We investigated the novel role of HCA2 (GPR109A) and its ligand nicotinic acid in regulating macrophage function. Hca2 expression in the RAW264.7 murine macrophage cell line is strongly induced by ...LPS treatment and correlates with the expression of TNF‐α. Treatment with 300 μM nicotinic acid (reported EC50 3 μM, peak plasma concentration 50–300 μM), significantly inhibited TNF‐α, IL‐6, IL‐12p40, and IL‐1β production (P<0.05) in LPS (1 ng/ml)‐stimulated wild‐type murine bone marrow‐derived macrophages (BMMs) but failed to do so in Hca2–/– BMMs. Treatment with nicotinic acid reduced nuclear factor κB (NF‐κB) activation levels by 43% (P<0.03) in wild‐type BMMs 6 h after LPS stimulation but not in Hca2–/– BMMs. Nicotinic acid significantly inhibited wild‐type BMM chemotaxis (P<0.001), but had no effect on the chemotaxis of Hca2–/– BMMs. A significant increase in low‐density lipoprotein uptake by both wild‐type (P<0.006) andHca2–/– BMMs (P<0.03) in response to LPS was observed, which was significantly suppressed by nicotinic acid in wild‐type BMMs (P< 0.04) but not in Hca2–/– BMMs. Our results suggest that the nicotinic acid‐HCA2 axis is a novel negative regulator of macrophage activation.—Zandi‐Nejad, K., Takakura, A., Jurewicz, M., Chandraker, A K., Offermanns, S., Mount, D., Abdi, R. The role of HCA2 (GPR109A) in regulating macrophage function. FASEB J. 27, 4366–4374 (2013). www.fasebj.org
Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B ...cell-targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease.
We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence.
In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies.
Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.
The ability to replace organs and tissues on demand could save or improve millions of lives each year globally and create public health benefits on par with curing cancer. Unmet needs for organ and ...tissue preservation place enormous logistical limitations on transplantation, regenerative medicine, drug discovery, and a variety of rapidly advancing areas spanning biomedicine. A growing coalition of researchers, clinicians, advocacy organizations, academic institutions, and other stakeholders has assembled to address the unmet need for preservation advances, outlining remaining challenges and identifying areas of underinvestment and untapped opportunities. Meanwhile, recent discoveries provide proofs of principle for breakthroughs in a family of research areas surrounding biopreservation. These developments indicate that a new paradigm, integrating multiple existing preservation approaches and new technologies that have flourished in the past 10 years, could transform preservation research. Capitalizing on these opportunities will require engagement across many research areas and stakeholder groups. A coordinated effort is needed to expedite preservation advances that can transform several areas of medicine and medical science.
Kidney transplant patients require life-long surveillance to detect allograft rejection. Repeated biopsy, albeit the clinical gold standard, is an invasive procedure with the risk of complications ...and comparatively high cost. Conversely, serum creatinine or urinary proteins are noninvasive alternatives but are late markers with low specificity. We report a urine-based platform to detect kidney transplant rejection. Termed iKEA (integrated kidney exosome analysis), the approach detects extracellular vesicles (EVs) released by immune cells into urine; we reasoned that T cells, attacking kidney allografts, would shed EVs, which in turn can be used as a surrogate marker for inflammation. We optimized iKEA to detect T-cell-derived EVs and implemented a portable sensing system. When applied to clinical urine samples, iKEA revealed high level of CD3-positive EVs in kidney rejection patients and achieved high detection accuracy (91.1%). Fast, noninvasive, and cost-effective, iKEA could offer new opportunities in managing transplant recipients, perhaps even in a home setting.
Five-Year Follow-up after Face Transplantation Tasigiorgos, Sotirios; Kollar, Branislav; Turk, Marvee ...
The New England journal of medicine,
06/2019, Letnik:
380, Številka:
26
Journal Article
Recenzirano
Odprti dostop
Facial allograft may restore form and function to patients with severe facial disfigurement for whom other satisfactory therapeutic options are lacking. This letter presents the 5-year follow-up of ...six patients.
Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is ...mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-beta1 (TGF-beta1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Whether calcium oxalate (CaOx) deposition in kidney allografts following transplantation (Tx) adversely affects patient outcomes is uncertain, as are its associated risk factors.
...Methods
We performed a retrospective cohort study of patients who had kidney allograft biopsies performed within 3 months of Tx at Brigham and Women’s Hospital and examined the association of CaOx deposition with the composite outcome of death or graft failure within 5 years.
Results
Biopsies from 67 of 346 patients (19.4%) had CaOx deposition. In a multivariable logistic regression model, higher serum creatinine odds ratio (OR) = 1.28 per mg/dL, 95% confidence interval (CI) 1.15–1.43, longer time on dialysis (OR = 1.11 per additional year, 95% CI 1.01–1.23) and diabetes (OR = 2.26, 95% CI 1.09–4.66) were found to be independently associated with CaOx deposition. CaOx deposition was strongly associated with delayed graft function (DGF; OR = 11.31, 95% CI 5.97–21.40), and with increased hazard of the composite outcome after adjusting for black recipient race, donor type, time on dialysis before Tx, diabetes and borderline or acute rejection (hazard ratio 1.90, 95% CI 1.13–3.20).
Conclusions
CaOx deposition is common in allografts with poor function and portends worse outcomes up to 5 years after Tx. The extent to which CaOx deposition may contribute to versus result from DGF, however, cannot be determined based on our retrospective and observational data. Future studies should examine whether reducing plasma and urine oxalate prevents CaOx deposition in the newly transplanted kidney and whether this has an effect on clinical outcomes.
Cemiplimab is approved for treating locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). Solid organ transplant recipients have been excluded from immunotherapy trials, given ...concern for allograft rejection despite their increased risk of skin cancers. Chronic immunosuppression is necessary to prevent organ rejection but may attenuate antitumor response with PD-1 inhibitors.
We report a phase I study of cemiplimab for kidney transplant recipients (KTRs) with advanced CSCC. After cross-taper to a mammalian target of rapamycin (mTOR) inhibitor and pulsed dose corticosteroids (prednisone 40 mg once daily, the day before and on days 1-3 of each cycle, followed by 20 mg once daily on days 4-6, then 10 mg once daily until the day before each subsequent cycle), patients received cemiplimab 350 mg intravenously once every 3 weeks for up to 2 years and were assessed for response every 8 weeks. The primary end point was the rate of kidney rejection, with key secondary end points including rate and duration of response, and survival.
Twelve patients were treated. No kidney rejection or loss was observed. A response to cemiplimab was observed in five of 11 evaluable patients (46%; 90% CI, 22 to 73), including two with durable responses beyond a year. Median follow-up was 6.8 months (range, 0.7-29.8). Treatment-related grade 3 or greater adverse events occurred in five patients (42%), including diarrhea, infection, and metabolic disturbances. One patient died of angioedema and anaphylaxis attributed to mTOR inhibitor cross-taper.
mTOR inhibitor and corticosteroids represent a favorable immunosuppressive regimen for KTRs with advanced CSCC receiving immunotherapy. This combination resulted in durable antitumor responses with no kidney rejection events (funded by Regeneron Pharmaceuticals ClinicalTrials.gov identifier: NCT04339062).
The prevalence of Hepatitis C Virus (HCV) infection is significantly higher in patients with end-stage renal disease compared to the general population and poses important clinical challenges in ...patients who undergo kidney transplantation. Historically, interferon-based treatment options have been limited by low rates of efficacy and significant side effects, including risk of precipitating rejection. Limited data exist on the use of all-oral, interferon-free direct-acting antiviral (DAA) therapies in kidney transplant recipients. In this study, we performed a retrospective chart review with prospective clinical follow-up of post-kidney transplant patients treated with DAA therapies at three major hospitals in Boston, MA. A total of 24 kidney recipients with HCV infection received all-oral DAA therapy post-transplant. Patients were predominantly male (79%) with a median age of 60 years (range 34-70 years), median creatinine of 1.2 mg/dL (0.66-1.76), and 42% had advanced fibrosis or cirrhosis. The majority had HCV genotype 1a infection (58%). All patients received full-dose sofosbuvir; it was paired with simeprevir (9 patients without and 3 patients with ribavirin), ledipasvir (7 patients without and 1 patient with ribavirin) or ribavirin alone (4 patients). The overall sustained virologic response (SVR12) was 91% (21 out of 23 patients). One patient achieved SVR4 but demised prior to SVR12 check point due to treatment unrelated cause. Two treatment failures were successfully retreated with alternative DAA regimens and achieved SVR. Both initials failures occurred in patients with advanced fibrosis or cirrhosis, with genotype 1a infection, and prior HCV treatment failure. Adverse events were reported in 11 patients (46%) and were managed clinically without discontinuation of therapy. Calcineurin inhibitor trough levels did not significantly change during therapy. In this multi-center series of patients, all-oral DAA therapy appears to be safe and effective in post-kidney transplant patients with chronic HCV infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic inflammation as an important epigenetic and environmental factor for putative tumorigenesis and tumor progression may be associated with specific activation of Toll-like receptors (TLR). ...Recently, carcinogenesis has been suggested to be dependent on TLR7 signaling. In the present study, we determined the role of both TLR7 and TLR8 expression and signaling in tumor cell proliferation and chemoresistance in pancreatic cancer. Expression of TLR7/TLR8 in UICC stage I-IV pancreatic cancer, chronic pancreatitis, normal pancreatic tissue and human pancreatic (PANC1) cancer cell line was examined. For in vitro/in vivo studies TLR7/TLR8 overexpressing PANC1 cell lines were generated and analyzed for effects of (un-)stimulated TLR expression on tumor cell proliferation and chemoresistance. TLR expression was increased in pancreatic cancer, with stage-dependent upregulation in advanced tumors, compared to earlier stages and chronic pancreatitis. Stimulation of TLR7/TLR8 overexpressing PANC1 cells resulted in elevated NF-κB and COX-2 expression, increased cancer cell proliferation and reduced chemosensitivity. More importantly, TLR7/TLR8 expression increased tumor growth in vivo. Our data demonstrate a stage-dependent upregulation of both TLR7 and TLR8 expression in pancreatic cancer. Functional analysis in human pancreatic cancer cells point to a significant role of both TLRs in chronic inflammation-mediated TLR7/TLR8 signaling leading to tumor cell proliferation and chemoresistance.
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