scholarly journals Programmed Cell Death in the Developing Brachypodium distachyon Grain

2019 ◽  
Author(s):  
Safia Saada ◽  
Charles Ugochukwu Solomon ◽  
Sinéad Drea
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Grain Shape ◽  
Brachypodium Distachyon ◽  
Endosperm Development ◽  
List Type ◽  
Developmental Sequence ◽  
Model Species ◽  
Processing Enzymes ◽  
Molecular Aspects

SummaryThe normal developmental sequence in a grass grain entails the death of several maternal and filial tissues in a genetically regulated process termed programmed cell death (PCD). The progression and molecular aspects of PCD in developing grain have been reported for domesticated species like barley, rice, maize and wheat. Here, we report a detailed investigation of PCD in the developing grain of a wild model species, Brachypodium distachyon.We detected PCD in developing Brachypodium grains using molecular and histological approaches. We also identified and surveyed the expression of Brachypodium orthologs of protease genes known to contribute to grain PCD.We found that Brachypodium nucellus degenerates by PCD in a centrifugal pattern following anthesis, although at a slower rate compared to cultivated cereals. Mesocarp PCD was not coordinated with endosperm development. Brachypodium lacks an expansion of vacuolar processing enzymes known for their roles in nucellar PCD.Combined with existing knowledge on grain PCD, our study suggests the importance of rapid nucellar PCD for grain size and that the pattern of mesocarp PCD affects grain shape.

scholarly journals Programmed Cell Death in Developing Brachypodium distachyon Grain

2021 ◽  
Vol 22 (16) ◽  
pp. 9086
Author(s):  
Safia Saada ◽  
Charles Ugochukwu Solomon ◽  
Sinéad Drea
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Grain Shape ◽  
Brachypodium Distachyon ◽  
Endosperm Development ◽  
Developmental Sequence ◽  
Model Species ◽  
Processing Enzymes ◽  
Molecular Aspects ◽  
Developing Grains

The normal developmental sequence in a grass grain entails the death of several maternal and filial tissues in a genetically regulated process termed programmed cell death (PCD). The progression and molecular aspects of PCD in developing grains have been reported for domesticated species such as barley, rice, maize and wheat. Here, we report a detailed investigation of PCD in the developing grain of the wild model species Brachypodium distachyon. We detected PCD in developing Brachypodium grains using molecular and histological approaches. We also identified in Brachypodium the orthologs of protease genes known to contribute to grain PCD and surveyed their expression. We found that, similar to cereals, PCD in the Brachypodium nucellus occurs in a centrifugal pattern following anthesis. However, compared to cereals, the rate of post-mortem clearance in the Brachypodium nucellus is slower. However, compared to wheat and barley, mesocarp PCD in Brachypodium proceeds more rapidly in lateral cells. Remarkably, Brachypodium mesocarp PCD is not coordinated with endosperm development. Phylogenetic analysis suggests that barley and wheat possess more vacuolar processing enzymes that drive nucellar PCD compared to Brachypodium and rice. Our expression analysis highlighted putative grain-specific PCD proteases in Brachypodium. Combined with existing knowledge on grain PCD, our study suggests that the rate of nucellar PCD moderates grain size and that the pattern of mesocarp PCD influences grain shape.

scholarly journals New-onset insulin-dependent diabetes due to nivolumab

2018 ◽  
Vol 2018 ◽  
Author(s):  
Ali A Zaied ◽  
Halis K Akturk ◽  
Richard W Joseph ◽  
Augustine S Lee
Keyword(s):  
Diabetes Mellitus ◽  
Cell Death ◽  
Metabolic Acidosis ◽  
Programmed Cell Death ◽  
Diabetic Ketoacidosis ◽  
De Novo ◽  
Autoimmune Diabetes ◽  
List Type ◽  
Programmed Cell Death 1 ◽  
Insulin Dependent

Summary Nivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab. Learning points: Diabetic ketoacidosis should be considered in the differential of patients presenting with metabolic acidosis following treatment with antibodies to programmed cell death-1 receptor (anti-PD-1). Autoimmune islet cell damage is the presumed mechanism for how insulin requiring diabetes mellitus can develop de novo following administration of anti-PD-1. Because anti-PD-1 works by the activation of T-cells and reduction of ‘self-tolerance’, other autoimmune disorders are likely to be increasingly recognized with increased use of these agents.

scholarly journals Vacuolar processing enzymes, AmVPE1 and AmVPE2, as potential executors of ethylene regulated programmed cell death in the lace plant (Aponogeton madagascariensis)

Botany ◽  
2018 ◽  
Vol 96 (4) ◽  
pp. 235-247 ◽  
Author(s):  
Gaolathe Rantong ◽  
Arunika H.L.A.N. Gunawardena
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Leaf Development ◽  
Cell Types ◽  
Ethylene Biosynthesis ◽  
Activity Levels ◽  
Developmentally Regulated ◽  
Transcript Levels ◽  
Processing Enzymes ◽  
Laser Capture Microscopy

Perforation formation in Aponogeton madagascariensis (Mirb.) H.Bruggen (lace plant) is an excellent model for studying developmentally regulated programmed cell death (PCD). In this study, we isolated and identified two lace plant vacuolar processing enzymes (VPEs) and investigated their involvement in PCD and throughout leaf development. Lace plant VPE transcript levels were determined during seven different stages of leaf development. PCD and non-PCD cells from “window” stage leaves (in which perforations are forming) were separated through laser-capture microscopy and their transcript levels were also determined. VPE activity was also studied between the cell types, through a VPE activity-based probe JOPD1. Additionally, VPE transcript levels were studied in plants treated with an ethylene biosynthesis inhibitor, aminoethoxyvinylglycine (AVG). The two isolated VPEs, AmVPE1 and AmVPE2, are vegetative type VPEs. AmVPE1 had higher transcript levels during a pre-perforation developmental stage, immediately prior to visible signs of PCD. AmVPE2 transcript levels were higher later during window and late window stages. Both VPEs had higher transcript and activity levels in PCD compared with the non-PCD cells. AVG treatment inhibited PCD and associated increases in VPE transcript levels. Our results suggested that VPEs are involved in the execution of the ethylene-related PCD in the lace plant.

scholarly journals Clinical heterogeneity of hypophysitis secondary to PD-1/PD-L1 blockade: insights from four cases

2019 ◽  
Vol 2019 ◽  
Author(s):  
Isabella Lupi ◽  
Alessandro Brancatella ◽  
Mirco Cosottini ◽  
Nicola Viola ◽  
Giulia Lanzolla ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Clinical Presentation ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Case Series ◽  
List Type ◽  
Cell Death Protein

Summary Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) pathways are key regulators in T-cell activation and tolerance. Nivolumab, pembrolizumab (PD-1 inhibitors), atezolizumab (PD-L1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are monoclonal antibodies approved for treatment of several advanced cancers. Immune checkpoint inhibitors (ICIs)-related hypophysitis is described more frequently in patients treated with anti-CTLA-4; however, recent studies reported an increasing prevalence of anti-PD-1/PD-L1-induced hypophysitis which also exhibits slightly different clinical features. We report our experience on hypophysitis induced by anti-PD-1/anti-PD-L1 treatment. We present four cases, diagnosed in the past 12 months, of hypophysitis occurring in two patients receiving anti-PD-1, in one patient receiving anti-PD-1 and anti-CTLA-4 combined therapy and in one patient receiving anti-PD-L1. In this case series, timing, clinical presentation and association with other immune-related adverse events appeared to be extremely variable; central hypoadrenalism and hyponatremia were constantly detected although sellar magnetic resonance imaging did not reveal specific signs of pituitary inflammation. These differences highlight the complexity of ICI-related hypophysitis and the existence of different mechanisms of action leading to heterogeneity of clinical presentation in patients receiving immunotherapy. Learning points: PD-1/PD-L1 blockade can induce hypophysitis with a different clinical presentation when compared to CTLA-4 blockade. Diagnosis of PD-1/PD-L1 induced hypophysitis is mainly made on clinical grounds and sellar MRI does not show radiological abnormalities. Hyponatremia due to acute secondary adrenal insufficiency is often the principal sign of PD-1/PD-L1-induced hypophysitis and can be masked by other symptoms due to oncologic disease. PD-1/PD-L1-induced hypophysitis can present as an isolated manifestation of irAEs or be in association with other autoimmune diseases

scholarly journals Molecular and structural aspects of gasdermin family pores and insights into gasdermin-elicited programmed cell death

2021 ◽  
Author(s):  
Ayesha Zahid ◽  
Hazrat Ismail ◽  
Tengchuan Jin
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Programmed Cell Death ◽  
Pore Formation ◽  
Current Knowledge ◽  
Functional Consequences ◽  
Molecular Aspects ◽  
Pore Forming Proteins ◽  
Structural Aspects

Pyroptosis is a highly inflammatory and lytic type of programmed cell death (PCD) commenced by inflammasomes, which sense perturbations in the cytosolic environment. Recently, several ground-breaking studies have linked a family of pore-forming proteins known as gasdermins (GSDMs) to pyroptosis. The human genome encodes six GSDM proteins which have a characteristic feature of forming pores in the plasma membrane resulting in the disruption of cellular homeostasis and subsequent induction of cell death. GSDMs have an N-terminal cytotoxic domain and an auto-inhibitory C-terminal domain linked together through a flexible hinge region whose proteolytic cleavage by various enzymes releases the N-terminal fragment that can insert itself into the inner leaflet of the plasma membrane by binding to acidic lipids leading to pore formation. Emerging studies have disclosed the involvement of GSDMs in various modalities of PCD highlighting their role in diverse cellular and pathological processes. Recently, the cryo-EM structures of the GSDMA3 and GSDMD pores were resolved which have provided valuable insights into the pore formation process of GSDMs. Here, we discuss the current knowledge regarding the role of GSDMs in PCD, structural and molecular aspects of autoinhibition, and pore formation mechanism followed by a summary of functional consequences of gasdermin-induced membrane permeabilization.

scholarly journals 51 A novel cross-site analysis of Vectra® Polaris™ multiplex fluorescence PD-1/PD-L1 immunohistochemistry on colorectal cancer with high and low microsatellite instability

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A58-A58
Author(s):  
Sara Pollan ◽  
Bethany Remeniuk ◽  
Arezoo Hanifi ◽  
Kristin Roman ◽  
Bei Hopkins ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Microsatellite Instability ◽  
Imaging System ◽  
The United States ◽  
Cancer Site ◽  
List Type ◽  
Serial Sections ◽  
Cross Site

BackgroundColorectal cancer (CRC) is the third most diagnosed cancer in the United States with a projected 52,980 deaths in 2021.1 Microsatellite instability-high (MSI-H) CRCs with deficiencies in mismatch repair (MMR) are significantly associated with positive response to immunotherapy and improved outcomes when treated with immune checkpoint inhibitors. Programmed cell death ligand-1 (PD-L1) is an effective biomarker of MSI-H status to identify CRC patients who will respond to treatment, however, reproducible quantification of programmed cell death receptor-1 (PD-1)/PD-L1 in the tumor microenvironment (TME) across laboratory sites has been under-reported.2–3 In this study, our group directly addressed this issue by interrogating PD-1/PD-L1 cross-site at Akoya Biosciences and NeoGenomics Laboratories by employing the MOTiF™ PD-1/PD-L1 Panel kit along with the Vectra Polaris imaging system.MethodsSerial sections from 40 CRC samples with known MSI status were stained at Akoya and NeoGenomics Laboratories using a modified MOTiF PD-1/PD-L1 Lung Panel Kit on the Leica BOND RX. Sections were scanned using the Vectra Polaris imaging system at both sites. Inter-site staining reproducibility was assessed using image analysis algorithms developed with inForm tissue analysis software. Cell counts and densities were calculated using the R-script package PhenoptrReports and correlations were plotted per marker.ResultsThe average signal intensity for all markers/Opal fluorophores was within the recommended ranges of 10–30 normalized counts, with the exception of Polaris 780, which has an advised range of 1–10. This indicates the protocol stained successfully and reproducibly across all serial sections at both sites. Inter-site concordance analysis of cell densities for each marker yielded an average R2 value of ≥0.70. H-Score of PD-L1 quantified at the cell membrane trended with MSI status (stable/high).ConclusionsThis study demonstrated that the MOTiF PD-1/PD-L1 Panel kit imaged in conjunction with the Vectra Polaris is not only a reliable assay that can be run across different sites, based on the concordant cross-site data, but that re-optimization of the kit allows for the assay panel to be successfully adapted to other cancers, such as CRC, which can then capture biological differences across a multitude of samples.ReferencesAmerican Cancer Society https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.htmlYi M, Jiao D, Xu H, Liu Q, Zhao W, Han X, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer 2018;17(1):129Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site - when a biomarker defines the indication. N Engl J Med 2017;377(15):1409–12.

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