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Triple-negative breast cancer (TNBC) presents a formidable challenge in oncology due to its aggressive phenotype and the immunosuppressive nature of its tumor microenvironment (TME). In this issue of the JCI, Zhu, Banerjee, and colleagues investigated the potential of targeting the OTU domain-containing protein 4 (OTUD4)/CD73 axis to mitigate immunosuppression in TNBC. They identified elevated CD73 expression as a hallmark of immunosuppression in TNBC. Notably, the CD73 expression was regulated by OTUD4-mediated posttranslational modifications. Using ST80, a pharmacologic inhibitor of OTUD4, the authors demonstrated the restoration of cytotoxic T cell function and enhanced efficacy of anti-PD-LI therapy in preclinical models. These findings underscore the therapeutic potential of targeting the OTUD4/CD73 axis in TNBC., Overcoming immunosuppressive tumor microenvironment in breast cancer Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human [...]

Under European Union legislation (Article 32, Regulation (EC) No 396/2005), the European Food Safety Authority provides an annual report assessing the pesticide residue levels in foods on the European market. In 2022, 96.3% of the overall 110,829 samples analysed fell below the maximum residue level (MRL), 3.7% exceeded this level, of which 2.2% were non‐compliant, i.e. results in a given sample exceeded the MRL after taking into account the measurement uncertainty. For the EU‐coordinated multiannual control programme subset, 11,727 samples were analysed of which 0.9% were non‐compliant. To assess acute and chronic risk to consumer health, dietary exposure to pesticide residues was estimated and compared with available health‐based guidance values (HBGV). Continuation of the probabilistic assessment methodology was consolidated to all pesticides listed in the 2022 EU Regulation providing the probability of a consumer being exposed to an exceedance of the HBGV. Overall, the assessed risk to EU consumer's health is low. Recommendations to risk managers are given to increase the effectiveness of European control systems and to ensure a high level of consumer protection throughout the EU. This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2024.EN-8751/full [ABSTRACT FROM AUTHOR]

Background Urine concentrating defect is a common dysfunction in ciliopathies, even though its underlying mechanism and its prognostic meaning are largely unknown. This study assesses renal function in a cohort of 54 Bardet–Biedl syndrome (BBS) individuals and analyses whether renal hyposthenuria is the result of specific tubule dysfunction and predicts renal disease progression. Methods The estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (ACR) and maximum urine osmolality (max-Uosm) were measured in all patients. Genetic analysis was conducted in 43 patients. Annual eGFR decline (ΔeGFR) was measured in patients with a median follow-up period of 6.5 years. Urine aquaporin-2 (uAQP2) excretion was measured and the furosemide test was performed in patients and controls. Results At baseline, 33 (61.1%), 12 (22.2%) and 9 (16.7%) patients showed an eGFR >90, 60–90 and <60 mL/min/1.73 m2, respectively; 27.3% showed an ACR >30 mg/g and 55.8% of patients showed urine concentrating defect in the absence of renal insufficiency. Baseline eGFR, but not max-Uosm, correlated negatively with age. Conversely, truncating mutations affected max-Uosm and showed a trend towards a reduction in eGFR. Max-Uosm correlated with ΔeGFR (P < 0.005), suggesting that urine concentrating defect may predict disease progression. uAQP2 excretion and Na+ and Cl− fractional excretion after furosemide did not differ between hyposthenuric patients and controls, suggesting that specific collecting duct and thick ascending limb dysfunctions are unlikely to play a central role in the pathogenesis of hyposthenuria. Conclusions Hyposthenuria is a warning sign predicting poor renal outcome in BBS. The pathophysiology of this defect is most likely beyond defective tubular function. [ABSTRACT FROM AUTHOR]

The use of phytosanitary products in the production of agri-food products can be dangerous due to the possible persistence of their residues and the presence of products resulting from their possible degradation; for this reason it is important and necessary to carry out analytically the control of the residues of these products to ensure that the contents are lower than or equal to the maximum residue level (MRL) set by the EC Regulation 396/2005 [1] specific for pesticide residues. For several years the Innovhub s.r.l. laboratory has carried out this control activity in different types of food products, both for analysis request and for its own research interest. The analysis was carried out using the UHPLC-MS/MS (Ultra High Performance Liquid Chromatography-Mass Spectrometry) technique which combines the separation power of liquid chromatography with the ability of the mass spectrometer to selectively identify compounds and confirm their molecular identity. The technique used has been validated on the base of SANTE protocols which are constantly updated; the one in force at the time of carrying out this survey was No. 11813/2017 [2]. This work reports the results of the controls conducted in the decade 2009-2019, constituting a survey aimed at assessing the compliance with current legislation of some products on the market. 172 total samples were considered and particular attention was paid to the 103 samples of extra virgin olive oil of which 4 were found to be non-compliant, in particular in the years 2012, 2013 and 2015 reporting a percentage of non-compliance respectively in the years equal to 7%, 11% and 22%. In all the other years of the period considered none non-conformities was identifie [ABSTRACT FROM AUTHOR]

The primary cilium (PC) was considered as a vestigial organelle with no significant physiological importance, until the discovery that PC perturbation disturbs several signalling pathways and results in the dysfunction of a variety of organs. Genetic studies have demonstrated that mutations affecting PC proteins or its anchoring structure, the basal body, underlie a class of human disorders (known as ciliopathies) characterized by a constellation of clinical signs. Further investigations have demonstrated that the PC is involved in a broad range of biological processes, in both developing and mature tissues. Kidney disease is a common clinical feature of cilia disorders, supporting the hypothesis of a crucial role of the PC in kidney homoeostasis. Clinical proteomics and metabolomics are an expanding research area. Interestingly, the application of these methodologies to the analysis of urine, a biological sample that can be collected in a non-invasive fashion and possibly in large amounts, makes these studies feasible also in patients. The present article describes the most recent proteomic and metabolomic studies exploring kidney dysfunction in the setting of ciliopathies, showing the potential of these methodologies in the elucidation of disease pathophysiology and in the discovery of biomarkers. [ABSTRACT FROM AUTHOR]

Thymic Stromal Lymphopoietin (TSLP) plays a prominent role in inducing type 2 immune response, commonly associated with atopic diseases. TSLP-activated CD4 + T helper 2 cells block early carcinogenesis by inducing terminal differentiation in spontaneous breast and lung cancer models. However, the impact of TSLP induction on advanced cancer with altered cellular phenotypes is unclear. Using an established MMTV-PyMt tg breast cancer cell line, we demonstrate that TSLP-stimulated CD4 + T cells possess an antitumor effect in advanced breast cancer. In contrast to early breast cancer suppression, the antitumor immunity mediated by TSLP-stimulated CD4 + T cells in advanced breast cancer is mediated by the induction of a senescent-like phenotype in cancer cells. Inflammatory CD4 + T cells drive breast cancer cells into senescence by releasing interferon-gamma and tumor necrosis factor-alpha, which directly bind to their receptors on cancer cells. Our findings reveal a novel mechanism of TSLP-activated CD4 + T cell immunity against advanced breast cancer, mediated by cellular senescence as a distinct effector mechanism for cancer immunotherapy., Competing Interests: MB is an employee of Zelluna Immunotherapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Boieri, Marchese, Pham, Azin, Steidl, Malishkevich and Demehri.)

The recent application of proteomics and metabolomics to clinical medicine has demonstrated their potential role in complementing genomics for a better understanding of diseases' patho-physiology. These technologies offer the clear opportunity to identify risk factors, disease-specific or stage-specific biomarkers and to predict therapeutic response. This article is an overview of the recent insights obtained by metabolomic and proteomic studies in inherited kidney disorders. Proteomics studies have allowed the definition of a detailed picture of protein composition, post-translational modifications and interactions in kidney-derived samples, improving our understanding of renal physiology, especially of tubular transport and primary cilium-related functions. Studies on patients' urine samples and experimental models of inherited kidney diseases have provided clues suggesting novel potential pathological mechanisms and biomarkers of disease, for example in polycystic kidney disease. Metabolomic-based studies have been recently applied to assess biological system disturbances caused by specific genetic mutations resulting in inherited kidney disorders. These studies have been mainly carried out on mouse and rat models of cystic and metabolic disorders (such as Fabry disease), and on patients' urine samples. They have provided a significant contribution in understanding disease pathophysiology, promoting the discovery of aberrant biochemical pathways and contributing to the development of targeted therapies., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)