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Nature Communications Sep 2023Immune checkpoint inhibitors cause side effects ranging from autoimmune endocrine disorders to severe cardiotoxicity. Periodic Fasting mimicking diet (FMD) cycles are...
Immune checkpoint inhibitors cause side effects ranging from autoimmune endocrine disorders to severe cardiotoxicity. Periodic Fasting mimicking diet (FMD) cycles are emerging as promising enhancers of a wide range of cancer therapies including immunotherapy. Here, either FMD cycles alone or in combination with anti-OX40/anti-PD-L1 are much more effective than immune checkpoint inhibitors alone in delaying melanoma growth in mice. FMD cycles in combination with anti-OX40/anti-PD-L1 also show a trend for increased effects against a lung cancer model. As importantly, the cardiac fibrosis, necrosis and hypertrophy caused by immune checkpoint inhibitors are prevented/reversed by FMD treatment in both cancer models whereas immune infiltration of CD3 and CD8 cells in myocardial tissues and systemic and myocardial markers of oxidative stress and inflammation are reduced. These results indicate that FMD cycles in combination with immunotherapy can delay cancer growth while reducing side effects including cardiotoxicity.
Topics: Animals; Mice; Cardiotoxicity; Immune Checkpoint Inhibitors; Fasting; Diet; Drug-Related Side Effects and Adverse Reactions; Immunotherapy; Lung Neoplasms; Myocardium
PubMed: 37684243
DOI: 10.1038/s41467-023-41066-3 -
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 -
The EMBO Journal Aug 2023N -methyladenosine (m A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of the m A reader...
N -methyladenosine (m A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of the m A reader YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that the loss of YTHDF2 in regulatory T (Treg) cells reduces tumor growth in mice. Deletion of Ythdf2 in Tregs does not affect peripheral immune homeostasis but leads to increased apoptosis and impaired suppressive function of Treg cells in the TME. Elevated tumor necrosis factor (TNF) signaling in the TME promotes YTHDF2 expression, which in turn regulates NF-κB signaling by accelerating the degradation of m A-modified transcripts that encode NF-κB-negative regulators. This TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a potential target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance anti-tumor immune response while avoiding Treg cells in the periphery to minimize undesired inflammations.
Topics: Mice; Animals; NF-kappa B; Neoplasms; Signal Transduction; Immunotherapy; Inflammation; Tumor Microenvironment
PubMed: 37345898
DOI: 10.15252/embj.2022113126 -
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 -
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 -
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 -
Gland Surgery Aug 2023The debate over when to perform flaps in patients undergoing radiation remains an ongoing dilemma without definitive resolution. Classically, reconstructive surgeons... (Review)
Review
The debate over when to perform flaps in patients undergoing radiation remains an ongoing dilemma without definitive resolution. Classically, reconstructive surgeons recommended avoiding exposure of autologous flaps to radiotherapy due to concerns over surgical complications and poor aesthetic outcomes. However, delayed reconstruction carries its own risk profile and aesthetic limitations, given the irreversible changes to the breast envelope. Immediate reconstruction not only confers psychosocial benefits but allows for preservation of the native breast skin and footprint. In recent years, a growing body of evidence suggests that with modern radiation techniques, long-term outcomes of immediate delayed autologous reconstruction may be more similar than previously thought. This review examines the advantages and disadvantages of each treatment algorithm and critically evaluates the existing literature on autologous breast reconstruction in the setting of post-mastectomy radiotherapy. Importantly, radiation regimens have varied widely over time and between institutions, introducing significant heterogeneity in published outcomes of flap contracture or fat necrosis after immediate reconstruction. While delayed autologous reconstruction remains a reasonable pathway, the benefits of immediate reconstruction should not be dismissed. Our findings ultimately corroborate the view that immediate flap reconstruction is a sound treatment option that can be safely offered to patients. The decision regarding which pathway to pursue should ultimately be patient-centric and driven by multidisciplinary consensus, rather than by prior dogma.
PubMed: 37701302
DOI: 10.21037/gs-23-154 -
The Oncologist Feb 2024Transarterial radioembolization (TARE) with Yttrium-90 (Y90) is a growing area of study due to its benefits in early-, intermediate-, and late-stage hepatocellular...
Transarterial radioembolization (TARE) with Yttrium-90 (Y90) is a growing area of study due to its benefits in early-, intermediate-, and late-stage hepatocellular carcinoma. Treatment intent, including curative therapy, bridging to transplant, and downstaging disease, informs treatment approach and dosimetry goals. Radiation lobectomy (RL) and radiation segmentectomy (RS) are the 2 main forms of Y90 administration which have shown improved survival outcomes with the development of personalized dosimetry. RS aims to achieve complete pathological necrosis with dose escalation and RL aims for local disease control as well as induction of contralateral lobe hypertrophy to improve hepatic reserve. Furthermore, TARE has been validated in head-to-head comparison to other locoregional and systemic therapies. Lastly, early potential exists for combination therapy between TARE and immune checkpoint inhibitors for advanced stage disease.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Embolization, Therapeutic; Yttrium Radioisotopes
PubMed: 38128565
DOI: 10.1093/oncolo/oyad327