scholarly journals Immune Modulation and Stereotactic Radiation: Improving Local and Abscopal Responses

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Jing Zeng ◽  
Timothy J. Harris ◽  
Michael Lim ◽  
Charles G. Drake ◽  
Phuoc T. Tran
Keyword(s):  
Immune Modulation ◽  
Synergistic Effects ◽  
Treatment Strategies ◽  
Tumor Model ◽  
The Body ◽  
Model Systems ◽  
Dose Fractionation ◽  
Tumor Control ◽  
Stereotactic Radiation ◽  
Preclinical Treatment

New and innovative treatment strategies for cancer patients in the fields of immunotherapy and radiotherapy are rapidly developing in parallel. Among the most promising preclinical treatment approaches is combining immunotherapy with radiotherapy where early data suggest synergistic effects in several tumor model systems. These studies demonstrate that radiation combined with immunotherapy can result in superior efficacy for local tumor control. More alluring is the emergence of data suggesting an equally profound systemic response also known as “abscopal” effects with the combination of radiation and certain immunotherapies. Studies addressing optimal radiation dose, fractionation, and modality to be used in combination with immunotherapy still require further exploration. However, recent anecdotal clinical reports combining stereotactic or hypofractionated radiation regimens with immunotherapy have resulted in dramatic sustained clinical responses, both local and abscopal. Technologic advances in clinical radiation therapy has made it possible to deliver hypofractionated regimens anywhere in the body using stereotactic radiation techniques, facilitating further clinical investigations. Thus, stereotactic radiation in combination with immunotherapy agents represents an exciting and potentially fruitful new space for improving cancer therapeutic responses.

scholarly journals Systematic identification of synergistic combinations of targeted agents and immunotherapies in breast cancer using intratumor multiplex implantable microdevice assay

2021 ◽  
Author(s):  
Zuzana Tatarova ◽  
Dylan Blumberg ◽  
James Korkola ◽  
Laura Heiser ◽  
John Muschler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Synergistic Effects ◽  
Spatial Association ◽  
Treatment Strategies ◽  
Cancer Control ◽  
Immunological Response ◽  
Tumor Control ◽  
Targeted Agents ◽  
Multiple Drugs ◽  
Synergistic Combinations

Abstract Systematically identifying synergistic combinations between targeted agents and immunotherapies in cancer based on genomic or other static biomarkers remains elusive. Here we integrate two novel high-content and high-throughput techniques, an implantable microdevice to administer multiple drugs into different sites in tumors at nanodoses; and spatial systems analysis of tumor microenvironmental states to describe tumor cell and immunological response signatures and rapidly, within days, identify effective combinations from among numerous agents. We demonstrate in systemic follow-up studies across three mammary carcinoma models that combinations identified by this approach lead to highly synergistic effects. Biomarkers associated with resistance to each agent allowed us to prioritize at least five novel treatment strategies of which the panobinostat/venetoclax/anti-CD40 was the most effective inducing complete tumor control across models. We show that spatial association of cancer stem cells with dendritic cells during immunogenic cell death is a potential mechanism of action underlying long-term breast cancer control.

Radiotherapy for Brain Tumors: Current Practice and Future Directions

2020 ◽  
Vol 16 (3) ◽  
pp. 182-195
Author(s):  
Sarah Baker ◽  
Natalie Logie ◽  
Kim Paulson ◽  
Adele Duimering ◽  
Albert Murtha
Keyword(s):  
Brain Tumors ◽  
Treatment Strategies ◽  
Brain Parenchyma ◽  
Benign Tumors ◽  
Tumor Control ◽  
Normal Brain ◽  
Neurocognitive Deficits ◽  
Close Proximity ◽  
Recent Developments ◽  
High Level

Radiotherapy is an important component of the treatment for primary and metastatic brain tumors. Due to the close proximity of critical structures and normal brain parenchyma, Central Nervous System (CNS) radiotherapy is associated with adverse effects such as neurocognitive deficits, which must be weighed against the benefit of improved tumor control. Advanced radiotherapy technology may help to mitigate toxicity risks, although there is a paucity of high-level evidence to support its use. Recent advances have been made in the treatment for gliomas, meningiomas, benign tumors, and metastases, although outcomes remain poor for many high grade tumors. This review highlights recent developments in CNS radiotherapy, discusses common treatment toxicities, critically reviews advanced radiotherapy technologies, and highlights promising treatment strategies to improve clinical outcomes in the future.

scholarly journals Role of Chiral Configuration in the Photoinduced Interaction of D- and L-Tryptophan with Optical Isomers of Ketoprofen in Linked Systems

2021 ◽  
Vol 22 (12) ◽  
pp. 6198
Author(s):  
Aleksandra A. Ageeva ◽  
Ilya M. Magin ◽  
Alexander B. Doktorov ◽  
Victor F. Plyusnin ◽  
Polina S. Kuznetsova ◽  
...  
Keyword(s):  
Amino Acid ◽  
Excited States ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Dipole Interaction ◽  
The Body ◽  
Model Systems ◽  
Optical Isomers ◽  
Amino Acid Properties ◽  
Parkinson’S Diseases

The study of the L- and D-amino acid properties in proteins and peptides has attracted considerable attention in recent years, as the replacement of even one L-amino acid by its D-analogue due to aging of the body is resulted in a number of pathological conditions, including Alzheimer’s and Parkinson’s diseases. A recent trend is using short model systems to study the peculiarities of proteins with D-amino acids. In this report, the comparison of the excited states quenching of L- and D-tryptophan (Trp) in a model donor–acceptor dyad with (R)- and (S)-ketoprofen (KP-Trp) was carried out by photochemically induced dynamic nuclear polarization (CIDNP) and fluorescence spectroscopy. Quenching of the Trp excited states, which occurs via two mechanisms: prevailing resonance energy transfer (RET) and electron transfer (ET), indeed demonstrates some peculiarities for all three studied configurations of the dyad: (R,S)-, (S,R)-, and (S,S)-. Thus, the ET efficiency is identical for (S,R)- and (R,S)-enantiomers, while RET differs by 1.6 times. For (S,S)-, the CIDNP coefficient is almost an order of magnitude greater than for (R,S)- and (S,R)-. To understand the source of this difference, hyperpolarization of (S,S)-and (R,S)- has been calculated using theory involving the electron dipole–dipole interaction in the secular equation.

scholarly journals Monoclonal Antibody-Based Immunotherapy and Its Role in the Development of Cardiac Toxicity

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 86
Author(s):  
Mohit Kumar ◽  
Chellappagounder Thangavel ◽  
Richard C. Becker ◽  
Sakthivel Sadayappan
Keyword(s):  
Cancer Patients ◽  
Immune Modulation ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Induced Pluripotent Stem Cell ◽  
High Volume ◽  
Oncolytic Viruses ◽  
Model Systems ◽  
Volume Data ◽  
Late Cardiotoxicity

Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At the same time, however, they can cause inflammation and promote adverse cardiac immune modulation and cardiac failure among some cancer patients as late as five to ten years following immunotherapy. In this review, we discuss cardiotoxicity associated with immunotherapy. We also propose using human-induced pluripotent stem cell-derived cardiomyocytes/ cardiac-stromal progenitor cells and cardiac organoid cultures as innovative experimental model systems to (1) mimic clinical treatment, resulting in reproducible data, and (2) promote the identification of immunotherapy-induced biomarkers of both early and late cardiotoxicity. Finally, we introduce the integration of omics-derived high-volume data and cardiac biology as a pathway toward the discovery of new and efficient non-toxic immunotherapy.

scholarly journals Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR

2021 ◽  
Vol 9 (9) ◽  
pp. e002627
Author(s):  
Nicholas L Bayless ◽  
Jeffrey A Bluestone ◽  
Samantha Bucktrout ◽  
Lisa H Butterfield ◽  
Elizabeth M Jaffee ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Action Plan ◽  
Treatment Strategies ◽  
Model Systems ◽  
Preclinical Model ◽  
Programmed Death ◽  
Organ Systems

Recent advances in cancer immunotherapy have completely revolutionized cancer treatment strategies. Nonetheless, the increasing incidence of immune-related adverse events (irAEs) is now limiting the overall benefits of these treatments. irAEs are well-recognized side effects of some of the most effective cancer immunotherapy agents, including antibody blockade of the cytotoxic T-lymphocyte-associated protein 4 and programmed death protein 1/programmed-death ligand 1 pathways. To develop an action plan on the key elements needed to unravel and understand the key mechanisms driving irAEs, the Society for Immunotherapy for Cancer and the American Association for Cancer Research partnered to bring together research and clinical experts in cancer immunotherapy, autoimmunity, immune regulation, genetics and informatics who are investigating irAEs using animal models, clinical data and patient specimens to discuss current strategies and identify the critical next steps needed to create breakthroughs in our understanding of these toxicities. The genetic and environmental risk factors, immune cell subsets and other key immunological mediators and the unique clinical presentations of irAEs across the different organ systems were the foundation for identifying key opportunities and future directions described in this report. These include the pressing need for significantly improved preclinical model systems, broader collection of biospecimens with standardized collection and clinical annotation made available for research and integration of electronic health record and multiomic data with harmonized and standardized methods, definitions and terminologies to further our understanding of irAE pathogenesis. Based on these needs, this report makes a set of recommendations to advance our understanding of irAE mechanisms, which will be crucial to prevent their occurrence and improve their treatment.

Craniopharyngioma: a comparison of tumor control with various treatment strategies

2010 ◽  
Vol 28 (4) ◽  
pp. E5 ◽  
Author(s):  
Isaac Yang ◽  
Michael E. Sughrue ◽  
Martin J. Rutkowski ◽  
Rajwant Kaur ◽  
Michael E. Ivan ◽  
...  
Keyword(s):  
Tumor Resection ◽  
Treatment Strategies ◽  
Group Versus ◽  
Outcome Data ◽  
Treatment Modalities ◽  
Rank Test ◽  
Tumor Control ◽  
Subtotal Resection ◽  
Log Rank Test ◽  
Significant Difference

Object Craniopharyngiomas have a propensity to recur after resection, potentially causing death through their aggressive local behavior in their critical site of origin. Recent data suggest that subtotal resection (STR) followed by adjuvant radiotherapy (XRT) may be an appealing substitute for gross-total resection (GTR), providing similar rates of tumor control without the morbidity associated with aggressive resection. Here, the authors summarize the published literature regarding rates of tumor control with various treatment modalities for craniopharyngiomas. Methods The authors performed a comprehensive search of the English language literature to identify studies publishing outcome data on patients undergoing surgery for craniopharyngioma. Rates of progression-free survival (PFS) and overall survival (OS) were determined through Kaplan-Meier analysis. Results There were 442 patients who underwent tumor resection. Among these patients, GTR was achieved in 256 cases (58%), STR in 101 cases (23%), and STR+XRT in 85 cases (19%). The 2- and 5-year PFS rates for the GTR group versus the STR+XRT group were 88 versus 91%, and 67 versus 69%, respectively. The 5- and 10-year OS rates for the GTR group versus the STR+XRT group were 98 versus 99%, and 98 versus 95%, respectively. There was no significant difference in PFS (log-rank test) or OS with GTR (log-rank test). Conclusions Given the relative rarity of craniopharyngioma, this study provides estimates of outcome for a variety of treatment combinations, as not all treatments are an option for all patients with these tumors.

scholarly journals Nucleosides and nucleotides: natural bioactive substances in milk and colostrum

2000 ◽  
Vol 84 (S1) ◽  
pp. 59-68 ◽  
Author(s):  
Eckhard Schlimme ◽  
D. Martin ◽  
H. Meisel
Keyword(s):  
Immune Modulation ◽  
Bovine Milk ◽  
Specific Pattern ◽  
The Body ◽  
Lactation Period ◽  
Nursing Time ◽  
Bioactive Substances ◽  
Protein Nitrogen ◽  
Physiological Capacity

Nucleotides, nucleosides and nucleobases belong to the non-protein-nitrogen (NPN) fraction of milk. The largest amounts of ribonucleosides and ribonucleotides – ribose forms only were considered in this review – were measured directly after parturition in bovine milk and other ruminants as well as in the milk of humans. Generally, concentrations of most of the nucleos(t)ides tend to decrease gradually with advancing lactation period or nursing time. The species-specific pattern of these minor constituents in milk from different mammals is a remarkable property and confirms, at least, the specific physiological impact of these minor compounds in early life. The physiological capacity of these compounds in milk is given by the total potentially available nucleosides. The main dietary sources of nucleos(t)ides are nucleoproteins and nucleic acids which are converted in the course of intestinal digestion into nucleosides and nucleobases the preferred forms for absorption in the intestine. Thus, nucleosides and nucleobases are suggested to be the acting components of dietary and/or supplemented nucleic acid-related compounds in the gut. They are used by the body as exogenous trophochemical sources and can be important for optimal metabolic functions. Up to 15 % of the total daily need for a breast-fed infant was calculated to come from this dietary source. Concerning their biological role they not only act as metabolites but are also involved as bioactive substances in the regulation of body functions. Dietary nucleotides affect immune modulation, e.g. they enhance antibody responses of infants as shown by a study with more than 300 full-term healthy infants. Dietary nucleos(t)ides are found to contribute to iron absorption in the gut and to influence desaturation and elongation rates in fatty acid synthesis, in particular long-chain polyunsaturated fatty acids in early stages of life. Thein vitromodulation of cell proliferation and apoptosis has been described by ribonucleosides, in particular by modified components using human cell culture models. Due to the bio- and trophochemical properties of dietary nucleos(t)ides, the European Commission has allowed the use of supplementation with specific ribonucleotides in the manufacture of infant and follow-on formula. From the technochemical point of view, the ribonucleoside pattern is influenced by thermal treatment of milk. In addition ribonucleosides are useful indicators for quantifying adulterations of milk and milk products.

Lumen-oriented versus wall-oriented treatment strategies for intracranial aneurysms – A systematic review of suggested therapeutic concepts

2021 ◽  
pp. 0271678X2110574
Author(s):  
Basil E Grüter ◽  
Fabio von Faber-Castell ◽  
Serge Marbacher
Keyword(s):  
Systematic Review ◽  
Intracranial Aneurysms ◽  
Cell Injury ◽  
Treatment Strategies ◽  
Aneurysm Wall ◽  
Starting Point ◽  
Preclinical Treatment ◽  
Major Interest ◽  
Therapeutic Concepts ◽  
New Treatment

The development of new treatment strategies for intracranial aneurysms (IAs) has been and continues to be a major interest in neurovascular research. Initial treatment concepts were mainly based on a physical-mechanistic disease understanding for IA occlusion (lumen-oriented therapies). However, a growing body of literature indicates the important role of aneurysm wall biology (wall-oriented therapies) for complete IA obliteration. This systematic literature review identified studies that explored endovascular treatment strategies for aneurysm treatment in a preclinical setting. Of 5278 publications screened, 641 studies were included, categorized, and screened for eventual translation in a clinical trial. Lumen-oriented strategies included (1) enhanced intraluminal thrombus organization, (2) enhanced intraluminal packing, (3) bridging of the intraluminal space, and (4) other, alternative concepts. Wall-oriented strategies included (1) stimulation of proliferative response, (2) prevention of aneurysm wall cell injury, (3) inhibition of inflammation and oxidative stress, and (4) inhibition of extracellular matrix degradation. Overall, lumen-oriented strategies numerically still dominate over wall-oriented strategies. Among the plethora of suggested preclinical treatment strategies, only a small minority were translated into clinically applicable concepts (36 of 400 lumen-oriented and 6 of 241 wall-oriented). This systematic review provides a comprehensive overview that may provide a starting point for the development of new treatment strategies.

Radiofrequency Ablation of Spine Metastases: A Clinical and Technical Approach

2021 ◽  
Vol 25 (06) ◽  
pp. 795-804
Author(s):  
Steven Yevich ◽  
Stephen Chen ◽  
Zeyad Metwalli ◽  
Joshua Kuban ◽  
Stephen Lee ◽  
...  
Keyword(s):  
Radiofrequency Ablation ◽  
Multidisciplinary Treatment ◽  
Treatment Algorithm ◽  
Treatment Strategies ◽  
Clinical Work ◽  
Additional Treatment ◽  
Vertebral Compression Fractures ◽  
Tumor Control ◽  
Technical Approach ◽  
Spine Metastases

AbstractPercutaneous radiofrequency ablation (RFA) is an integral component of the multidisciplinary treatment algorithm for both local tumor control and palliation of painful spine metastases. This minimally invasive therapy complements additional treatment strategies, such as pain medications, systemic chemotherapy, surgical resection, and radiotherapy. The location and size of the metastatic lesion dictate preprocedure planning and the technical approach. For example, ablation of lesions along the spinal canal, within the posterior vertebral elements, or with paraspinal soft tissue extension are associated with a higher risk of injury to adjacent spinal nerves. Additional interventions may be indicated in conjunction with RFA. For example, ablation of vertebral body lesions can precipitate new, or exacerbate existing, pathologic vertebral compression fractures that can be prevented with vertebral augmentation. This article reviews the indications, clinical work-up, and technical approach for RFA of spine metastases.

Liposomal ET-18-OCH3 Induces Cytochrome c-Mediated Apoptosis Independently of CD95 (APO-1/Fas) Signaling

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3583-3592 ◽  
Author(s):  
Olivier Cuvillier ◽  
Eric Mayhew ◽  
Andrew S. Janoff ◽  
Sarah Spiegel
Keyword(s):  
Cytochrome C ◽  
Critical Role ◽  
Ether Lipid ◽  
Tumor Model ◽  
Model Systems ◽  
Triggered Release ◽  
Receptor System ◽  
Cd95 Ligand ◽  
Fas Signaling ◽  
Induced Apoptosis

ELL-12, a liposome formulation of the ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3), is a nonmyelosuppressive antiproliferative agent that is more effective and less toxic than the ether lipid itself in tumor model systems. We found that ELL-12 induced apoptosis in Jurkat, H9, and U-937 cells that was preceded by activation of executioner caspases. In addition, ELL-12 triggered release of cytochrome c from mitochondria to the cytoplasm before caspase-9 activation. Apoptosis, activation of caspases, and cytochromec release were blocked by Bcl-xL overexpression in Jurkat T cells, suggesting a critical role for mitochondria in ELL-12–triggered cell death. Furthermore, ELL-12 had no effect on expression of CD95 ligand, and inhibition of the Fas signaling pathway with antagonistic anti-CD95 antibody did not affect apoptosis induced by ELL-12. Hence, ELL-12 could be a promising adjunct for the treatment of tumors in addition to myelosuppressive chemotherapeutic drugs and/or those that use the CD95-ligand/receptor system to trigger apoptosis.

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