaluated under greenhouse conditions and data were collected for 24 IPGRI discrete phenotypic traits. Grouping of accessions largely reflected the fruit shape and size; four different fruit types were recorded across accessions (flattened, heart-shaped, rounded and highly rounded). Moreover, a single run panel consisting of ten SSRs was developed and applied in order to genetically characterize 190 Cypriot genotypes and foreign heirloom varieties. Based on genetic indexes it was established that tomato landraces have a rather low level of heterogeneity and genetic variation. Finally, mineral and phytochemical analyses were conducted in order to estimate biochemical attributes (total phenolics, ascorbic acid, lycopene, β-carotene, total soluble content, titratable acidity) across genotypes; thus, ascertaining that the Cypriot panel has a high nutritional value. Due to the thermo-drought adaptation and tolerance of these genotypes, the current study serves as a roadmap for future breeding efforts in order to incorporate desirable traits or develop novel tomato lines combining resilience and alimentary value.

The development of immune system modulating agents, such as immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment. Nivolumab, a human monoclonal antibody against PD-1, has emerged as an efficient treatment for various malignancies, including non-small cell lung cancer (NSCLC); however, it is associated with important immune related side-effects, attributed to organ-specific inflammation, such as immune-mediated pneumonitis, a relatively uncommon, albeit potentially fatal adverse event. We herein present the unique case of severe interstitial pneumonitis with concomitant detection of Human Herpes Virus 6 (HHV-6) in a nivolumab treated patient with NSCLC. Potential pathogenetic mechanisms are discussed.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Increased density of tumor-associated lymphatic vessels correlates with poor patient survival in melanoma and other cancers, yet lymphatic drainage is essential for initiating an immune response. Here we asked whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes (LNs) from patients with cutaneous melanoma. Using immunohistochemistry and quantitative image analysis, we found significant positive correlations between LVD and CD8+ T cell infiltration as well as expression of the immunosuppressive molecules inducible nitric oxide synthase (iNOS) and 2,3-dioxygénase (IDO). Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating loco-regional effects of tumors. Our data suggest that lymphatic vessels play multiple roles at tumor sites and LNs, promoting both T cell infiltration and adaptive immunosuppressive mechanisms. Lymph vessel associated T cell infiltration may increase immunotherapy success rates provided that the treatment overcomes adaptive immune resistance.

Plasmablastic lymphoma (PBL) is a rare, aggressive type of B-cell non-Hodgkin lymphoma with the vast majority of patients responding poorly to treatment or progressing shortly thereafter. Cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) or CHOP-like regimens have disappointing results in this setting. We report a case of PBL arising in a previously diagnosed myelodysplastic/myeloproliferative (MDS/MPN) with ring sideroblasts and thrombocytopenia (RS-T), HIV-negative patient treated with the combination of CHOP and bortezomib. The patient achieved complete metabolic response, which has lasted one year, longer by far than would have been expected with the sole use of CHOP.

Abstract The insulin/insulin‐like growth factor‐1 signalling (IIS) pathway regulates cellular and organismal metabolism and controls the rate of aging. Gain‐of‐function mutations in p110α, the principal mammalian IIS‐responsive isoform of PI 3‐kinase (PI3K), promote cancer. In contrast, loss‐of‐function mutations in p110α impair insulin signalling and cause insulin resistance, inducing a pre‐diabetic state. It remains unknown if long‐term p110α inactivation induces further metabolic deterioration over time, leading to overt unsustainable pathology. Surprisingly, we find that chronic p110α partial inactivation in mice protects from age‐related reduction in insulin sensitivity, glucose tolerance and fat accumulation, and extends the lifespan of male mice. This beneficial effect of p110α inactivation derives in part from a suppressed down‐regulation of insulin receptor substrate (IRS) protein levels induced by age‐related hyperinsulinemia, and correlates with enhanced insulin‐induced Akt signalling in aged p110α‐deficient mice. This temporal metabolic plasticity upon p110α inactivation indicates that prolonged PI3K inhibition, as intended in human cancer treatment, might not negatively impact on organismal metabolism.