High‐grade serous ovarian cancer (HGSOC) is the deadliest gynecological malignancy. The most common form of metastatic spread of HGSOC is transcoelomic dissemination. In this process, detached cells ...from the primary tumor aggregate as tumorspheres and promote the accumulation of peritoneal ascites. This represents an early event in HGSOC development and is indicative of poor prognosis. In this study, based on tumorspheres isolated from ascitic liquid samples from HGSOC patients, ovarian cancer spheroid 3D cultures, and in vivo models, we describe a key signal for tumorsphere formation in HGSOC. We report that platelet‐derived growth factor receptor beta (PDGFRβ) is essential for fibronectin‐mediated cell clustering of ovarian cancer cells into tumorspheres. This effect is mediated by the kinase NUAK family SNF1‐like kinase 1 (NUAK1) and blocked by PDGFRβ pharmacological or genetic inhibition. In the absence of PDGFRβ, ovarian cancer cells can be provided with fibronectin by cancer‐associated fibroblasts to generate chimeric spheroids. This work provides new insights that uncover potential targets to prevent peritoneal dissemination, the main cause of advanced disease in HGSOC patients.
In this study, we describe a key signal for tumorsphere formation in high‐grade serous ovarian cancer (HGSOC). We report that platelet‐derived growth factor receptor beta (PDGFRβ) is essential for fibronectin‐mediated cell aggregation of ovarian cancer cells into tumorspheres. In the absence of PDGFRβ, ovarian cancer cells can be provided with fibronectin by cancer‐associated fibroblasts (CAFs) to generate chimeric clusters.
Multiple lines of evidence are indicating that cancer development and malignant progression are not exclusively epithelial cancer cell-autonomous processes but may also depend on crosstalk with the ...surrounding tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are abundantly represented in the TME and are continuously interacting with cancer cells. CAFs are regulating key mechanisms during progression to metastasis and response to treatment by enhancing cancer cells survival and aggressiveness. The latest advances in CAFs biology are pointing to CAFs-secreted factors as druggable targets and companion tools for cancer diagnosis and prognosis. Especially, extensive research conducted in the recent years has underscored the potential of several cytokines as actionable biomarkers that are currently evaluated in the clinical setting. In this review, we explore the current understanding of CAFs secretome determinants and functions to discuss their clinical implication in oncology.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, requiring novel treatments to target both cancer cells and cancer stem cells (CSCs). Altered splicing is emerging as both a novel ...cancer hallmark and an attractive therapeutic target. The core splicing factor SF3B1 is heavily altered in cancer and can be inhibited by Pladienolide-B, but its actionability in PDAC is unknown. We explored the presence and role of SF3B1 in PDAC and interrogated its potential as an actionable target.
SF3B1 was analyzed in PDAC tissues, an RNA-seq dataset, and publicly available databases, examining associations with splicing alterations and key features/genes. Functional assays in PDAC cell lines and PDX-derived CSCs served to test Pladienolide-B treatment effects in vitro, and in vivo in zebrafish and mice.
SF3B1 was overexpressed in human PDAC and associated with tumor grade and lymph-node involvement. SF3B1 levels closely associated with distinct splicing event profiles and expression of key PDAC players (KRAS, TP53). In PDAC cells, Pladienolide-B increased apoptosis and decreased multiple tumor-related features, including cell proliferation, migration, and colony/sphere formation, altering AKT and JNK signaling, and favoring proapoptotic splicing variants (BCL-XS/BCL-XL, KRASa/KRAS, Δ133TP53/TP53). Importantly, Pladienolide-B similarly impaired CSCs, reducing their stemness capacity and increasing their sensitivity to chemotherapy. Pladienolide-B also reduced PDAC/CSCs xenograft tumor growth in vivo in zebrafish and in mice.
SF3B1 overexpression represents a therapeutic vulnerability in PDAC, as altered splicing can be targeted with Pladienolide-B both in cancer cells and CSCs, paving the way for novel therapies for this lethal cancer.
Abstract
Background
The coronavirus disease (COVID-19) pandemic has already affected more than 400 million people, with increasing numbers of survivors. These data indicate that a myriad of people ...may be affected by pulmonary sequelae of the infection. The aim of this study was to evaluate pulmonary sequelae in patients with bilateral COVID-19 pneumonia according to severity 1 year after hospital discharge.
Methods
COVID-FIBROTIC is a multicenter prospective observational cohort study for admitted patients with bilateral COVID-19 pneumonia. Pulmonary functional outcomes and chest computed tomography sequelae were analyzed 12 months after hospital discharge and we classified patients into three groups according to severity. A post hoc analysis model was designed to establish how functional test changed between groups and over time. A multivariable logistic regression model was created to study prognostic factors for lung diffusion impairment and radiological fibrotic-like changes at 12 months.
Results
Among 488 hospitalized patients with COVID-19 pneumonia, 284 patients had completed the entire evaluation at 12 months. Median age was 60.5 ± 11.9 and 55.3% were men. We found between-group differences in male sex, length of hospital stay, radiological involvement and inflammatory laboratory parameters. The functional evaluation of pulmonary sequelae showed that severe patients had statistically worse levels of lung diffusion at 2 months but no between group differences were found in subsequent controls. At 12-month follow up, however, we found impaired lung diffusion in 39.8% unrelated to severity. Radiological fibrotic-like changes at 12 months were reported in 22.7% of patients (102/448), only associated with radiological involvement at admission (OR: 1.55, 95% CI 1.06–2.38; p = 0.02) and LDH (OR: 0.99, 95% CI 0.98–0.99; p = 0.046).
Conclusion
Our data suggest that a significant percentage of individuals would develop pulmonary sequelae after COVID 19 pneumonia, regardless of severity of the acute process.
Trial registration
clinicaltrials.gov NCT04409275 (June 1, 2020)
Immunotherapy with checkpoint inhibitors has changed the paradigm of treatment for many tumors, and endometrial carcinoma is not an exception. Approved treatment options are pembrolizumab or ...dostarlimab for mismatch repair deficient tumors, pembrolizumab for tumors with high mutational load, and, more recently, pembrolizumab/lenvatinib for all patients with endometrial cancer. Endometrial cancer is a heterogeneous disease with distinct molecular subtypes and different prognoses. Differences between molecular subgroups regarding antigenicity and immunogenicity should be relevant to develop more tailored immunotherapeutic approaches. In this review, we aim to summarize and discuss the current evidence-Facts, and future opportunities-Hopes-of immunotherapy for endometrial cancer, focusing on relevant molecular and tumor microenvironment features of The Cancer Genome Atlas endometrial cancer subtypes.
Calcium biomineralisation is widely documented in plants. However, crystallisation of Ca‐sulphate‐containing minerals is closely related to water content, and sample processing, such as drying, ...alters the water balance of plant tissues. We hypothesised that common sample processing practices may favour the formation of crystals, leading to spurious crystallisation not observed in unaltered plant tissues. We selected three species (Ononis tridentata, Helianthemum squamatum and Gypsophila struthium) with reported gypsum biomineralisation. We used x‐ray diffractometry on fresh intact or sliced leaves, and on the same leaves processed by subsequent drying, to address whether sample processing alters crystal formation. Ca‐sulphate crystals were detected in dry samples of all species but not in fresh intact samples. Ca‐sulphate crystallisation occurred in some cut fresh samples, although the accumulation greatly increased after drying. In addition, G. struthium exhibited Ca‐oxalate crystals in both fresh and dry treatments, with a tendency for greater accumulation in dry treatments. Our results demonstrate that the Ca‐sulphate crystals observed by x‐ray diffractometry in these species are artefacts caused by common sample processing practices, such as excessive drying and slicing samples. We encourage future studies on the biomineral potential of plants to avoid the use of procedures that alter the water balance of tissues.
Strategies for expanding hematopoietic stem cells (HSCs) include coculture with cells that recapitulate their natural microenvironment, such as bone marrow stromal stem/progenitor cells (BMSCs). ...Plastic-adherent BMSCs may be insufficient to preserve primitive HSCs. Here, we describe a method of isolating and culturing human BMSCs as nonadherent mesenchymal spheres. Human mesenspheres were derived from CD45− CD31− CD71− CD146+ CD105+ nestin+ cells but could also be simply grown from fetal and adult BM CD45−-enriched cells. Human mesenspheres robustly differentiated into mesenchymal lineages. In culture conditions where they displayed a relatively undifferentiated phenotype, with decreased adherence to plastic and increased self-renewal, they promoted enhanced expansion of cord blood CD34+ cells through secreted soluble factors. Expanded HSCs were serially transplantable in immunodeficient mice and significantly increased long-term human hematopoietic engraftment. These results pave the way for culture techniques that preserve the self-renewal of human BMSCs and their ability to support functional HSCs.
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•Human MSCs can be simply isolated, preserved, and expanded as nonadherent mesenspheres•Human bone marrow mesenspheres derive from CD45−CD31−CD71−CD146+CD105+ nestin+ cells•Human mesenspheres expand hematopoietic stem cells (HSCs) through secreted factors•Mesensphere attachment to plastic changes their phenotype and decreases HSC support
In this study, Méndez-Ferrer and colleagues report a method of isolating and culturing human mesenchymal stem cells (MSCs) as nonadherent clonal spheres. Human mesenspheres could simply be grown from bone marrow CD45neg-enriched cells. In culture conditions where they displayed a primitive phenotype and decreased adherence to plastic, they promoted expansion of blood stem cells through secreted factors. This method may preserve the self-renewal of human MSCs and their ability to support functional blood stem cells in culture.
This research aims to empirically test the effect of employee involvement on lean manufacturing (LM), and the effect of LM on production outcomes. Employee involvement is operationalised through four ...related variables: empowerment, training, contingent remuneration and communication. The effects are tested by recording management perceptions in a different industrial sector from those usually studied in previous research - ceramic manufacturers, a highly competitive and internationally successful sector. We obtained data from 101 ceramic tile plants (64% of response rate) in the Valencia region of Spain. This approach is developed using a statistical method called partial least squares. All paths are significant except for contingent remuneration; specifically, relationships were found between empowerment, training, communication and LM, and between LM and performance.
This paper focuses on the interrelationships among the different dimensions of supply chain integration. Specifically, it examines the relationship between employee commitment and supply chain ...integration dimensions to explain several performance measures, such as flexibility, delivery, quality, inventory and customer satisfaction. Very little research has been conducted onto this topic, since employee commitment is rarely included as an antecedent of the effect of supply chain integration on performance. Seven research models have been analysed with Structural Equation Models using a multiple-informant international sample of 266 mid-to-large-size manufacturing plants. The findings suggest that the relationship between employee commitment and operational performance is fully mediated by supply chain integration. Employee commitment contributes to improving internal integration, and internal integration affects performance both directly and indirectly. Moreover, obtaining internal integration helps to achieve supplier and customer integration. As a result, companies should strive to achieve both employee commitment and internal integration, as they mutually reinforce each other. Similarly, managers should achieve internal integration before external integration and include external integration at the strategic level in order to reap the greatest advantages from supply chain integration. Meanwhile, managers should promote employee commitment not only for better supply chain success, but also to mitigate the barriers of supply chain management implementation.
Radiotherapy (RT) with concomitant cisplatin (CRT) or cetuximab (ERT) are accepted treatment options for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Long-term adverse ...events (AEs) have a vast impact on patients' quality of life. This study explored tissue biomarkers which could help predict late toxicity.
Single-institution prospective study including patients aged ≥ 18 with histologically confirmed newly diagnosed LA-SCCHN treated with RT and either concomitant cisplatin q3w or weekly cetuximab, according to institutional protocols. All patients underwent pre- and post-treatment skin biopsies of neck regions included in the clinical target volume. Angiogenesis, macrophages, and extracellular matrix (ECM) markers were evaluated by immunohistochemistry (IHC).
From April 15, 2016, to December 11, 2017; 31 patients were evaluated CRT = 12 (38.7%) and ERT = 19 (61.3%). 27 patients (87%) had received induction chemotherapy. All patients finished RT as planned. IHC expression of vasculature (CD34) and collagen (Masson's Trichrome) did not differ significantly between and within CRT and ERT arms. Conversely, an increased CD68 and CD163 macrophage infiltration expression was observed after treatment, without significant impact of treatment modality. Patients with higher late toxicity showed lower expression of macrophage markers in pre-treatment samples compared with those with lower late toxicity, with statistically significant differences for CD68.
Angiogenesis and ECM biomarkers did not differ significantly between CRT and ERT. Macrophage markers increased after both treatments and deserve further investigation as predictors of late toxicity in LA-SCCHN patients. Protocol code: TOX-TTCC-2015-01/Spanish registry of clinical studies (REec): 2015-003012-21/Date of registration: 27/01/2016.
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