Smart Design of ZnFe and ZnFe@Fe Nanoparticles for MRI-Tracked Magnetic Hyperthermia Therapy: Challenging Classical Theories of Nanoparticles Growth and Nanomagnetism.

Iron Oxide Nanoparticles (IONPs) hold the potential to exert significant influence on fighting cancer through their theranostics capabilities as contrast agents (CAs) for magnetic resonance imaging (MRI) and as mediators for magnetic hyperthermia (MH). In addition, these capabilities can be improved by doping IONPs with other elements. In this work, the synthesis and characterization of single-core and alloy ZnFe novel magnetic nanoparticles (MNPs), with improved magnetic properties and more efficient magnetic-to-heat conversion, are reported. Remarkably, the results challenge classical nucleation and growth theories, which cannot fully predict the final size/shape of these nanoparticles and, consequently, their magnetic properties, implying the need for further studies to better understand the nanomagnetism phenomenon. On the other hand, leveraging the enhanced properties of these new NPs, successful tumor therapy by MH is achieved following their intravenous administration and tumor accumulation via the enhanced permeability and retention (EPR) effect. Notably, these results are obtained using a single low dose of MNPs and a single exposure to clinically suitable alternating magnetic fields (AMF). Therefore, as far as the authors are aware, for the first time, the successful application of intravenously administered MNPs for MRI-tracked MH tumor therapy in passively targeted tumor xenografts using clinically suitable conditions is demonstrated.

Oncological outcomes in robot-assisted radical prostatectomy: the value of PSA density as a preoperative predictive factor.

Background: Pretreatment assessment of patients diagnosed with localized prostate cancer (PCa) is essential for therapeutic decision-making. Currently available staging systems based on prostate-specific antigen (PSA), Gleason score, and clinical stage allow for determining the prognostic characteristics of these patients. Several studies have evaluated the preoperative use of prostate-specific antigen density (PSAD) as a prognostic factor for further risk stratification. To date, the role of PSAD in this setting is still an object of debate. Objectives: The present analysis aimed to assess the predictive potential of PSAD for adverse oncological outcomes after robot-assisted radical prostatectomy (RARP) and to compare its accuracy to preoperative PSA (pPSA). Design and methods: We retrospectively reviewed 427 patients diagnosed with localized PCa who underwent RARP at a single institution between January 2015 and January 2020. Generating receiver operator characteristic (ROC) curves, calculating areas under the curves (AUCs), and using a linear regression model, we analyzed the association of PSAD and pPSA with postoperative positive surgical margins (PSM), Gleason score ⩾ 7, persistent PSA, and biochemical recurrence (BCR), with a median follow-up of 47 months. Results: PSAD showed a significant association with PSM (p < 0.0001), PSA persistence (p < 0.0001), and Gleason ⩾ 7 (p < 0.0001), without being statistically significant in predicting BCR (p = 0.098). The predictive value of PSAD was comparable to pPSA for outcomes of PSA persistence (AUC 0.727 versus 0.771) and Gleason ⩾ 7 (AUC 0.683 versus 0.649). Conclusion: PSAD is a predictive factor for postoperative oncological outcomes of PSM, Gleason score ⩾ 7, and persistence of PSA. Despite the need for further studies, PSAD could be useful as a prognostic parameter in conjunction with established staging systems.

Oncological outcomes in robot-assisted radical prostatectomy: the value of PSA density as a preoperative predictive factor Prostate-specific antigen density (PSAD) has an established role in the diagnostic process of prostate cancer (PCa). However, controversy remains on the assessment of its value as a pretreatment prognostic factor. The aim of our study was to evaluate the predictive ability of PSAD for oncological outcomes in PCa patients treated with robot-assisted radical prostatectomy (RARP) and to compare with the value of preoperative PSA (pPSA). The present analysis showed a significant association of PSAD with positive surgical margins (PSM), Gleason Score >=7 and prostate-specific antigen (PSA) persistence after RARP. Moreover, PSAD demonstrated to perform comparably to pPSA in predicting the outcomes of clinically significant PCa (csPCa) and post-RARP PSA persistence. Therefore, PSAD is considered a preoperative predictive factor potentially useful in conjunction with other previously established prognostic criteria and clinical features.

Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation.

IMPORTANCE: Viruses modulate host cell metabolism to support the mass production of viral progeny. For human cytomegalovirus, we find that the viral UL38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as UL38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that UL38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of UL38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis.

Suramin, a drug for the treatment of trypanosomiasis, reduces the prothrombotic and metastatic phenotypes of colorectal cancer cells by inhibiting hepsin.

Recently, our group identified serine-protease hepsin from primary tumor as a biomarker of metastasis and thrombosis in patients with localized colorectal cancer. We described hepsin promotes invasion and thrombin generation of colorectal cancer cells in vitro and in vivo and identified venetoclax as a hepsin inhibitor that suppresses these effects. Now, we aspire to identify additional hepsin inhibitors, aiming to broaden the therapeutic choices for targeted intervention in colorectal cancer. METHODS: We developed a virtual screening based on molecular docking between the hepsin active site and 2000 compounds from DrugBank. The most promising drug was validated in a hepsin activity assay. Subsequently, we measured the hepsin inhibitor effect on colorectal cancer cells with basal or overexpression of hepsin via wound-healing, gelatin matrix invasion, and plasma thrombin generation assays. Finally, a zebrafish model determined whether hepsin inhibition reduced the invasion of colorectal cancer cells overexpressing hepsin. RESULTS: Suramin was the most potent hepsin inhibitor (docking score: -11.9691 Kcal/mol), with an IC50 of 0.66 µM. In Caco-2 cells with basal or overexpression of hepsin, suramin decreased migration and significantly reduced invasion and thrombin generation. Suramin did not reduce the thrombotic phenotype in the hepsin-negative colorectal cancer cells HCT-116 and DLD-1. Finally, suramin significantly reduced the in vivo invasion of Caco-2 cells overexpressing hepsin. CONCLUSION: Suramin is a novel hepsin inhibitor that reduces its protumorigenic and prothrombotic effects in colorectal cancer cells. This suggests the possibility of repurposing suramin and its derivatives to augment the repertoire of molecular targeted therapies against colorectal cancer.

Gastric variceal bleeding as a form of presentation of a pancreatic neuroendocrine tumor.

NETs (neuroendocrine tumors) constitute a heterogeneous group of epithelial-type neoplasms with a predominantly neuroendocrine differentiation. Although the most common locations are the pancreas, digestive tract, and lung, this type of neoplasm can arise in virtually any organ in the body. They are rare tumors with a wide variety of clinical presentations. Symptomatic tumors are more frequent in younger patients and present at more advanced pathological stages. We present the case of a 42-year-old male with idiopathic splenomegaly and bicytopenia (anaemia and thrombocytopenia) under study by haematology department who was admitted due to an episode of melena and hemoglobin of 4.5 mg/dl. Isolated gastric varices (IGV1) with red spots were confirmed at gastroscopy and endoscopic variceal obturation using cyanoacrylate was performed in two sessions. An endoscopic ultrasonography was performed, showing thrombosis of the splenic vein extending towards the splenoportal confluence with anechoic serpiginous structures outside and inside the gastric wall suggestive of collateral circulation with gastric varices (GV). An increase in portal caliber was observed, with no signs of liver cirrhosis. Computed tomography confirms the findings. Two months/week/days later he was readmitted with rebleeding signs after starting anticoagulant treatment, so it was decided to perform a splenectomy due to failure of the endoscopic treatment. Histology revealed infiltration of the spleen by a well-differentiated neuroendocrine tumor (NET). Gallium PET/CT and Octreotid scan showed uptake in the body and tail of the pancreas with positivity for somatostatin receptors previously undetected by other means. Finally, treatment was completed with distal pancreatectomy and splenoportal axis trombectomy with vascular esplenic resection and the patient was discharged from hospital.

Venetoclax is a potent hepsin inhibitor that reduces the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells.

Introduction: Hepsin is a type II transmembrane serine protease and its expression has been linked to greater tumorigenicity and worse prognosis in different tumors. Recently, our group demonstrated that high hepsin levels from primary tumor were associated with a higher risk of metastasis and thrombosis in localized colorectal cancer patients. This study aims to explore the molecular role of hepsin in colorectal cancer. Methods: Hepsin levels in plasma from resected and metastatic colorectal cancer patients were analyzed by ELISA. The effect of hepsin levels on cell migration, invasion, and proliferation, as well as on the activation of crucial cancer signaling pathways, was performed in vitro using colorectal cancer cells. A thrombin generation assay determined the procoagulant function of hepsin from these cells. A virtual screening of a database containing more than 2000 FDA-approved compounds was performed to screen hepsin inhibitors, and selected compounds were tested in vitro for their ability to suppress hepsin effects in colorectal cancer cells. Xenotransplantation assays were done in zebrafish larvae to study the impact of venetoclax on invasion promoted by hepsin. Results: Our results showed higher plasma hepsin levels in metastatic patients, among which, hepsin was higher in those suffering thrombosis. Hepsin overexpression increased colorectal cancer cell invasion, Erk1/2 and STAT3 phosphorylation, and thrombin generation in plasma. In addition, we identified venetoclax as a potent hepsin inhibitor that reduced the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells. Interestingly, pretreatment with Venetoclax of cells overexpressing hepsin reduced their invasiveness in vivo. Discussion: Our results demonstrate that hepsin overexpression correlates with a more aggressive and prothrombotic tumor phenotype. Likewise, they demonstrate the antitumor role of venetoclax as a hepsin inhibitor, laying the groundwork for molecular-targeted therapy for colorectal cancer.

Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose limitation.

Human cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV UL38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally-induced metabolic alterations might induce novel therapeutic vulnerabilities in virally infected cells. Here, we explore how HCMV infection and the UL38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of UL38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through UL38's inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Further, expression of UL38 or the inactivation of TSC2 results in anabolic rigidity in that the resulting increased levels of fatty acid biosynthesis are insensitive to glucose limitation. This failure to regulate fatty acid biosynthesis in response to glucose availability sensitizes cells to glucose limitation, resulting in cell death unless fatty acid biosynthesis is inhibited. These experiments identify a regulatory circuit between glycolysis and fatty acid biosynthesis that is critical for cell survival upon glucose limitation and highlight a metabolic vulnerability associated with viral infection and the inactivation of normal metabolic regulatory controls.

Antioxidant, Immunostimulatory, and Anticancer Properties of Hydrolyzed Wheat Bran Mediated through Macrophages Stimulation.

Previous studies demonstrated that enzymatic hydrolysis enhances wheat bran (WB) biological properties. This study evaluated the immunostimulatory effect of a WB hydrolysate (HYD) and a mousse enriched with HYD (MH) before and after in vitro digestion on murine and human macrophages. The antiproliferative activity of the harvested macrophage supernatant on colorectal cancer (CRC) cells was also analyzed. MH showed significantly higher content than control mousse (M) in soluble poly- and oligosaccharides (OLSC), as well as total soluble phenolic compounds (TSPC). Although in vitro gastrointestinal digestion slightly reduced the TSPC bioaccessibility of MH, ferulic acid (FA) levels remained stable. HYD showed the highest antioxidant activity followed by MH, which demonstrated a greater antioxidant activity before and after digestion as compared with M. RAW264.7 and THP-1 cells released the highest amounts of pro-inflammatory cytokines after being treated with 0.5 mg/mL of digested WB samples. Treatment with digested HYD-stimulated RAW264.7 supernatant for 96 h showed the most anticancer effect, and spent medium reduced cancer cell colonies more than direct WB sample treatments. Although a lack of inner mitochondrial membrane potential alteration was found, increased Bax:Bcl-2 ratio and caspase-3 expression suggested activation of the mitochondrial apoptotic pathway when CRC cells were treated with macrophage supernatants. Intracellular reactive oxygen species (ROS) were positively correlated with the cell viability in CRC cells exposed to RAW264.7 supernatants (r = 0.78, p < 0.05) but was not correlated in CRC cells treated with THP-1 conditioned media. Supernatant from WB-stimulated THP-1 cells may be able to stimulate ROS production in HT-29 cells, leading to a decrease of viable cells in a time-dependent manner. Therefore, our present study revealed a novel anti-tumour mechanism of HYD through the stimulation of cytokine production in macrophages and the indirect inhibition of cell proliferation, colony formation, and activation of pro-apoptotic proteins expression in CRC cells.

Dual Role of DUOX1-Derived Reactive Oxygen Species in Melanoma.

Melanoma is the most serious type of skin cancer. Inflammation and oxidative stress play an essential role in the development of several types of cancer, including melanoma. Although oxidative stress promotes tumor growth, once cells escape from the primary tumor, they are subjected to a more hostile environment, with higher levels of oxidative stress typically killing most cancer cells. As Dual Oxidase 1 (DUOX1) is a major producer of reactive oxygen species (ROS) in epithelia, we used allotransplantation and autochthonous melanoma models in zebrafish together with in silico analysis of the occurrence and relevance of DUOX1 expression of the skin cutaneous melanoma (SKCM) cohort of The Cancer Genome Atlas (TCGA) to address the role of this enzyme in the aggressiveness of melanoma cells in vivo. It was found that high transcript levels of the gene encoding DUOX1 were associated with the poor prognosis of patients in the early-stage melanoma of TCGA cohort. However, DUOX1 transcript levels were not found to be associated to the prognosis of late-stage SKCM patients. In addition, the transcript level of DUOX1 in metastatic SKCM was lower than in primary SKCM. Using zebrafish primary melanoma and allotransplantation models, we interrogated the role of DUOX1 in vivo. Our results confirmed a dual role of DUOX1, which restrains melanoma proliferation but promotes metastasis. As this effect is only observed in immunocompromised individuals, the immune system appears to be able to counteract this elevated metastatic potential of DUOX1-deficient melanomas.

Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant.

BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.

Effectiveness of aquatic therapy on sleep in persons with fibromyalgia. A meta-analysis.

CONTEXT: Fibromyalgia syndrome (FMS) is a chronic musculoskeletal condition characterized by persistent, widespread pain, myofascial tenderness, negative affect, fatigue, memory problems and sleep disturbances. OBJECTIVE: To summarize the evidence of the effects of aquatic therapy on sleep quality in patients with FMS. METHODS: This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2020 (PRISMA) guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO), whit the registration number CRD42021249982. Cochrane library, Medline (PubMed), Science Direct Web of Science (WOS), Scopus, and PEDro were searched from inception until September 2021. The search included only randomized clinical trials. RESULTS: Of the 7711 studies identified in the initial search, a total of 7 trials (361 participants) satisfied the eligibility criteria. Finally, a meta-analysis was conducted with 6 studies (311 participants). The overall pooled effect favored aquatic therapy interventions in improving sleep quality in patients with FMS (pooled MD, -2.05; 95% CI, -4.35 to 0.25). CONCLUSIONS: The results of this systematic review and meta-analysis provide evidence that aquatic therapy improved sleep quality in patients with FMS. This study highlights the importance of aquatic therapy for sleep. Nonetheless, although an aquatic therapy intervention may represent a good option to improve sleep, given the low number of studies the evidence should be taken with caution.

Real world experience with ropeginterferon alpha-2b (Besremi) in essential thrombocythaemia and polycythaemia vera following exposure to pegylated interferon alfa-2a (Pegasys).

Despite widespread use of Pegylated forms of Inteferon in the management of Myeloproliferative Neoplasms (MPN), most clinicians have experience predominantly with peginterferon alfa-2a (Pegasys). Third generation pegylated IFNα, ropeginterferon alfa-2b (ropegIFN; Besremi), was recommended by the European Medicine Authority (EMA) for treatment of Polycythaemia Vera (PV) following a Phase III trial (PROUD-PV / CONTINUATION-PV). FDA approval for PV, regardless of treatment history, was subsequently granted in November 2021. We hereby demonstrate the safety and tolerability of ropegIFN in a series of MPN patients at variable doses. It corroborates reports of efficacy of ropegIFN in patients with PV and use in pregnancy.

Optimisation of processing methods to improve success in the derivation of human multipotent mesenchymal stromal cells from cryopreserved umbilical cord tissue fragments.

Wharton's Jelly (WJ)-derived Mesenchymal Stromal Cells (MSC) are currently in the spotlight for the development of innovative MSC-based therapies due to their ease of sourcing, high proliferation capacity and improved immunopotency over MSC from other tissue sources. However, the short time window for derivation from donated fresh umbilical cord (UC) tissue fragments does not allow to consider biological features of the donor beyond serological safety testing. This limits the scope of MSC banking to rapid, prospective derivation of MSC, WJ lines without considering biological and genetic characteristics of the donor that may influence their suitability for clinical use (e.g. HLA type, inherited gene variants). In the present study, we describe a simple, efficient and reproducible approach for the cryopreservation of UC tissue fragments, compatible with established workflows in existing public frameworks for cord blood and tissue collection while guaranteeing pharmaceutical grade of starting materials for further processing under GMP standards. Herein we demonstrated the feasibility of time and cost-saving methods for cryopreservation of unprocessed UC tissue fragments directly at reception of the donated tissues using 10% Me2SO-based cryosolution and a commercial clinical-grade defined cryopreservation medium (Cryostor®), showing the preservation of all Critical Quality Attributes in terms of identity, potency and kinetic parameters. In summary, our study provides evidence that cryopreservation of large unprocessed UC tissue fragments (5-13.5 cm) supports subsequent progenitor cell isolation and derivation of MSC,WJ, preserving their viability, identity, proliferation rates and potency.

Zebrafish Models to Study the Crosstalk between Inflammation and NADPH Oxidase-Derived Oxidative Stress in Melanoma.

Melanoma is the deadliest form of skin cancer, and its incidence continues to increase. In the early stages of melanoma, when the malignant cells have not spread to lymph nodes, they can be removed by simple surgery and there is usually low recurrence. Melanoma has a high mortality rate due to its ability to metastasize; once melanoma has spread, it becomes a major health complication. For these reasons, it is important to study how healthy melanocytes transform into melanoma cells, how they interact with the immune system, which mechanisms they use to escape immunosurveillance, and, finally, how they spread and colonize other tissues, metastasizing. Inflammation and oxidative stress play important roles in the development of several types of cancer, including melanoma, but it is not yet clear under which conditions they are beneficial or detrimental. Models capable of studying the relevance of inflammation and oxidative stress in the early steps of melanocyte transformation are urgently needed, as they are expected to help recognize premetastatic lesions in patients by improving both early detection and the development of new therapies.

3D and organoid culture in research: physiology, hereditary genetic diseases and cancer.

In nature, cells reside in tissues subject to complex cell-cell interactions, signals from extracellular molecules and niche soluble and mechanical signaling. These microenvironment interactions are responsible for cellular phenotypes and functions, especially in normal settings. However, in 2D cultures, where interactions are limited to the horizontal plane, cells are exposed uniformly to factors or drugs; therefore, this model does not reconstitute the interactions of a natural microenvironment. 3D culture systems more closely resemble the architectural and functional properties of in vivo tissues. In these 3D cultures, the cells are exposed to different concentrations of nutrients, growth factors, oxygen or cytotoxic agents depending on their localization and communication. The 3D architecture also differentially alters the physiological, biochemical, and biomechanical properties that can affect cell growth, cell survival, differentiation and morphogenesis, cell migration and EMT properties, mechanical responses and therapy resistance. This latter point may, in part, explain the failure of current therapies and affect drug discovery research. Organoids are a promising 3D culture system between 2D cultures and in vivo models that allow the manipulation of signaling pathways and genome editing of cells in a body-like environment but lack the many disadvantages of a living system. In this review, we will focus on the role of stem cells in the establishment of organoids and the possible therapeutic applications of this model, especially in the field of cancer research.

Successful treatment and integrated genomic analysis of an infant with FIP1L1-RARA fusion-associated myeloid neoplasm.

FIP1L1-RARA-a ssociated neoplasm is a very rare and aggressive disease, with only 3 previously reported cases in the literature. Here, we describe a 9-month-old boy who presented with a FIP1L1-RARA fusion-associated myelodysplastic/myeloproliferative neoplasm-like overlap syndrome, with similarities and distinct features to both acute promyelocytic leukemia and juvenile myelomonocytic leukemia. Using a combined approach of chemotherapy, differentiating agents, and allogeneic hematopoietic stem cell transplant (allo-HCT), this patient remains in remission 20 months after allo-HCT. To our knowledge, this is only the second published pediatric case involving this condition and the only case with a favorable long-term outcome. Given the aggressive disease described in the previously published case report, as well as the successful treatment course described, the combinatorial use of chemotherapy, differentiation therapy, and allo-HCT for treatment of FIP1L1-RARA fusion-associated myeloid neoplasms should be considered.

A Dictyostelium model for BPAN disease reveals a functional relationship between the WDR45/WIPI4 homolog Wdr45l and Vmp1 in the regulation of autophagy-associated PtdIns3P and ER stress.

PROPPINs are conserved PtdIns3P-binding proteins required for autophagosome biogenesis that fold into a characteristic group of seven-bladed beta-propellers. Mutations in WDR45/WIPI4, a human member of this family, lead to BPAN, a rare form of neurodegeneration. We have generated mutants for the two PROPPIN proteins present in the model system Dictyostelium discoideum (Atg18 and Wdr45l) and characterized their function. Lack of Wdr45l greatly impairs autophagy, while Atg18 only causes subtle defects in the maturation of autolysosomes. The strong phenotype of the Wdr45l mutant is strikingly similar to that observed in Dictyostelium cells lacking Vmp1, an ER protein required for omegasome formation. Common phenotypes include impaired growth in axenic medium, lack of aggregation, and local enrichment of PtdIns3P as determined by the use of lipid reporters. In addition, Vmp1 and Wdr45l mutants show a chronically active response to ER stress. For both mutants, this altered PtdIns3P localization can be prevented by the additional mutation of the upstream regulator Atg1, which also leads to recovery of axenic growth and reduction of ER stress. We propose that, in addition to an autophagy defect, local autophagy-associated PtdIns3P accumulation might contribute to the pathogenesis of BPAN by disrupting ER homeostasis. The introduction of BPAN-associated mutations in Dictyostelium Wdr45l reveals the impact of pathogenic residues on the function and localization of the protein.

Microalgae fortification of low-fat oil-in-water food emulsions: an evaluation of the physicochemical and rheological properties.

Reducing the fat content in emulsions can give additional nutritional health benefits. Hence, developing low-fat oil-in-water emulsions, fortified with healthy microalgae providing advantageous properties, is an interesting topic. In this study, the addition of Arthrospira platensis (Spirulina), Chlorella vulgaris (Chlorella), and Dunaliella salina (Dunaliella) microalgae biomass on the physicochemical properties of low-fat oil-in-water emulsion formulations were evaluated. The rheological properties of food emulsions were measured in terms of the viscoelastic, flow behaviour, and textural properties, with all properties studied during 60 days. pH values of all the emulsions ranged between 3.0 and 3.7 and agreed to the Codex Alimentarius Commission. Moreover, their rheological behaviour may be classified as weak gel-like, a distinguishing characteristic of low-fat emulsion products. Substantial differences in rheological properties were observed between the fortified microalgae emulsions over the storage time (60 days). However, incorporating Spirulina or Dunaliella gave emulsions with stable texture, viscoelastic, and rheological properties. The prepared emulsions displayed good colour stability for Chlorella and Dunaliella. Overall, the fortified microalgae low-fat emulsions are expected to provide a blueprint for the design of low-fat mayonnaise-like food emulsions.

Respiratory disturbances in fibromyalgia: A systematic review and meta-analysis of case control studies.

Background: Fibromyalgia is a debilitating syndrome characterized by diffuse and chronic musculoskeletal pain.Objective: To perform a systematic review and meta-analysis of case-control studies to explore the respiratory disturbances among persons with fibromyalgia.Study appraisal and synthesis method: This review was performed in accordance with PRISMA guidelines (PROSPERO; identification number CRD: 42,020,196,835). We systematically searched seven electronic databases for articles published before December 2020.Eligibility criteria: Case-control studies comparing adults with fibromyalgia syndrome and healthy individuals with regard to the respiratory disturbances.Results: A total of six studies were included in the quantitative analysis. Pooled analysis showed that persons with fibromyalgia reported reduced chest expansion (MD -0.72, 95% CI, -1.70 to 0.27, I2 = 95%, p = 0.016), maximum expiratory pressure (MD -10.67, 95% CI, -18.62 to -2.72, I2 = 77%, p = 0.009), maximum inspiratory pressure (MD 11.04, 95% CI, -14.45 to -7.62, I2 = 0%, p < 0.001) and maximal voluntary ventilation (MD 11.79, 95% CI, -16.80 to -7.78, I2 = 0%, p < 0.001).Conclusion: Persons with fibromyalgia experience respiratory disturbances, such as reduced chest expansion, maximum expiratory pressure, maximum inspiratory pressure, and maximal voluntary ventilation.

Perfeccionamiento de competencias y habilidades comunicativas y lingüísticas del futuro médico general: experiencias asociadas / Improvement of communication and linguistic competences and skills of the future general practitioner: associated experiences

RESUMEN Fundamento: en las universidades de ciencias médicas constituye una necesidad abordar el desarrollo de competencias y habilidades comunicativas y lingüísticas del futuro médico general, por ser herramientas esenciales para su profesión. Objetivo: exponer las experiencias adquiridas con la aplicación de una estrategia para el perfeccionamiento de las competencias y habilidades comunicativas y lingüísticas del médico general en formación. Métodos: se realizó una investigación de desarrollo en la Universidad de Ciencias Médicas de Villa Clara durante 2018. Se emplearon métodos teóricos: análisis-síntesis, inducción-deducción e histórico-lógico; y empíricos: revisión de planes de estudio, exámenes finales y prueba diagnóstica para constatar si promovían la escritura y redacción de textos y la correcta aplicación de la Instrucción 1/09, además, la técnica grupo nominal y la valoración por especialistas. Resultados: se constataron las dificultades para el desarrollo de las competencias y habilidades mencionadas en los estudiantes; en los docentes, carencias de conocimientos, de metodologías adecuadas para la correcta aplicación de la Instrucción 1/09 y la inexistencia de formas de superación; se elaboró una estrategia que contiene varios materiales de apoyo bibliográfico, cursos de pregrado y posgrado, talleres metodológicos y otras acciones. Fue valorada por criterios de especialistas. Conclusiones: su aplicación generó varias experiencias positivas, entre las que destacan su pertinencia para aplicar de manera uniforme la Instrucción 1/09 en todos los descuentos relacionados con la ortografía, redacción y expresión oral, y su utilidad para resolver las carencias lingüísticas y metodológicas, como basamento científico necesario para el desarrollo de competencias y habilidades comunicativas.

ABSTRACT Background: it is necessary to address the development of communication and linguistic competencies and skills of the future general practitioner in the universities of medical sciences, as they are essential tools for their profession. Objective: to present the experiences acquired with the application of a strategy for the improvement of communicative and linguistic competences and skills of the general practitioner in training. Methods: a development investigation was carried out at Villa Clara University of Medical Sciences during 2018. Theoretical methods were used: analysis-synthesis, induction-deduction and historical-logical; and empirical ones: revision of study plans, final exams and diagnostic test to verify if they promote the writing of texts and the correct application of Instruction 1/09, in addition, the nominal group technique and the assessment by specialists. Results: the difficulties for the development of the skills and abilities mentioned in the students were verified; in the teachers, lack of knowledge, of adequate methodologies for the correct application of Instruction 1/09 and the lack of upgrading ways; a strategy was developed that contains various bibliographic supporting materials, undergraduate and graduate courses, methodological workshops, and other actions. It was assessed by specialist criteria. Conclusions: its implementation generated several positive experiences, among them its relevance to uniformly apply Instruction 1/09 in all discounts related to spelling, writing and speaking, and its usefulness to solve linguistic and methodological deficiencies, as a necessary scientific foundation for the development of communication skills and abilities.