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Background: Stroke is a highly prevalent disease that can provoke severe disability. We evaluate a predictive model based on the Minimum Basic Data Set (MBDS) compiled by the Spain Health Ministry, obtained for the period 2008–2012 for patients with ischaemic stroke in Spain, to establish the model's validity and to optimise its calibration. The MBDS is the main clinical-administrative database for hospitalisations recorded in Spain, and to our knowledge, no predictive models for stroke mortality have previously been developed using this resource. The main study aim is to perform an external validation and recalibration of the coefficients of this predictive model with respect to a chronologically later cohort. Material and Methods: External validation (testing the model on a different cohort to assess its performance) and recalibration (validation with optimisation of model coefficients) were performed using the MBDS for patients admitted for ischaemic stroke in the period 2016–2018. A cohort study was designed, in which a recalibrated model was obtained by applying the variables of the original model without their coefficients. The variables from the original model were then applied to the subsequent cohort, together with the coefficients from the initial model. The areas under the curve (AUC) of the recalibration and the external validation procedure were compared. Results: The recalibrated model produced an AUC of 0.743 and was composed of the following variables: age (odds ratio, OR:1.073), female sex (OR:1.143), ischaemic heart disease (OR:1.192), hypertension (OR:0.719), atrial fibrillation (OR:1.414), hyperlipidaemia (OR:0.652), heart failure (OR:2.133) and posterior circulation stroke (OR: 0.755). External validation produced an AUC of 0.726. Conclusions: The recalibrated clinical model thus obtained presented moderate-high discriminant ability and was generalisable to predict death for patients with ischaemic stroke. Rigorous external validation slightly decreased the AUC but confirmed the validity of the baseline model for the chronologically later cohort. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis is a chronic, progressive and lethal disease of unknown etiology that ranks among the most frequent interstitial lung diseases. Idiopathic pulmonary fibrosis is characterized by dysregulated healing mechanisms that lead to the accumulation of large amounts of collagen in the lung tissue that disrupts the alveolar architecture. The two currently available treatments, nintedanib and pirfenidone, are only able to slow down the disease without being curative. We demonstrated in the past that HSPB5, a low molecular weight heat shock protein, was involved in the development of fibrosis and therefore was a potential therapeutic target. Here, we have explored whether NCI-41356, a chemical inhibitor of HSPB5, can limit the development of pulmonary fibrosis. In vivo, we used a mouse model in which fibrosis was induced by intratracheal injection of bleomycin. Mice were treated with NaCl or NCI-41356 (six times intravenously or three times intratracheally). Fibrosis was evaluated by collagen quantification, immunofluorescence and TGF-β gene expression. In vitro, we studied the specific role of NCI-41356 on the chaperone function of HSPB5 and the inhibitory properties of NCI-41356 on HSPB5 interaction with its partner SMAD4 during fibrosis. TGF-β1 signaling was evaluated by immunofluorescence and Western Blot in epithelial cells treated with TGF-β1 with or without NCI-41356. In vivo, NCI-41356 reduced the accumulation of collagen, the expression of TGF-β1 and pro-fibrotic markers (PAI-1, α-SMA). In vitro, NCI-41356 decreased the interaction between HSPB5 and SMAD4 and thus modulated the SMAD4 canonical nuclear translocation involved in TGF-β1 signaling, which may explain NCI-41356 anti-fibrotic properties. In this study, we determined that inhibition of HSPB5 by NCI-41356 could limit pulmonary fibrosis in mice by limiting the synthesis of collagen and pro-fibrotic markers. At the molecular level, this outcome may be explained by the effect of NCI-41356 inhibiting HSPB5/SMAD4 interaction, thus modulating SMAD4 and TGF-β1 signaling. Further investigations are needed to determine whether these results can be transposed to humans. [ABSTRACT FROM AUTHOR]

Simple Summary: Heat-shock proteins (HSPs) are molecular chaperones overexpressed in tumor cells and are necessary for their survival. In leukemia and lymphoma, HSPs have been reported to have unique cytoprotective effects on different cell death and growth pathways. In this review, we describe the implication of HSPs in those pathways in hematological malignancies and discuss the pertinence of detecting and targeting them for future innovative treatment strategies. Heat-shock proteins (HSPs) are powerful chaperones that provide support for cellular functions under stress conditions but also for the homeostasis of basic cellular machinery. All cancer cells strongly rely on HSPs, as they must continuously adapt to internal but also microenvironmental stresses to survive. In solid tumors, HSPs have been described as helping to correct the folding of misfolded proteins, sustain oncogenic pathways, and prevent apoptosis. Leukemias and lymphomas also overexpress HSPs, which are frequently associated with resistance to therapy. HSPs have therefore been proposed as new therapeutic targets. Given the specific biology of hematological malignancies, it is essential to revise their role in this field, providing a more adaptable and comprehensive picture that would help design future clinical trials. To that end, this review will describe the different pathways and functions regulated by HSP27, HSP70, HSP90, and, not least, HSP110 in leukemias and lymphomas. [ABSTRACT FROM AUTHOR]

Nowadays, the impact of the tumor-immune microenvironment (TME) in non-small-cell lung cancer (NSCLC) prognosis and treatment response remains unclear. Thus, we evaluated the expression of PD-L1, tumor-infiltrating lymphocytes (TILs), and transforming growth factor beta (TGF-β) in NSCLC to identify differences in TME, detect possible new prognostic factors, and assess their relationship. We retrospectively analyzed 55 samples from patients who underwent NSCLC surgery and had over a 5-year follow-up. PD-L1 expression was determined by immunohistochemistry following standard techniques. The presence of TILs was evaluated at low magnification and classified into two categories, "intense" and "non-intense". Cytoplasmic TGF-β staining visualization was divided into four categories, and unequivocal nuclear staining in >1% of viable tumor cells was defined as "present" or "absent". Our aim was to identify differences in disease-free survival (DFS) and overall survival (OS). Tumor stage was the only objective prognostic factor for OS. PD-L1 expression and the presence of TILs had no prognostic impact, neither their combination. There seems to be a lower expression of PD-L1 and a higher expression of TILs in early stages of the disease. Our TGF-β nuclear staining analysis was promising, since it was associated with worse DFS, revealing this protein as a possible prognostic biomarker of recurrence for resectable NSCLC. [ABSTRACT FROM AUTHOR]

Many signaling pathways, molecular and cellular actors which are critical for wound healing have been implicated in cancer metastasis. These two conditions are a complex succession of cellular biological events and accurate regulation of these events is essential. Apart from inflammation, macrophages-released ROS arise as major regulators of these processes. But, whatever the pathology concerned, oxidative stress is a complicated phenomenon to control and requires a finely tuned balance over the different stages and responding cells. This review provides an overview of the pivotal role of oxidative stress in both wound healing and metastasis, encompassing the contribution of macrophages. Indeed, macrophages are major ROS producers but also appear as their targets since ROS interfere with their differentiation and function. Elucidating ROS functions in wound healing and metastatic spread may allow the development of innovative therapeutic strategies involving redox modulators. [ABSTRACT FROM AUTHOR]

Maternal obesity is associated with a wide spectrum of labour disorders, including preterm birth. Leptin, a pro-inflammatory adipokine and a key factor of obesity, is suspected to play a major role in these disorders. OB-R, its receptor, is expressed on macrophages and myocytes, two cell types critical for labour onset. Macrophages secrete reactive oxygen species/pro-inflammatory cytokines, responsible for myometrial differentiation while myocytes control uterine contractions. In this study, we assessed the effect of leptin on myometrial contraction and differentiation using our validated co-culture model of human primary macrophages and myocytes. We demonstrated that leptin had a different effect on myocytes and macrophages depending on the dose. A low leptin concentration induced a tocolytic effect by preventing myocytes' contraction, differentiation, and macrophage-induced ROS production. Additionally, leptin led to an increase in HLA-G expression, suggesting that the tocolytic effect of leptin may be driven by HLA-G, a tolerogenic molecule. Finally, we observed that recombinant HLA-G also prevented LPS-induced ROS production by macrophages. Altogether, these data provide a putative molecular mechanism by which leptin may induce immune tolerance and therefore interfere with labour-associated mechanisms. Therefore, HLA-G represents a potential innovative therapeutic target in the pharmacological management of preterm labour. [ABSTRACT FROM AUTHOR]

Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of "non-classical" targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of "non-classical" HSF target genes. We also present an update on the compounds with potent HSF1- modulating activity of potential interest as anti-cancer therapeutic agents. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and is not eligible for hormone and anti-HER2 therapies. Identifying therapeutic targets and associated biomarkers in TNBC is a clinical challenge to improve patients' outcome and management. High infiltration of CD206+ M2-like macrophages in the tumor microenvironment (TME) indicates poor prognosis and survival in TNBC patients. As we previously showed that membrane expression of GRP94, an endoplasmic reticulum chaperone, was associated with the anti-inflammatory profile of human PBMC-derived M2 macrophages, we hypothesized that intra-tumoral CD206+ M2 macrophages expressing GRP94 may represent innovative targets in TNBC for theranostic purposes. We demonstrate in a preclinical model of 4T1 breast tumor-bearing BALB/c mice that (i) CD206-expressing M2-like macrophages in the TME of TNBC can be specifically detected and quantified using in vivo SPECT imaging with 99mTc-Tilmanocept, and (ii) the inhibition of GRP94 with the chemical inhibitor PU-WS13 induces a decrease in CD206-expressing M2-like macrophages in TME. This result correlated with reduced tumor growth and collagen content, as well as an increase in CD8+ cells in the TME. 99mTc-Tilmanocept SPECT imaging might represent an innovative non-invasive strategy to quantify CD206+ tumor-associated macrophages as a biomarker of anti-GRP94 therapy efficacy and TNBC tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapies such as anti-PD-1/PD-L1 have garnered increasing importance in cancer therapy, leading to substantial improvements in patient care and survival. However, a certain proportion of patients present tumors that resist these treatments. Exosomes, small vesicles secreted by almost every cell, including tumor cells, have proven to be key actors in this resistance. In this review, we describe the involvement of immune checkpoints and immune modulators in tumor-derived exosomes (TEXs) in the context of cancer. We will focus on the most promising proteins under scrutiny for use in combination with PD-1 blockade therapy in a clinical setting: PD-L1, CTLA-4, TIM-3, CD73/39, LAG-3, and TIGIT. Finally, we will discuss how they can change the game in immunotherapy, notably through their role in immunoresistance and how they can guide therapeutic decisions, as well as the current obstacles in the field. Recently, immunotherapy has garnered increasing importance in cancer therapy, leading to substantial improvements in patient care and survival. By blocking the immune checkpoints—protein regulators of the immune system—immunotherapy prevents immune tolerance toward tumors and reactivates the immune system, prompting it to fight cancer cell growth and diffusion. A widespread strategy for this is the blockade of the interaction between PD-L1 and PD-1. However, while patients generally respond well to immunotherapy, a certain proportion of patients present tumors that resist these treatments. This portion can be very high in some cancers and hinders cancer curability. For this reason, current efforts are focusing on combining PD-1/PD-L1 immunotherapy with the targeting of other immune checkpoints to counter resistance and achieve better results. Exosomes, small vesicles secreted by almost any cell, including tumor cells, have proven to be key actors in this resistance. The exosomes released by tumor cells spread the immune-suppressive properties of the tumor throughout the tumor microenvironment and participate in establishing metastatic niches. In this review, we will describe immune checkpoints and immune modulators whose presence in tumor-derived exosomes (TEXs) has been established. We will focus on the most promising proteins under scrutiny for use in combination with PD-1 blockade therapy in a clinical setting, such as PD-L1, CTLA-4, TIM-3, CD73/39, LAG-3, and TIGIT. We will explore the immunosuppressive impact of these exosomal proteins on a variety of immune cells. Finally, we will discuss how they can change the game in immunotherapy and guide therapeutic decisions, as well as the current limits of this approach. Depending on the viewpoint, these exosomal proteins may either provide key missing information on tumor growth and resistance mechanisms or they may be the next big challenge to overcome in improving cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumors are not only composed of cancer cells but also of various infiltrating cells constituting the tumor microenvironment (TME); all these cells produce growth factors which contribute to tumor progression and invasiveness. Among them, transforming growth factor-β1 (TGF-β1) has been shown to be a potent immunosuppressive cytokine favoring cell proliferation and invasion and to be associated with resistance to anticancer treatments. Glycoprotein-A repetition predominant (GARP) plays a critical role in the activation of TGF-β1 and has been shown to be expressed at the membrane of cancer cells and also of regulatory T cells and platelets in the TME. An increased GARP expression has been shown in a variety of cancers. The objective of this review is to highlight GARP's expression and function in cancer and to evaluate its potential as a predictive and therapeutic follow-up biomarker that could be assessed, in real time, by molecular imaging. Glycoprotein-A repetitions predominant (GARP) is the docking receptor for latent transforming growth factor (LTGF-β) and promotes its activation. In cancer, increased GARP expression has been found in many types of cancer. GARP is expressed by regulatory T cells and platelets in the tumor microenvironment (TME) and can be also expressed by tumor cells themselves. Thus, GARP can be widely present in tumors in which it plays a major role in the production of active TGF-β, contributing to immune evasion and cancer progression via the GARP-TGF-β pathway. The objective of this review is to highlight GARP expression and function in cancer and to evaluate the potential of membrane GARP as a predictive and therapeutic follow-up biomarker that could be assessed, in real time, by molecular imaging. Moreover, as GARP can be secreted, a focus will also be made on soluble GARP as a circulating biomarker. [ABSTRACT FROM AUTHOR]

Interstitial lung diseases (ILDs) include a large number of diseases and causes with variable outcomes often associated with progressive fibrosis. Although each of the individual fibrosing ILDs are rare, collectively, they affect a considerable number of patients, representing a significant burden of disease. Idiopathic pulmonary fibrosis (IPF) is the typical chronic fibrosing ILD associated with progressive decline in lung. Other fibrosing ILDs are often associated with connective tissues diseases, including rheumatoid arthritis-ILD (RA-ILD) and systemic sclerosis-associated ILD (SSc-ILD), or environmental/drug exposure. Given the vast number of progressive fibrosing ILDs and the disparities in clinical patterns and disease features, the course of these diseases is heterogeneous and cannot accurately be predicted for an individual patient. As a consequence, the discovery of novel biomarkers for these types of diseases is a major clinical challenge. Heat shock proteins (HSPs) are molecular chaperons that have been extensively described to be involved in fibrogenesis. Their extracellular forms (eHSPs) have been recently and successfully used as therapeutic targets or circulating biomarkers in cancer. The current review will describe the role of eHSPs in fibrosing ILDs, highlighting the importance of these particular stress proteins to develop new therapeutic strategies and discover potential biomarkers in these diseases. [ABSTRACT FROM AUTHOR]

Rheumatic diseases (RD) and hereditary thrombophilias (HT) can be associated with high-risk pregnancies. This study describes obstetric outcomes after receiving medical care at a multidisciplinary consultation (MC) and compares adverse neonatal outcomes (ANOs) before and after medical care at an MC. This study is a retrospective observational study among pregnant women with RD and HT treated at an MC of a university hospital (southern Spain) from 2012 to 2018. Absolute risk reduction (ARR) and number needed to treat (NNT) were calculated. A total of 198 pregnancies were registered in 143 women (112 with RD, 31 with HT), with 191 (96.5%) pregnancies without ANOs and seven (3.5%) pregnancies with some ANOs (five miscarriages and two foetal deaths). Results previous to the MC showed 60.8% of women had more than one miscarriage, with 4.2% experiencing foetal death. MC reduced the ANO rate by AAR = 60.1% (95%CI: 51.6−68.7%). The NNT to avoid one miscarriage was 1.74 (95%CI: 1.5–2.1) and to avoid one foetal death NNT = 35.75 (95CI%: 15.2–90.9). A total of 84.8% of newborns and 93.2% of women did not experience any complication. As a conclusion, the follow-up of RD or HT pregnant women in the MC drastically reduced the risk of ANOs in this population with a previous high risk. [ABSTRACT FROM AUTHOR]

Simple Summary: Myeloproliferative neoplasms (MPN), which are a heterogeneous group of rare disorders that affect blood cell production in bone marrow, present many significant challenges for clinicians. Though considerable progress has been made, in particular with the JAK1/2 inhibitor ruxolitinib, more effective alternative therapeutic approaches are needed. In the search for new and more efficient therapies, heat shock proteins, also known as stress proteins, and the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint axis have been found to be of great interest in hematologic malignancies. Here, we review the therapeutic potential of stress protein inhibitors in the management of patients diagnosed with MPN and summarize the accumulating evidence of the role of the PD-1/PD-L1 axis in MPN in order to provide perspectives on future therapeutic opportunities relative to the inhibition of these targets. Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce MPN-related symptoms in myelofibrosis, they do not influence the underlying cause of the disease and are not curative. Due to these limitations, there is a need for alternative therapeutic strategies and targets. Heat shock proteins (HSPs) are cytoprotective stress-response chaperones involved in protein homeostasis and in many critical pathways, including inflammation. Over the last decade, several research teams have unraveled the mechanistic connection between STAT signaling and several HSPs, showing that HSPs are potential therapeutic targets for MPN. These HSPs include HSP70, HSP90 (chaperoning JAK2) and both HSP110 and HSP27, which are key factors modulating STAT3 phosphorylation status. Like the HSPs, the PD-1/PD-L1 signaling pathway has been widely studied in cancer, but the importance of PD-L1-mediated immune escape in MPN was only recently reported. In this review, we summarize the role of HSPs and PD-1/PD-L1 signaling, the modalities of their experimental blockade, and the effect in MPN. Finally, we discuss the potential of these emerging targeted approaches in MPN therapy. [ABSTRACT FROM AUTHOR]

While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. This general control of protein quality involves the expression and the activity of molecular chaperones such as heat shock proteins (HSPs). HSPs, through their interaction with the STAT3/STAT5 transcription factor pathway, can be crucial both for the tumorigenic properties of cancer cells (cell proliferation, survival) and for the microenvironmental immune cell compartment (differentiation, activation, cytokine secretion) that contributes to immunosuppression, which, in turn, potentially promotes tumor progression. Understanding the contribution of chaperones such as HSP27, HSP70, HSP90, and HSP110 to the STAT3/5 signaling pathway has raised the possibility of targeting such HSPs to specifically restrain STAT3/5 oncogenic functions. In this review, we present how HSPs control STAT3 and STAT5 activation, and vice versa, how the STAT signaling pathways modulate HSP expression. We also discuss whether targeting HSPs is a valid therapeutic option and which HSP would be the best candidate for such a strategy. [ABSTRACT FROM AUTHOR]