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Glomerular Diseases Aug 2021De novo glomerular diseases comprising those both common and unique to transplant may develop in the renal allograft leading to posttransplant proteinuria, hematuria, or... (Review)
Review
BACKGROUND
De novo glomerular diseases comprising those both common and unique to transplant may develop in the renal allograft leading to posttransplant proteinuria, hematuria, or allograft failure. Electron microscopy (EM) is a useful adjunct to the standard light and immunofluorescence microscopy for accurately diagnosing these diseases and subsequently aiding the clinician in initiating appropriate treatments.
SUMMARY
De novo diseases are those new-onset diseases in renal transplantation that are unrelated to the original kidney disease in the recipient. They include virtually any primary or secondary glomerular, tubulointerstitial, or vascular diseases, ranging from subclinical to clinically overt, having acute, subacute, or chronic clinical presentations. This review focuses on common or significant, mainly glomerular, entities, with particular attention to the EM findings. The time of onset, stage, and severity of these diseases may often be modified by the current immunosuppressive protocols and other donor and recipient predisposing characteristics.
KEY MESSAGES
A renal allograft biopsy not only improves our understanding of the pathophysiology but also provides diagnostic accuracy prognostic information, and potential for reversibility. In some cases, the biopsy leads to detection of unsuspected or clinically asymptomatic de novo diseases in the setting of other concomitant rejection processes, infection, or toxicity, which can dictate appropriate therapy. Routine EM in transplant kidney biopsies is a valuable modality in recognizing fully developed or early/subtle features of evolving de novo diseases, often during the subclinical phases, in "for cause" or surveillance/protocol allograft biopsies.
PubMed: 36751493
DOI: 10.1159/000517124 -
Best Practice & Research. Clinical... 2020Survival following liver transplantation has changed dramatically owing to improvement in surgical techniques, peri-operative care and optimal immunosuppressive therapy.... (Review)
Review
Survival following liver transplantation has changed dramatically owing to improvement in surgical techniques, peri-operative care and optimal immunosuppressive therapy. Post-Liver transplant (LT) de novo or recurrent viral infection continues to cause major allograft dysfunction, leading to poor graft and patient survival in untreated patients. Availability of highly effective antiviral drugs has significantly improved post-LT survival. Patients transplanted for chronic hepatitis B infection should receive life-long nucleos(t)ide analogues, with or without HBIg for effective viral control. Patients with chronic hepatitis C should be commenced on directly acting antiviral (DAA) drugs prior to transplantation. DAA therapy for post-LT recurrent hepatitis C infection is associated with close to 100% sustained virological response (SVR), irrespective of genotype. De novo chronic Hepatitis E infection is an increasingly recognised cause of allograft dysfunction in LT recipients. Untreated chronic HEV infection of the graft may lead to liver fibrosis and allograft failure. CMV and EBV can reactivate leading to systemic illness following liver transplantation. With COVID-19 pandemic, post-transplant patients are at risk of SARS-Co-V2 infection. Majority of the LT recipients require hospitalization, and the mortality in this population is around 20%. Early recognition of allograft dysfunction and identification of viral aetiology is essential in the management of post-LT de novo or recurrent infections. Optimising immunosuppression is an important step in reducing the severity of allograft damage in the treatment of post-transplant viral infections. Viral clearance or control can be achieved by early initiation of high potency antiviral therapy.
Topics: Humans; Liver Transplantation; Recurrence; Risk Factors; Survival Analysis; Virus Diseases
PubMed: 33158469
DOI: 10.1016/j.bpg.2020.101689 -
Journal of Neurological Surgery. Part... Apr 2023Atypical meningiomas are uncommon in skull base practice and present a management challenge. We aimed to review all de novo atypical skull base meningioma cases...
Atypical meningiomas are uncommon in skull base practice and present a management challenge. We aimed to review all de novo atypical skull base meningioma cases within a single unit to analyze presentation and outcome. A retrospective review of all patients undergoing surgery for intracranial meningioma identified consecutive cases of de novo atypical skull base meningioma. Electronic case records were analyzed for patient demographics, tumor location and size, extent of resection, and outcome. Tumor grading is based on the 2016 WHO criteria. Eighteen patients with de novo atypical skull base meningiomas were identified. The most common tumor location was the sphenoid wing in 10 patients (56%). Gross total resection (GTR) was achieved in 13 patients (72%) and subtotal resection (STR) in 5 patients (28%). There was no tumor recurrence recorded in patients who had undergone GTR. Patients with tumors >6 cm were more likely to undergo a STR as opposed to a GTR ( < 0.01). Patients who had undergone a STR were more likely to have postoperative tumor progression and be referred for radiotherapy ( = 0.02 and <0.01, respectively). On multiple regression analysis, tumor size is the only significant factor correlating with overall survival ( = 0.048). The incidence of de novo atypical skull base meningioma is higher in our series than currently published data. Tumor size was a significant indicator for patient outcome and extent of resection. Those undergoing a STR were more likely to have tumor recurrence. Multicenter studies of skull base meningiomas with associated molecular genetics are needed to guide management.
PubMed: 36895814
DOI: 10.1055/a-1757-3212 -
The Journal of Cell Biology May 2021Centrioles form centrosomes and cilia. In most proliferating cells, centrioles assemble through canonical duplication, which is spatially, temporally, and numerically...
Centrioles form centrosomes and cilia. In most proliferating cells, centrioles assemble through canonical duplication, which is spatially, temporally, and numerically regulated by the cell cycle and the presence of mature centrioles. However, in certain cell types, centrioles assemble de novo, yet by poorly understood mechanisms. Herein, we established a controlled system to investigate de novo centriole biogenesis, using Drosophila melanogaster egg explants overexpressing Polo-like kinase 4 (Plk4), a trigger for centriole biogenesis. We show that at a high Plk4 concentration, centrioles form de novo, mature, and duplicate, independently of cell cycle progression and of the presence of other centrioles. Plk4 concentration determines the temporal onset of centriole assembly. Moreover, our results suggest that distinct biochemical kinetics regulate de novo and canonical biogenesis. Finally, we investigated which other factors modulate de novo centriole assembly and found that proteins of the pericentriolar material (PCM), and in particular γ-tubulin, promote biogenesis, likely by locally concentrating critical components.
Topics: Animals; Cell Cycle; Cell Cycle Proteins; Cell Division; Cells, Cultured; Centrioles; Centrosome; Drosophila Proteins; Drosophila melanogaster; Female; Male; Protein Serine-Threonine Kinases; Tubulin
PubMed: 33760919
DOI: 10.1083/jcb.202008090 -
Frontiers in Chemistry 2023Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization... (Review)
Review
Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization process, dnDD is naturally categorized as a many-objective optimization problem (ManyOOP), where more than three objectives must be simultaneously optimized. However, a large number of objectives typically pose several challenges that affect the choice and the design of optimization methodologies. Herein, we cover the application of multi- and many-objective optimization methods, particularly those based on Evolutionary Computation and Machine Learning techniques, to enlighten their potential application in dnDD. Additionally, we comprehensively analyze how molecular properties used in the optimization process are applied as either objectives or constraints to the problem. Finally, we discuss future research in many-objective optimization for dnDD, highlighting two important possible impacts: i) its integration with the development of multi-target approaches to accelerate the discovery of innovative and more efficacious drug therapies and ii) its role as a catalyst for new developments in more fundamental and general methodological frameworks in the field.
PubMed: 38192501
DOI: 10.3389/fchem.2023.1288626 -
Autoimmune hepatitis and liver transplantation: Indications, and recurrent and autoimmune hepatitis.World Journal of Transplantation Mar 2022Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels. Liver... (Review)
Review
Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels. Liver transplantation may be required for patients with acute liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Recurrence is defined as development of the same disease in the allograft following liver transplantation. Autoimmune hepatitis recurs in 36%-68% of the recipients 5 years after liver transplantation. autoimmune hepatitis is the development of autoimmune hepatitis like clinical and laboratory characteristics in patients who had undergone liver transplantation for causes other than autoimmune hepatitis. Diagnostic work up for recurrent and autoimmune hepatitis is similar to the diagnosis of the original disease, and it is usually difficult. Predniso(lo)ne with or without azathioprine is the main treatment for recurrent and autoimmune hepatitis. Early diagnosis and treatment are vital for patient prognosis because autoimmune hepatitis and recurrent autoimmune hepatitis cause graft loss and result in subsequent retransplantation if medical treatment fails.
PubMed: 35433333
DOI: 10.5500/wjt.v12.i3.59 -
Seminars in Liver Disease Feb 2022Metabolic rewiring is one of the hallmarks of cancer. Altered de novo lipogenesis is one of the pivotal metabolic events deregulated in cancers. Sterol regulatory...
Metabolic rewiring is one of the hallmarks of cancer. Altered de novo lipogenesis is one of the pivotal metabolic events deregulated in cancers. Sterol regulatory element-binding transcription factor 1 (SREBP1) controls the transcription of major enzymes involved in de novo lipogenesis, including ACLY, ACACA, FASN, and SCD. Studies have shown the increased de novo lipogenesis in human hepatocellular carcinoma (HCC) samples. Multiple mechanisms, such as activation of the AKT/mechanistic target of rapamycin (mTOR) pathway, lead to high SREBP1 induction and the coordinated enhanced expression of , , and genes. Subsequent functional analyses have unraveled these enzymes' critical role(s) and the related de novo lipogenesis in hepatocarcinogenesis. Importantly, targeting these molecules might be a promising strategy for HCC treatment. This paper comprehensively summarizes de novo lipogenesis rewiring in HCC and how this pathway might be therapeutically targeted.
Topics: Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Lipogenesis; Liver Neoplasms
PubMed: 34311471
DOI: 10.1055/s-0041-1731709 -
Frontiers in Plant Science 2023Plants, unlike animals, possess a unique developmental plasticity, that allows them to adapt to changing environmental conditions. A fundamental aspect of this... (Review)
Review
Plants, unlike animals, possess a unique developmental plasticity, that allows them to adapt to changing environmental conditions. A fundamental aspect of this plasticity is their ability to undergo postembryonic organogenesis. This requires the presence of regulators that trigger and mediate specific spatiotemporal changes in developmental programs. The phytohormone cytokinin has been known as a principal regulator of plant development for more than six decades. In shoot organogenesis and shoot regeneration, cytokinins are the prime candidates for the signal that determines shoot identity. Both processes of shoot apical meristem development are accompanied by changes in gene expression, cell fate reprogramming, and the switching-on of the shoot-specific homeodomain regulator, WUSCHEL. Current understanding about the role of cytokinins in the shoot regeneration will be discussed.
PubMed: 37662179
DOI: 10.3389/fpls.2023.1239133 -
Breast (Edinburgh, Scotland) Oct 2023Information of brain metastasis (BM) in de novo stage IV breast cancer is lacking, which is an unavoidable problem and dilemma in practice. Understanding the current...
OBJECTIVES
Information of brain metastasis (BM) in de novo stage IV breast cancer is lacking, which is an unavoidable problem and dilemma in practice. Understanding the current situation is helpful for the clinical cognition and decision-making.
METHODS
We retrospectively analyzed the clinical and survival information of de novo stage IV breast cancer with BM between 2015 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable logistic and Cox regression analyses were performed to identify predictors of BM and factors associated with all-cause mortality in de novo stage IV breast cancer, respectively. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests.
RESULTS
Our cohort consisted of 1366 patients with BM in de novo stage IV breast cancer, with an incidence of 8.38% in patients with metastatic disease to any distant site. Incidence was highest among patients with metastatic disease with HR-HER2+ (12.95%) and HR-HER2- (13.40%) subtypes. The higher the number of extracranial metastases, the higher the BM incidence. The median OS was 12.0 (95%CI: 10.426-13.574) months in BM group; it was longest in HR + HER2+ (19.0[95%CI: 11.793-26.207] months), and shortest in HR-HER2- (7.0 [95%CI:5.354-8.646] months). Marital status, subtype, and abundance of metastatic sites influenced morbidity and OS of BM in de novo stage IV breast cancer.
CONCLUSIONS
Population-based estimates of the incidence and prognosis for patients with BM in de novo stage IV breast cancer were closely associated with subtype and metastatic burden. These findings may be helpful in developing diagnostic strategies, especially for brain screening.
Topics: Humans; Female; Breast Neoplasms; Retrospective Studies; Brain Neoplasms; Brain; Cognition; Prognosis; Neoplasm Metastasis
PubMed: 37499376
DOI: 10.1016/j.breast.2023.07.005 -
Frontiers in Pediatrics 2021encodes an α1 isoform of Na/K-ATPase, which is expressed abundantly in kidneys and central nervous system. variants may cause Na/K-ATPase loss of function and lead...
encodes an α1 isoform of Na/K-ATPase, which is expressed abundantly in kidneys and central nervous system. variants may cause Na/K-ATPase loss of function and lead to a wide spectrum of phenotypes. This study aims to summarize the clinical and genetic features of mutation-related disorders and explore the potential correlations between phenotypes and genotypes. We analyzed two new cases harboring novel variants and reviewed all reported cases. Both our probands had developmental delay, patient 1 accompanied with sleep disorders, irritability, and patient 2 with refractory seizures. They each had a novel heterozygous missense variant, c.2797G>A[p.Asp933Asn] (NM_000701) and c.2590G>A[p.Gly864Arg] (NM_000701) respectively. Four patients with variants have been reported in two previous papers. Among them, three patients had refractory seizures and one patient had complex hereditary spastic paraplegia (HSP). Therefore, all six patients had developmental delay, and four of them had epilepsy. All variants located in the transmembrane regions M3, M4, M7, and M8 of ATP1A1 protein. Four patients with mutations in M3 and M7 had more severe phenotypes, including developmental delay and epileptic encephalopathy, three of them with hypomagnesemia, whereas two patients with mutations in M4 and M8 had milder phenotypes, only with mild developmental delay, without seizures or hypomagnesemia. Correcting hypomagnesemia had not controlled those seizures. Two novel variants identified in two patients here enriched the genotypic and phenotypic spectrum of mutation-related disorder. Our findings suggest that hypomagnesemia in this disorder might relate to more severe phenotype and indicate more severe Na/K-ATPase dysfunction. Variations in M3 and M7 transmembrane regions were related to more severe phenotype than those in M4 and M8, which suggested that variations in M3 and M7 might cause more severe functional defect.
PubMed: 33968856
DOI: 10.3389/fped.2021.657256