Addressing liver fibrosis by TRAIL targetied to hepatic stellate cells

De voornaamste complicaties bij patiënten met chronische leverziekte is leverfibrose. Een lever transplantatie is de enige therapeutische optie in het eindstadium van de ziekte. Daarom is een werkbare alternatieve therapie om het fibrotische proces tegen te gaan gewenst. Activering van leverstellaatcellen (Hepatic Stellate Cells, HSC) en afzetting van extracellulaire matrix is het belangrijkste onderliggende mechanisme van leverfibrose. In dit proefschrift werd de toepassing van tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) derivaten en varianten getest als een mogelijke therapie tegen geactiveerde HSCs. Eerdere studies hebben aangetoond dat de verhoging van TRAIL receptoren op het oppervlak van HSCs tijdens de activering geassocieerd is met een toename van de gevoeligheid van de HSCs voor TRAIL-geïnduceerde apoptose (celdood). De korte halfwaardetijd van TRAIL in vivo en de ontwikkeling van anti-apoptotische signalerings mechanismen in TRAIL-resistente geactiveerde HSCs zijn belangrijke hindernissen voor de therapeutische toepassing van TRAIL voor de behandeling van leverfibrose. Dit proefschrift handelt over de toepassing van doelgerichte TRAIL genen en eiwitten als een nieuwe technologie om leverfibrose succesvol te behandelen.Liver fibrosis is considered as an end stage liver diseases and the primary cause of need for a liver transplant. The development of liver fibrosis is associated with progressive chronic liver disease. The best anti-fibrotic therapy is the elimination of the underlying disease process. In situations in which treating the underlying etiology is not possible, a specific anti-fibrotic therapy would be highly desirable. To date, many specific anti-fibrotic treatments have been tried, but the lack of overall efficiency and the cytotoxicity associated with these treatments form a barrier for their use in the clinic. The elaboration of the underlying pathophysiology of liver fibrosis showed that, despite the complex nexus of liver injury and the fibrotic process, activated Hepatic Stellate Cells (HSC) play a central role both as a causative and as a effector cell. Therefore, research focusing on the targeted elimination of activated HSCs as the first step in natural resolution of liver fibrosis is warranted. In this research we address this issue by TRAIL targeting to HSCs. Earlier studies have shown that the increase in TRAIL receptors on the surface of HSCs during activation is associated with an increase in HSC susceptibility to the TRAIL apoptosis effect. However, the short half-life of TRAIL in vivo and the development of anti-apoptotic signaling mechanisms that cause TRAIL resistance in activated HSCs have proven to be a major hurdle in enabling the therapeutic application of TRAIL as an option in treating liver fibrosis. This thesis deals with the application of targeting TRAIL genes and proteins as a novel technology having the potential to successfully treat liver fibrosis

Human Resource Risk Management Framework and Factors Influencing It

Nowadays, the importance of human resource risk in organizations has greatly increased, and some thinkers refer to it as a core competency and a key responsibility for any human resource professional. Thus, given the importance of the subject of the present article, the aim of this study is to analyze the human resource risk management framework and the factors influencing it. In this regard, using the library method, human resource risk framework was analyzed from the perspective of management science thinkers of Paul and Milcher, Ernst and Young, Meyer, Maenpaa & Voutilainen, Rotarsko, Li and Zhang, Pandey.  Then, the factors influencing human resource risk management were identified and mentioned, and Stevens' human resource risk policies and procedures were presented. Then, the perception of risk and the factors influencing attention to risk and action for it were stated.  In the final section, theories related to risk perception were discussed in the form of the Wild risk-homeostasis theory (1982) and the Naatanen & Summak zero-risk theory (1976). Studies show that human resource risk management frameworks provide a conceptual model for the systematic development and planning of human resource risk management activities. They are also useful for assessing and evaluating the level of human resource risk. These frameworks provide the basis for planning, evaluating, and implementing human resource risk management

Breast Cancer Vaccines: New insights into Immunomodulatory and Nano-therapeutic Approaches

Breast cancer (BC) is known to be a highly heterogeneous disease that is clinically subdivided into four primary molecular subtypes, each having distinct morphology and clinical implications. These subtypes are principally defined by hormone receptors and other proteins involved (or not involved) in BC development. BC therapeutic vaccines [including peptide-based vaccines, protein-based vaccines, nucleic acid-based vaccines (DNA/RNA vaccines), bacterial/viral-based vaccines, and different immune cell-based vaccines] have emerged as an appealing class of cancer immunotherapeutics when used alone or combined with other immunotherapies. Employing the immune system to eliminate BC cells is a novel therapeutic modality. The benefit of active immunotherapies is that they develop protection against neoplastic tissue and readjust the immune system to an anti-tumor monitoring state. Such immunovaccines have not yet shown effectiveness for BC treatment in clinical trials. In recent years, nanomedicines have opened new windows to increase the effectiveness of vaccinations to treat BC. In this context, some nanoplatforms have been designed to efficiently deliver molecular, cellular, or subcellular vaccines to BC cells, increasing the efficacy and persistence of anti-tumor immunity while minimizing undesirable side effects. Immunostimulatory nano-adjuvants, liposomal-based vaccines, polymeric vaccines, virus-like particles, lipid/calcium/phosphate nanoparticles, chitosan-derived nanostructures, porous silicon microparticles, and selenium nanoparticles are among the newly designed nanostructures that have been used to facilitate antigen internalization and presentation by antigen-presenting cells, increase antigen stability, enhance vaccine antigenicity and remedial effectivity, promote antigen escape from the endosome, improve cytotoxic T lymphocyte responses, and produce humoral immune responses in BC cells. Here, we summarized the existing subtypes of BC and shed light on immunomodulatory and nano-therapeutic strategies for BC vaccination. Finally, we reviewed ongoing clinical trials on BC vaccination and highlighted near-term opportunities for moving forward

Gluten restriction in irritable bowel syndrome, yes or no?: a GRADE-assessed systematic review and meta-analysis

BackgroundMore than half of patients with irritable bowel syndrome (IBS) report aggravating their symptoms with certain foods. Currently, Low fermentable oligo-, di-, and monosaccharides and polyols diet (LFD) is the most accepted dietary intervention for IBS. Recent randomized controlled trials (RCTs) have been suggested that gluten restriction may reduce the symptoms of patients with IBS. However, the results from these studies are conflicting. This study filled this knowledge gap by evaluating the impact of the gluten-free diet (GFD) on IBS symptoms.MethodsA systematic search was carried out in Pubmed/Medline, Cochrane CENTRAL, Scopus, and Web of Science up to April 2023. A random-effect model was applied to estimate the standardized mean difference (SMD) and 95% confidence interval (95% CI) for each outcome.ResultsA total of nine controlled trials were included in the meta-analysis. In contrast to gluten-containing diet, GFD was unable to reduce overall symptoms (SMD − 0.31; 95% CI −0.92, 0.31), bloating (SMD −0.37; 95% CI −1.03, 0.30), and quality of life (SMD −0.12, 95% CI −0.64, 0.39); but had a slight trend to reduce abdominal pain (SMD –0.68; 95% CI −1.36, −0.00). Also, LFD significantly reduced the IBS-Severity score system (SMD 0.66, 95% CI 0.31, 1.01) and improved quality of life (SMD −0.36, 95% CI −0.70, −0.01), compared to GFD.ConclusionA GFD is not robust enough to be routinely recommended for IBS patients, and its efficacy is significantly lower than that of an LFD. Only a certain subgroup of IBS patients may benefit from GFD; further studies are needed to target this subgroup

Deficiency of SARS-CoV-2 T-cell responses after vaccination in long-term allo-HSCT survivors translates into abated humoral immunity

Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological diseases are at risk of severe disease and death from COVID-19. To determine the safety and immunogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines, samples from 50 infection-naive allo-HSCT recipients (median, 92 months from transplantation, range, 7-340 months) and 39 healthy controls were analyzed for serum immunoglobulin G (IgG) against the receptor binding domain (RBD) within spike 1 (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; anti–RBD-S1 IgG) and for SARS-CoV-2–specific T-cell immunity, reflected by induction of T-cell–derived interferon-g in whole blood stimulated ex vivo with 15-mer SI-spanning peptides with 11 amino acid overlap S1-spanning peptides. The rate of seroconversion was not significantly lower in allo-transplanted patients than in controls with 24% (12/50) and 6% (3/50) of patients remaining seronegative after the first and second vaccination, respectively. However, 58% of transplanted patients lacked T-cell responses against S1 peptides after 1 vaccination compared with 19% of controls (odds ratio [OR] 0.17; P 5 .009, Fisher’s exact test) with a similar trend after the second vaccination where 28% of patients were devoid of detectable specific T-cell immunity, compared with 6% of controls (OR 0.18; P 5 .02, Fisher’s exact test). Importantly, lack of T-cell reactivity to S1 peptides after vaccination heralded substandard levels (,100 BAU/mL) of anti–RBD-S1 IgG 5 to 6 months after the second vaccine dose (OR 8.2; P 5 .007, Fisher’s exact test). We conclude that although allo-HSCT recipients achieve serum anti–RBD-S1 IgG against SARS-CoV-2 after 2 vaccinations, a deficiency of SARS-CoV-2–specific T-cell immunity may subsequently translate into insufficient humoral responses

An uncommon gastrointestinal bleeding in a patient with portal vein thrombosis: a case report and literature review

Portal vein thrombosis (PVT) is a rare condition that may congest bowel venous drainage and cause mesenteric ischemia. In acute settings, gastrointestinal bleeding (GIB) is rare, and acute abdominal pain is the most common clinical presentation. A 24-year-old man who presented with acute abdominal pain and a single episode of hematemesis is reported. Workups revealed evidence of thrombosis in the portal vein, but upper endoscopy was incapable to detect the source of the bleeding. We discuss the possible scenarios for the GIB in this case and review similar reports in the literature

Human Resource Risk Management Framework and Factors Influencing It

Nowadays, the importance of human resource risk in organizations has greatly increased, and some thinkers refer to it as a core competency and a key responsibility for any human resource professional. Thus, given the importance of the subject of the present article, the aim of this study is to analyze the human resource risk management framework and the factors influencing it. In this regard, using the library method, human resource risk framework was analyzed from the perspective of management science thinkers of Paul and Milcher, Ernst and Young, Meyer, Maenpaa & Voutilainen, Rotarsko, Li and Zhang, Pandey.  Then, the factors influencing human resource risk management were identified and mentioned, and Stevens' human resource risk policies and procedures were presented. Then, the perception of risk and the factors influencing attention to risk and action for it were stated.  In the final section, theories related to risk perception were discussed in the form of the Wild risk-homeostasis theory (1982) and the Naatanen & Summak zero-risk theory (1976). Studies show that human resource risk management frameworks provide a conceptual model for the systematic development and planning of human resource risk management activities. They are also useful for assessing and evaluating the level of human resource risk. These frameworks provide the basis for planning, evaluating, and implementing human resource risk management.Hoy en día, la importancia del riesgo de recursos humanos en las organizaciones ha aumentado considerablemente, y algunos pensadores se refieren a él como una competencia central y una responsabilidad clave para cualquier profesional de recursos humanos. Por lo tanto, dada la importancia del tema del presente artículo, el objetivo de este estudio es analizar el marco de gestión de riesgos de recursos humanos y los factores que lo influyen. En este sentido, utilizando el método de la biblioteca, se analizó el marco de riesgo de recursos humanos desde la perspectiva de los pensadores en ciencias de la gestión de Paul y Milcher, Ernst y Young, Meyer, Maenpaa y Voutilainen, Rotarsko, Li y Zhang, Pandey. Luego, se identificaron y mencionaron los factores que influyen en la gestión del riesgo de recursos humanos, y se presentaron las políticas y procedimientos de riesgo de recursos humanos de Stevens. Luego, se expuso la percepción del riesgo y los factores que influyen en la atención al riesgo y su acción. En la sección final, las teorías relacionadas con la percepción del riesgo se discutieron en forma de la teoría de riesgo de homeostasis de Wild (1982) y la teoría de riesgo cero de Naatanen & Summak (1976). Los estudios demuestran que los marcos de gestión de riesgos de recursos humanos proporcionan un modelo conceptual para el desarrollo sistemático y la planificación de actividades de gestión de riesgos de recursos humanos. También son útiles para evaluar y evaluar el nivel de riesgo de recursos humanos. Estos marcos proporcionan la base para planificar, evaluar e implementar la gestión de riesgos de recursos humanos