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Kidney regeneration is hindered by the limited pool of intrinsic reparative cells. Advanced therapies targeting renal regeneration have the potential to alleviate the clinical and financial burdens associated with kidney disease. Delivery systems for cells, extracellular vesicles, or growth factors aimed at enhancing regeneration can benefit from vehicles enabling targeted delivery and controlled release. Hydrogels, optimized to carry biological cargo while promoting regeneration, have emerged as promising candidates for this purpose. This study aims to develop a hydrogel from decellularized kidney extracellular matrix (DKECM) and explore its biocompatibility as a biomaterial for renal regeneration. The resulting hydrogel crosslinks with temperature and exhibits a high concentration of extracellular matrix. The decellularization process efficiently removes detergent residues, yielding a pathogen-free biomaterial that is non-hemolytic and devoid of α-gal epitope. Upon interaction with macrophages, the hydrogel induces differentiation into both pro-inflammatory and anti-inflammatory phenotypes, suggesting an adequate balance to promote biomaterial functionality in vivo. Renal progenitor cells encapsulated in the DKECM hydrogel demonstrate higher viability and proliferation than in commercial collagen-I hydrogels, while also expressing tubular cells and podocyte markers in long-term culture. Overall, the injectable biomaterial derived from porcine DKECM is anticipated to elicit minimal host reaction while fostering progenitor cell bioactivity, offering a potential avenue for enhancing renal regeneration in clinical settings. The quest to improve treatments for kidney disease is crucial, given the challenges faced by patients on dialysis or waiting for transplants. Exciting new therapies combining biomaterials with cells can revolutionize kidney repair. In this study, researchers created a hydrogel from pig kidney. This gel could be used to deliver cells and other substances that help in kidney regeneration. Despite coming from pigs, it's safe for use in humans, with no harmful substances and reduced risk of immune reactions. Importantly, it promotes a balanced healing response in the body. This research not only advances our knowledge of kidney repair but also offers hope for more effective treatments for kidney diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet + IFN-γ–producing group 1 ILCs (ILC1 and natural killer cells), CD8 + cytotoxic T cells (T C 1), and CD4 + T H 1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3 + ILC2s, T C 2 cells, and T H 2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid–related orphan receptor γt + ILC3s, T C 17 cells, and T H 17 cells producing IL-17, IL-22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases. [ABSTRACT FROM AUTHOR]

Background: Two variants of the CXCR3 receptor exist, one (CXCR3-A) reactive with CXCL9, CXCL10, and CXCL11 and the other (CXCR3-B) also reactive with CXCL4. Both variants are contemporarily expressed by human T cells. Objective: We sought to investigate the in vitro effects of CXCL10 and CXCL4 on the production of TH1 or TH2 cytokines. Methods: The cytokine profile of antigen-specific human CD4+ T-cell lines obtained in the absence or presence of CXCL10 or CXCL4 was evaluated by means of quantitative RT-PCR, flow cytometry, and ELISA. Results: CXCL10 upregulated IFN-γ and downregulated IL-4, IL-5, and IL-13 production, whereas CXCL4 downregulated IFN-γ and upregulated TH2 cytokines. Similar effects were also observed on polyclonally activated pure naive CD4+ T cells. The opposite effects of CXCL10 and CXCL4 on TH1 and TH2 cytokine production were inhibited by an anti-CXCR3 antibody able to neutralize both CXCR3-A and CXCR3-B and were apparently related to the activation of distinct signal transduction pathways. Moreover, CXCL10 upregulated mRNA levels of T-box expressed in T cells and downregulated GATA-3 expression, whereas CXCL4 downregulated T-box expressed in T cells and upregulated GATA-3. Finally, CXCL4, but not CXCL10, induced direct activation of IL-5 and IL-13 promoters. Conclusion: CXCL10 and CXCL4 exert opposite effects on the production of human TH1 and TH2 cytokines, likely through their respective interaction with CXCR3-A or CXCR3-B and the consequent activation of different signal transduction pathways. This might represent an internal regulatory pathway of TH cell responses and might contribute to the modulation of chronic inflammatory reactions, including allergy. [Copyright &y& Elsevier]

Summary Retinoids are essential in the development and function of several organs, exerting potent effects on stem cell systems. All-trans retinoic acid, through binding to the retinoic acid response elements, alters transcription of numerous genes in stem cells, leading to an exit from the self-renewing state and promoting differentiation. In the kidney, retinoids protect against injury and ameliorate function in multiple experimental models of disease. Recent evidence suggests that retinoids act on renal progenitors by promoting their differentiation into mature podocytes and retinoic acid–induced podocyte differentiation is impaired by proteinuria because of sequestration of retinoic acid by albumin. However, retinoic acid administration can revert renal progenitor differentiation and promote podocyte regeneration. A more complete understanding of retinoid-dependent renal progenitor differentiation into podocytes should reward us with new insights into the mechanisms of progression toward glomerulosclerosis. [ABSTRACT FROM AUTHOR]

Background: The mechanisms by which human dendritic cells (DCs) activate a TH1-polarizing or TH2-polarizing program are still partially unclear. Objective: Study of the mechanisms responsible for the TH1/TH2-polarizing activity of human circulating myeloid DCs before and after ligation of their Toll-like receptors (TLRs). Methods: IL-4 and IFN-γ production by CD4+ T cells was assessed in cocultures with myeloid DCs before or after TLR triggering. Expression of Jagged-1 and Delta-4 Notch ligands and of GATA-3 and T-box expressed in T cells transcription factors was evaluated by real-time quantitative PCR. Signal transducer and activator of transcription 4 and 6 phosphorylation was assessed by flow cytometry. Knockdown of Jagged-1 or Delta-4 was performed by transfection of DCs with appropriate silencing mRNAs. Results: Myeloid immature DCs constitutively expressed Jagged-1, which induces in CD4+ T cells a TH2 polarization, as shown by Jagged-1 gene silencing. The TH2 polarization associated with high GATA-3/T-box expressed in T cells ratio and was at least partially dependent on the early induction of IL-4. Maturation of DCs by TLR ligation resulted in the reduction of Jagged-1 and upregulation of Delta-4, which was at least in part responsible for the polarization of CD4+ T cells to the TH1 phenotype. Conclusion: CD4+ T-cell responses are usually characterized by a prevalent TH2 phenotype unless TLRs are triggered on DCs by microbial components. [Copyright &y& Elsevier]

Abstract: Laser-driven MeV proton beams are highly suitable for quantitative diagnosis of density profiles in dense matter by employing them as a particle probe in a point-projection imaging scheme. Via differential scattering and stopping, the technique allows to detect density modulations in dense compressed matter with intrinsic high spatial and temporal resolutions. The technique offers a viable alternative/complementary route to more established radiographic methods. A Monte-Carlo simulation package, MPRM, has been developed in order to quantify the density profile of the probed object from the experimentally obtained proton radiographs. A discussion of recent progress in this area is presented on the basis of analysis of experimental data, which has been supported by MPRM simulation. [Copyright &y& Elsevier]

Background: CD4+CD25+Foxp3+ T-regulatory (Treg) cells play a fundamental role in the control of autoimmunity. Whether human CD4+CD25+Foxp3+ Treg cells that recognize foreign antigens also exist is less clear. Objective: To investigate the existence in humans of circulating Treg cells able to recognize exogenous antigens, including allergens. Methods: CD4+CD25highFoxp3+ and CD4+CD25-Foxp3- cells were purified from human peripheral blood and cultured for 15 days with autologous dendritic cells (DCs), unloaded, or loaded with Der p 1 allergen or the bacterial antigen streptokinase (SK). Results: CD4+CD25highFoxp3+ circulating T cells obtained from healthy nonatopic subjects and cultured with Der p 1–loaded DCs, but not those cultured with either unloaded or SK-loaded DCs, suppressed the proliferative response to Der p 1 of autologous Der p 1–specific T cells generated from the CD4+CD25-Foxp3- subset. The antigen specificity of either Der p 1–CD4+CD25highFoxp3+ or SK–CD4+CD25highFoxp3+ T cells was confirmed even at clonal level. Finally, under the same experimental conditions, functionally active Der p 1–specific Treg cells were obtained from the pool of circulating CD4+CD25highFoxp3+ T cells of Der p 1–sensitive, atopic individuals. Conclusion: These data provide undoubted demonstration of the existence of human CD4+CD25highFoxp3+ circulating Treg cells specific for exogenous antigens, including the Der p 1 allergen, and indicate that CD4+CD25highFoxp3+ Treg cells specific for Der p 1 are present and functionally active in both nonatopic and Der p 1–sensitive, atopic individuals. Clinical implications: Caution should be advised in interpreting allergic disorders as simply resulting from defective Treg cell activity. [Copyright &y& Elsevier]

Background: Natural or synthetic ligands of Toll-like receptors (TLRs), such as CpG-containing oligodeoxynucleotides and imidazoquinolines, affect the functional phenotype of antigen-specific human T lymphocytes by inducing cytokine release by cells of the innate immunity. Objective: In vitro investigation of the ability of substitute adenines (SAs) to affect antigen-presenting cells and shift the functional phenotype of specific human TH2 cells was performed. Methods: The functional profile of hapten- and allergen-specific T-cell lines obtained in the absence or presence of modified adenines was assessed by means of quantitative real-time PCR, flow cytometry, and ELISAs. Activation of TLRs was evaluated by means of nucleofection of HEK293 cells. Results: The synthetic heterocycle, chemically related to adenine with substitution in positions 2-, 8-, and 9- (SA-2), but not its related derivative lacking 2- and 8- substitutions, stimulated the production of high amounts of IL-12, IL-10, TNF-α, and IL-6 by CD14+ cells and IFN-α and CXCL10 by blood dendritic cell antigen (BDCA)-4+ plasmacytoid dendritic cells. A nuclear factor κB–dependent signaling pathway mediated by SA-2 ligation of TLR7 was responsible for these effects. SA-2 also redirected the in vitro differentiation of either Dermatophagoides pteronyssinus group 1 or amoxicillin-specific TH2 cells toward the TH1/TH0 phenotype, with parallel downregulation of GATA-3 and upregulation of T-box expressed in T cells transcription factors. Conclusion: Critical substitutions of the adenine backbone confer the ability to activate TLR7, inducing the production of modulatory cytokines able to shift human allergen-specific TH2 cells to a TH1/TH0 phenotype. Clinical implications: Appropriately modified adenines might be used as effective adjuvants for the development of novel immunotherapeutic strategies of allergic disorders. [Copyright &y& Elsevier]

Abstract: An experiment was performed using high-energy protons, generated by an intense short laser pulse, to try to characterize in situ, the spatial and temporal evolution of a laser-driven shock propagating through a low-Z material. Radiography of the shock propagating through the low-Z transparent material could lead to density determination under compression. A first test of a proton radiography of the rear-side released state of a shocked aluminum foil has also been tried. [Copyright &y& Elsevier]

Background: Endoaneurysmorrhaphy with intraluminal graft placement, described by Creech, is the gold standard for abdominal aortic aneurysm (AAA) repair. Endovascular aneurysm repair has gained popularity for its minimal invasiveness and satisfying short-term results, but there are still many concerns about the long-term success of the procedure. Since 1998, laparoscopic surgery has been proposed for AAA treatment. The potential benefits of a minimally invasive procedure reproducing the endoaneurysmorrhaphy results over time have been advocated. In our experience, hand-assisted laparoscopic surgery (HALS) has been routinely used for the open-surgery transperitoneal/retroperitoneal approach and for endovascular aneurysm repair. After 4 years, we are able to define the early and middle-term results of such laparoscopic-assisted treatment. Methods: From October 2000 to March 2004, 604 consecutive nonurgent AAAs were treated at our institution. Of these, 122 (20.2%) were treated by HALS. Exclusion criteria for HALS were hostile abdomen (previous major abdominal or aortic surgery), bilateral diffuse common iliac and/or hypogastric aneurysms, massive aortoiliac calcifications, and severe cardiac (ejection fraction <35%) and respiratory (Po 2 <60 mm Hg or carbon dioxide >50 mm Hg) insufficiency. Juxtarenal and proximal iliac aneurysms were not a contraindication, nor was obesity. In all patients, we performed a minilaparotomy (7-8 cm) both for laparoscopic hand-assisted dissection and for endoaneurysmorrhaphy. All perioperative data were prospectively recorded. Follow-up consisted of ultrasonography and clinical evaluation after 6 and 12 months and then every year after surgery. Results: The mean laparoscopic and total operative times were respectively 64 ± 32 minutes and 257 ± 70 minutes, the mean aortic cross-clamping time was 76 ± 26 minutes, and the mean autotransfused blood volume was 1136 ± 711 mL. The overall mortality and morbidity were respectively 0% and 12.2%. Morbidity was surgery related in only two cases (bleeding from an ipogastric artery lesion and a leg graft thrombosis). The mean intensive care unit stay was 14.3 ± 13 hours. Oral food intake was resumed after 27.4 ± 15 hours, and patients were discharged after a mean of 4.4 ± 1.7 days. Operative times were not affected by obesity, suprarenal aortic cross-clamping, or aneurysm size. Both concomitant iliac aneurysms and bifurcated graft implantation (related to longer vascular reconstruction) involved significantly longer operative times. The learning curve of the procedure (comparing the first 30 patients with the last 92 patients) led to significantly shorter endoscopic, cross-clamping, and total operative times (P = .000). The mean follow-up was 28.6 ± 16 months. Three incisional hernias and one case of bowel occlusion were detected. All these cases (3.4%) required laparoscopic treatment. Conclusions: The HALS technique is a safe and minimally invasive treatment for AAA; it is useful for limiting the need for conventional open surgery and reducing the length of hospital stay. Despite the lack of randomized studies, HALS seems to be associated with a better postoperative course than standard open surgery. HALS can also be considered as an equivalent of a well-established procedure and as a bridge between open and total laparoscopic surgery. [Copyright &y& Elsevier]

Abstract: Endograft infection is a rare event, with few reports in the literature. This report describes delayed infection of an aortic endoprosthesis that eventually resulted in abdominal aortic aneurysm (AAA) rupture. The procedure was performed in an angiographic suite. In the postoperative period the patient developed a central venous line infection. This appears to be the first recognized and reported case in which the infected aortic neck completely dilated due to the radial force of the stent graft. [Copyright &y& Elsevier]

Background Protection against helminths consists of adaptive responses by T H 2 cells and innate responses by group 2 innate lymphoid cells (ILC2s), with these latter being well characterized in mice but less so in human subjects. Objective We sought to characterize human circulating ILC2s and compare their functional profile with that of autologous T H 2 cells. Methods Circulating ILC2s and T H 2 cells were isolated by means of fluorescence-activated cell sorting and magnetic cell sorting and expanded in vitro . ILC2s were then stimulated with phorbol 12-myristate 13-acetate plus ionomycin, IL-25 plus IL-33 (IL-25/IL-33), or a mixture of Toll-like receptor ligands to evaluate their ability to produce cytokines, express CD154, and induce IgE production by autologous B cells. Cytokines and transcription factor gene methylation were assessed. Results ILC2s expressed GATA-3, retinoic acid orphan receptor (RORC) 2, and RORα; were able to produce IL-5, IL-13, and IL-4; and, accordingly, were characterized by demethylation of IL4 , IL13 , IL5 , GATA3 , and RORC2 , whereas the IFNG , IFNG promoter, and TBX21 regions of interest were methylated. ILC2s expressed TLR1 , TLR4 , and TLR6 , and TLR stimulation induced IL-5 and IL-13 production. Moreover, ILC2s expressed CD154 in response to phorbol 12-myristate 13-acetate plus ionomycin, IL-25/IL-33, or a mixture of TLR ligands. Stimulated ILC2s also induced IgM, IgG, IgA, and IgE production by B cells. Finally, circulating ILC2s from atopic patients were not different in numbers and frequency but expressed higher IL-4 levels than those from nonatopic subjects. Conclusion This study provides the first evidence that human ILC2s can express CD154 and stimulate the production of IgE by B lymphocytes through IL-25/IL-33 stimulation or TLR triggering. [ABSTRACT FROM AUTHOR]

Background: Several approaches to find a better adjuvant, focus immunomodulation, and reduce allergenicity are under investigation to improve the efficacy and safety of specific immunotherapy. Objective: We performed an investigation of the in vitro and in vivo effects of a purified allergen chemically conjugated to a novel 8-OH modified adenine as an adjuvant. Methods: Purified group 2 major allergen from house dust mite chemically conjugated to 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid succinimidyl ester was analyzed by using mass spectrometry. The adduct (nDer p 2–Conj) was assayed for Toll-like receptor activation on transfected HEK293 cells, stimulation of innate cells, and effects on the functional phenotype of specific T-cell lines and clones by means of flow cytometry, real-time PCR, and expression of TH-related transcription factors. Lung cells and sera of nDer p 2–Conj–sensitized C57Bl/6 mice were studied by means of cytology, histology, real-time PCR, and ELISA. Results: nDer p 2–Conj stimulated IL-12 and IFN-α production from monocytes and plasmacytoid dendritic cells, respectively, retaining the ability to trigger Toll-like receptor 7 exclusively, and expanded human allergen-specific lymphocytes with reduced ability to produce TH2-related cytokines and increased IFN-γ levels, as based on GATA-3/T-bet expression. In vivo adduct-sensitized mice exhibited reduced eosinophil infiltration and IL-13 expression in the airways, IFN-γ upregulation together with IgE downregulation, and an increase in allergen-specific IgG2a levels in sera. The conjugate exhibited reduced ability to activate human FcεRI+ cells without inducing TH17 cells or autoantibodies. Conclusions: The codelivery of an allergen with a modified adenine as a conjugate inducing modulatory cytokines from innate cells redirects in vitro and in vivo pathogenic TH2 responses without eliciting harmful effects. [Copyright &y& Elsevier]

Background: IL-17A has been suggested to play a pathogenic role in bronchial asthma and other allergic disorders. Objective: Study of the relationship between human IL-17A–producing CD4+ TH cells (TH17) and IL-4–producing CD4+ TH (TH2) cells. Methods: T-cell clones generated from the CCR6+CD161+ fraction of human circulating CD4+ T cells, which contains virtually all TH17 cells, as well as circulating CD4+ T cells from both healthy subjects and patients with asthma, were assessed by flow cytometry for their cytokine production profile. Results: A small proportion of CCR6+CD161+CD4+ T-cell clones showed the ability to produce both IL-17A and IL-4 (TH17/TH2). TH17/TH2 clones also produced IL-5, IL-8, IL-9, IL-13, IL-21, and IL-22 and displayed the ability to induce the in vitro secretion of IgE. A very few TH17/TH2 cells were found among circulating CD4+ T cells from normal subjects, but their proportions were significantly increased in the circulation of patients with chronic asthma. TH17/TH2 cells could not be derived from naive umbilical cord blood CD4+ T cells under any experimental condition. However, when circulating memory CCR6+CD161+CD4+ T cells were cloned under appropriate polarizing conditions, TH17/TH2 clones originated in the presence of IL-4, suggesting that an IL-4–rich microenvironment may induce the shifting of memory TH17 cells into TH17/TH2 cells. Conclusion: Because of its peculiar functional properties and the increased numbers in the circulation of patients with bronchial asthma, this previously unknown population of TH17/TH2 cells may play some role in the pathogenesis of this disease. [Copyright &y& Elsevier]

Abstract: Endograft infection is a rare event, with few reports in the literature. This report describes delayed infection of an aortic endoprosthesis that eventually resulted in abdominal aortic aneurysm (AAA) rupture. The procedure was performed in an angiographic suite. In the post-operative period the patient developed a central venous line infection. This appears to be the first recognized and reported case in which the infected aortic neck completely dilated due to the radial force of the stent graft. [Copyright &y& Elsevier]