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Biomolecules Aug 2023Sepsis is triggered by microbial infection, injury, or even major surgery. Both innate and adaptive immune systems are involved in its pathogenesis. Cytoplasmic presence... (Review)
Review
Sepsis is triggered by microbial infection, injury, or even major surgery. Both innate and adaptive immune systems are involved in its pathogenesis. Cytoplasmic presence of DNA or RNA of the invading organisms or damaged nuclear material (in the form of micronucleus in the cytoplasm) in the host cell need to be eliminated by various nucleases; failure to do so leads to the triggering of inflammation by the cellular cGAS-STING system, which induces the release of IL-6, TNF-α, and IFNs. These cytokines activate phospholipase A2 (PLA2), leading to the release of polyunsaturated fatty acids (PUFAs), gamma-linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), which form precursors to various pro- and anti-inflammatory eicosanoids. On the other hand, corticosteroids inhibit PLA2 activity and, thus, suppress the release of GLA, AA, EPA, and DHA. PUFAs and their metabolites have a negative regulatory action on the cGAS-STING pathway and, thus, suppress the inflammatory process and initiate inflammation resolution. Pro-inflammatory cytokines and corticosteroids (corticosteroids > IL-6, TNF-α) suppress desaturases, which results in decreased formation of GLA, AA, and other PUFAs from the dietary essential fatty acids (EFAs). A deficiency of GLA, AA, EPA, and DHA results in decreased production of anti-inflammatory eicosanoids and failure to suppress the cGAS-STING system. This results in the continuation of the inflammatory process. Thus, altered concentrations of PUFAs and their metabolites, and failure to suppress the cGAS-STING system at an appropriate time, leads to the onset of sepsis. Similar abnormalities are also seen in radiation-induced inflammation. These results imply that timely administration of GLA, AA, EPA, and DHA, in combination with corticosteroids and anti-IL-6 and anti-TNF-α antibodies, may be of benefit in mitigating radiation-induced damage and sepsis.
Topics: Humans; Tumor Necrosis Factor-alpha; Interleukin-6; Tumor Necrosis Factor Inhibitors; Inflammation; Fatty Acids, Unsaturated; Eicosanoids; Eicosapentaenoic Acid; Arachidonic Acid; Cytokines; Docosahexaenoic Acids; Anti-Inflammatory Agents; Sepsis
PubMed: 37759732
DOI: 10.3390/biom13091332 -
Current Protocols Dec 2023Apoptosis is a mode of programmed cell death that plays important roles in tissue sculpting during development, in the maintenance of tissue homeostasis in the adult,...
Apoptosis is a mode of programmed cell death that plays important roles in tissue sculpting during development, in the maintenance of tissue homeostasis in the adult, and in the eradication of injured or infected cells during pathological processes. Numerous physiological as well as pathological stimuli trigger apoptosis, such as engagement of plasma-membrane-associated Fas, TRAIL, or TNF receptors, growth factor deprivation, hypoxia, radiation, and exposure to diverse cytotoxic drugs. Apoptosis is coordinated by members of the caspase family of cysteine proteases, which, upon activation, trigger a series of dramatic morphological and biochemical changes including retraction from the substratum, cell shrinkage, extensive and protracted plasma membrane blebbing, chromatin condensation, DNA hydrolysis, nuclear fragmentation, and proteolytic cleavage of numerous caspase substrates. These dramatic structural and biochemical alterations result not only in the controlled dismantling of the cell, but also in the rapid recognition and removal of apoptotic cells by phagocytes through the cell surface display of phagocytotic triggers such as phosphatidylserine. Necrosis, which is typically nonprogrammed or imposed upon the cell by overwhelming membrane or organelle damage, is characterized by high-amplitude cell swelling, followed by rapid plasma membrane rupture and release of cellular contents into the extracellular space. Necrosis is often provoked by infectious agents or severe departure from physiological conditions due to toxins, temperature extremes, or physical injury. However, forms of programmed necrosis (necroptosis, pyroptosis, ferroptosis) can also occur in specific circumstances. Nonprogrammed and programmed necrosis can be distinguished from apoptosis by morphological features, based on the rapid uptake of vital dyes, and through the application of specific inhibitors of key molecules associated with the latter modes of cell death. This unit describes protocols for the measurement of apoptosis and necrosis and for distinguishing apoptosis from programmed as well as conventional necrosis. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Analysis of cell morphology by phase-contrast microscopy Alternative Protocol 1: Assessment of morphological changes using eosin-methylene blue staining Alternative Protocol 2: Analysis of nuclear morphology by fluorescence microscopy Support Protocol: Preparation of cytospins Basic Protocol 2: Measurement of plasma membrane composition with annexin V and propidium iodide Basic Protocol 3: Measurement of DNA fragmentation by flow cytometry Alternative Protocol 3: Analysis of DNA fragmentation by the TUNEL assay Basic Protocol 4: Measurement of caspase activation by flow cytometry Basic Protocol 5: Discriminating between apoptosis, necrosis, necroptosis, and ferroptosis.
Topics: Humans; Flow Cytometry; Ferroptosis; Necroptosis; Apoptosis; Necrosis; Caspases; Microscopy, Fluorescence
PubMed: 38112058
DOI: 10.1002/cpz1.951 -
Current Treatment Options in Oncology Jul 2023Cranial radiation is ubiquitous in the treatment of primary malignant and benign brain tumors as well as brain metastases. Improvement in radiotherapy targeting and... (Review)
Review
Cranial radiation is ubiquitous in the treatment of primary malignant and benign brain tumors as well as brain metastases. Improvement in radiotherapy targeting and delivery has led to prolongation of survival outcomes. As long-term survivorship improves, we also focus on prevention of permanent side effects of radiation and mitigating the impact when they do occur. Such chronic treatment-related morbidity is a major concern with significant negative impact on patient's and caregiver's respective quality of life. The actual mechanisms responsible for radiation-induced brain injury remain incompletely understood. Multiple interventions have been introduced to potentially prevent, minimize, or reverse the cognitive deterioration. Hippocampal-sparing intensity modulated radiotherapy and memantine represent effective interventions to avoid damage to regions of adult neurogenesis. Radiation necrosis frequently develops in the high radiation dose region encompassing the tumor and surrounding normal tissue. The radiographic findings in addition to the clinical course of the patients' symptoms are taken into consideration to differentiate between tissue necrosis and tumor recurrence. Radiation-induced neuroendocrine dysfunction becomes more pronounced when the hypothalamo-pituitary (HP) axis is included in the radiation treatment field. Baseline and post-treatment evaluation of hormonal profile is warranted. Radiation-induced injury of the cataract and optic system can develop when these structures receive an amount of radiation that exceeds their tolerance. Special attention should always be paid to avoid irradiation of these sensitive structures, if possible, or minimize their dose to the lowest limit.
Topics: Adult; Humans; Quality of Life; Neoplasm Recurrence, Local; Cranial Irradiation; Brain Neoplasms; Brain; Radiation Injuries
PubMed: 37145381
DOI: 10.1007/s11864-023-01078-z -
Journal of the Belgian Society of... 2023Cystic brain necrosis is a rare but severe post-radiation complication; the late post-radiation context, the temporal location, and the MRI features can suggest the...
Cystic brain necrosis is a rare but severe post-radiation complication; the late post-radiation context, the temporal location, and the MRI features can suggest the diagnosis.
PubMed: 37577133
DOI: 10.5334/jbsr.3173 -
Cancer Radiotherapie : Journal de La... Sep 2023Ultracentral (UC) lung lesions are generally defined by the presence of the tumour or the Planning Target Volume (PTV) abutting proximal bronchial tree (PBT) or the... (Review)
Review
Ultracentral (UC) lung lesions are generally defined by the presence of the tumour or the Planning Target Volume (PTV) abutting proximal bronchial tree (PBT) or the esophagus. Initial reports rose awareness regarding the potential toxicity of stereotactic body radiotherapy (SBRT) when delivered to UC lesions. Major concerns include necrosis, stenosis, and bleeding of the PBT. Technological improvements now enable the delivery of more accurate treatments, possibly redefining the historical "no-fly zone". In this review, studies focusing on the treatment of UC lesions with SBRT are presented. The narrow therapeutic window requires a multidisciplinary approach.
Topics: Radiosurgery; Lung Neoplasms; Bronchi; Esophagus; Constriction, Pathologic; Necrosis; Blood Loss, Surgical; Humans; Margins of Excision
PubMed: 37516640
DOI: 10.1016/j.canrad.2023.06.021 -
Journal of Neurosurgery Sep 2023Management of patients with glioblastoma (GBM) is complex and involves implementing standard therapies including resection, radiation therapy, and chemotherapy, as well... (Review)
Review
Management of patients with glioblastoma (GBM) is complex and involves implementing standard therapies including resection, radiation therapy, and chemotherapy, as well as novel immunotherapies and targeted small-molecule inhibitors through clinical trials and precision medicine approaches. As treatments have advanced, the radiological and clinical assessment of patients with GBM has become even more challenging and nuanced. Advances in spatial resolution and both anatomical and physiological information that can be derived from MRI have greatly improved the noninvasive assessment of GBM before, during, and after therapy. Identification of pseudoprogression (PsP), defined as changes concerning for tumor progression that are, in fact, transient and related to treatment response, is critical for successful patient management. These temporary changes can produce new clinical symptoms due to mass effect and edema. Differentiating this entity from true tumor progression is a major decision point in the patient's management and prognosis. Providers may choose to start an alternative therapy, transition to a clinical trial, consider repeat resection, or continue with the current therapy in hopes of resolution. In this review, the authors describe the invasive and noninvasive techniques neurosurgeons need to be aware of to identify PsP and facilitate surgical decision-making.
Topics: Humans; Glioblastoma; Neurosurgeons; Brain Neoplasms; Disease Progression; Magnetic Resonance Imaging
PubMed: 36790010
DOI: 10.3171/2022.12.JNS222173 -
Radiotherapy and Oncology : Journal of... Dec 2023Emerging data suggest immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) or radiotherapy (SRT) may work synergistically, potentially increasing both...
BACKGROUND AND PURPOSE
Emerging data suggest immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) or radiotherapy (SRT) may work synergistically, potentially increasing both efficacy and toxicity. This manuscript characterizes factors associated with intracranial control and radiation necrosis in this group.
MATERIALS AND METHODS
All patients had non-small cell lung cancer, renal cell carcinoma, or melanoma and were treated from 2013 to 2021 at two institutions with ICI and SRS/SRT. Univariate and multivariate analysis were used to analyze factors associated with local failure (LF) and grade 2+ (G2 + ) radiation necrosis.
RESULTS
There were 179 patients with 549 metastases. The median follow up from SRS/SRT was 14.7 months and the median tumor size was 7 mm (46 tumors ≥ 20 mm). Rates of LF and G2 + radiation necrosis per metastasis were 5.8% (32/549) and 6.9% (38/549), respectively. LF rates for ICI +/- 1 month from time of radiation versus not were 3% (8/264) and 8% (24/285) (p = 0.01), respectively. G2 + radiation necrosis rates for PD-L1 ≥ 50% versus < 50% were 17% (11/65) and 3% (5/203) (p=<0.001), respectively. PD-L1 ≥ 50% remained significantly associated with G2 + radiation necrosis on multivariate analysis (p = 0.03). Rates of intracranial failure were 54% (80/147) and 17% (4/23) (p = 0.001) for those without and with G2 + radiation necrosis, respectively.
CONCLUSIONS
PD-L1 expression (≥50%) may be associated with higher rates of G2 + radiation necrosis, and there may be improved intracranial control following the development of radiation necrosis. Administration of ICIs with SRS/SRT is overall safe, and there may be some local control benefit to delivering these concurrently.
Topics: Humans; Radiosurgery; Immune Checkpoint Inhibitors; Carcinoma, Non-Small-Cell Lung; B7-H1 Antigen; Lung Neoplasms; Brain Neoplasms; Radiation Injuries; Kidney Neoplasms; Necrosis; Retrospective Studies
PubMed: 37769968
DOI: 10.1016/j.radonc.2023.109920 -
Current Oncology (Toronto, Ont.) Jul 2023Uveal melanoma represents the most prevalent form of primary malignant intraocular tumor in adults. Historically, enucleation was considered the gold-standard approach... (Review)
Review
Uveal melanoma represents the most prevalent form of primary malignant intraocular tumor in adults. Historically, enucleation was considered the gold-standard approach in the treatment of uveal melanoma. Currently, radiotherapy is the most commonly used therapy, aiming at a better quality of life. However, radiotherapy can result in several ocular complications, some of which may be vision-threatening. Radiation-induced dry eye, scleral necrosis, cataract, rubeosis iridis, neovascular glaucoma, radiation retinopathy, maculopathy, and optic neuropathy are the most common complications. This article aims to summarize the current literature regarding the ocular complications after radiotherapy, as well as their clinical features, risk factors, and management strategies. A thorough understanding of these issues is crucial for ophthalmologists and oncologists to provide optimal patient care, improve visual outcomes, and minimize long-term complications.
Topics: Adult; Humans; Quality of Life; Uveal Neoplasms; Melanoma; Risk Factors
PubMed: 37504330
DOI: 10.3390/curroncol30070470