-
Advances in Experimental Medicine and... 2021In 1891, Dr. William B. Coley, an American surgeon, made a compelling observation that immune system can be triggered to shrink tumors. The quest to exploit the power of...
In 1891, Dr. William B. Coley, an American surgeon, made a compelling observation that immune system can be triggered to shrink tumors. The quest to exploit the power of immunotherapy however was forestalled by an era of chemotherapy that ensued. During World War II, the accidental sinking of a US naval ship led to a group of sailors developing pancytopenia due to poisoning from mustard gas (nitrogen mustard). The observation prompted wide-scale screening of these chemical compounds with cytotoxic potential; further clinical trials led to the first Food and Drug Administration (FDA) approval of a chemotherapy drug, nitrogen mustard. Immunotherapy field took further impetus, not until the last two decades, due to our deeper understanding of the immune system and the cellular and molecular pathways leading to tumor development. Two groundbreaking therapies which have shown great promise in this field involve "taking the breaks off" and "pushing the pedal" of the immune system. These therapies, namely, immune checkpoint inhibitors and adoptive cell therapy, respectively, have been successful in a variety of malignancies, while the former mostly in solid tumors and the latter in hematological malignancies.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes
PubMed: 34972970
DOI: 10.1007/978-3-030-79308-1_10 -
American Journal of Disaster MedicineThe use and storage of chemical weapons in war was banned. However, chemical weapons continue to be used in wars. Therefore, in this study, we tried to identify the...
BACKGROUND
The use and storage of chemical weapons in war was banned. However, chemical weapons continue to be used in wars. Therefore, in this study, we tried to identify the chemical agents used by defining the characteristics of chemical attacks.
METHOD
We designed our study using the international dataset that can be accessed from www.start.umd.edu/gtd/. Chemical attacks between 1970 and 2020 were recorded in terms of decade, type of attack, success, suicidal purpose, property damage, number of deaths and injuries, and agents used.
RESULTS
A total of 347 attacks were reported. The highest number of attacks was 162 (46.7 percent), which occurred between 2010 and 2020. Among the chemical agents used, acidic substances (39, 11.2 percent), chlorine gas (32, 9.2 percent), and tearing agents (24, 6.9 percent) were found to be the most common. When the distribution of the five most common chemical agents by years was examined, it was found that the use of chlorine gas gradually increased in the last three decades. In the last decade, it was found that the use of mustard gas increased, whereas cyanide was not used.
CONCLUSION
In the last decade, we found that chemical attacks have increased more, especially chlorine and mustard gas were predominantly used.
Topics: Humans; Mustard Gas; Chemical Warfare Agents; Chlorine
PubMed: 37171569
DOI: 10.5055/ajdm.2022.0439 -
Toxicology Letters Feb 2020Sulfur mustard and related vesicants are cytotoxic alkylating agents that cause severe damage to the respiratory tract. Injury is progressive leading, over time, to... (Review)
Review
Sulfur mustard and related vesicants are cytotoxic alkylating agents that cause severe damage to the respiratory tract. Injury is progressive leading, over time, to asthma, bronchitis, bronchiectasis, airway stenosis, and pulmonary fibrosis. As there are no specific therapeutics available for victims of mustard gas poisoning, current clinical treatments mostly provide only symptomatic relief. In this article, the long-term effects of mustards on the respiratory tract are described in humans and experimental animal models in an effort to define cellular and molecular mechanisms contributing to lung injury and disease pathogenesis. A better understanding of mechanisms underlying pulmonary toxicity induced by mustards may help in identifying potential targets for the development of effective clinical therapeutics aimed at mitigating their adverse effects.
Topics: Alkylating Agents; Animals; Chemical Warfare Agents; Humans; Lung; Lung Injury; Mustard Compounds; Pulmonary Fibrosis; Respiratory Tract Diseases
PubMed: 31698045
DOI: 10.1016/j.toxlet.2019.10.026 -
International Journal of Molecular... Jun 2023Sulfur mustard (SM) is a highly toxic chemical agent that causes severe tissue damage, particularly to the eyes, lungs, and skin. Despite advances in treatment, there is... (Review)
Review
Sulfur mustard (SM) is a highly toxic chemical agent that causes severe tissue damage, particularly to the eyes, lungs, and skin. Despite advances in treatment, there is a need for more effective therapies for SM-induced tissue injury. Stem cell and exosome therapies are emerging as promising approaches for tissue repair and regeneration. Stem cells can differentiate into multiple cell types and promote tissue regeneration, while exosomes are small vesicles that can deliver therapeutic cargo to target cells. Several preclinical studies demonstrated the potential of stem cell, exosome, or combination therapy for various tissue injury, showing improvements in tissue repairing, inflammation, and fibrosis. However, there are also challenges associated with these therapies, such as the requirement for standardized methods for exosome isolation and characterization, the long-term safety and efficacy and reduced SM-induced tissue injury of these therapies. Stem cell or exosome therapy was used for SM-induced eye and lung injury. Despite the limited data on the use for SM-induced skin injury, this therapy is a promising area of research and may offer new treatment options in the future. In this review, we focused on optimizing these therapies, evaluating their safety and efficacy, and comparing their efficacy to other emerging therapeutic approaches potentially for SM-induced tissue injury in the eye, lung, and skin.
Topics: Mustard Gas; Exosomes; Skin; Stem Cells; Sulfur; Chemical Warfare Agents
PubMed: 37373093
DOI: 10.3390/ijms24129947 -
Toxicology Letters May 2020Sulfur mustard (SM) is a toxicant and chemical warfare agent with strong vesicant properties. The mechanisms behind SM-induced toxicity are not fully understood and no... (Review)
Review
Sulfur mustard (SM) is a toxicant and chemical warfare agent with strong vesicant properties. The mechanisms behind SM-induced toxicity are not fully understood and no antidote or effective therapy against SM exists. Both, the risk of SM release in asymmetric conflicts or terrorist attacks and the usage of SM-derived nitrogen mustards as cancer chemotherapeutics, render the mechanisms of mustard-induced toxicity a highly relevant research subject. Herein, we review a central role of the abundant cellular molecule nicotinamide adenine dinucleotide (NAD) in molecular mechanisms underlying SM toxicity. We also discuss the potential beneficial effects of NAD precursors in counteracting SM-induced damage.
Topics: Animals; Chemical Warfare Agents; Dietary Supplements; Humans; Mustard Gas; NAD; Niacinamide; Oxidative Stress; Poly(ADP-ribose) Polymerases; Reactive Nitrogen Species; Sirtuins
PubMed: 32017979
DOI: 10.1016/j.toxlet.2020.01.024 -
Experimental Eye Research Aug 2023Mustard agents are vesicants that were used in warfare multiple times. They are potent alkylating agents that activate cellular pathways of apoptosis, increase oxidative...
Mustard agents are vesicants that were used in warfare multiple times. They are potent alkylating agents that activate cellular pathways of apoptosis, increase oxidative stress, and induce inflammation. Eyes are particularly susceptible to mustard exposure with a wide range of ocular surface damage. Three main categories of mustard-related eye injuries are acute, chronic, and delayed-onset manifestations. Mustard keratopathy (MK) is a known complication characterized by corneal opacification, ulceration, thinning, and neovascularization that can lead to severe vision loss and discomfort. Recently, a few reports demonstrated the role of senescence induction as a new pathological mechanism in mustard-related injuries that could affect wound healing. We ran the first murine model of delayed-onset MK and nitrogen mustard-induced senescence, evaluating the pathological signs of senescence in the cornea using beta-galactosidase staining. Our results suggest that nitrogen mustard exposure causes senescence in the corneal cells, which could be the underlying mechanism for chronic and late-onset ocular surface damage. We also found a significant correlation between the percentage of positive beta-galactosidase staining and the degree of fibrosis in the cornea. This provides valuable insight into the possible role of anti-senescence drugs in the near future for accelerating corneal healing and restricting fibrosis in patients with mustard keratopathy.
Topics: Humans; Animals; Mice; Chemical Warfare Agents; Mustard Gas; Mechlorethamine; Corneal Diseases; Cornea; Cellular Senescence
PubMed: 37406956
DOI: 10.1016/j.exer.2023.109565 -
Pharmacology & Therapeutics Mar 2023In this review we trace the passage of fundamental ideas through 20 century cancer research that began with observations on mustard gas toxicity in World War I. The... (Review)
Review
In this review we trace the passage of fundamental ideas through 20 century cancer research that began with observations on mustard gas toxicity in World War I. The transmutation of these ideas across scientific and national boundaries, was channeled from chemical carcinogenesis labs in London via Yale and Chicago, then ultimately to the pharmaceutical industry in Bielefeld, Germany. These first efforts to checkmate cancer with chemicals led eventually to the creation of one of the most successful groups of cancer chemotherapeutic drugs, the oxazaphosphorines, first cyclophosphamide (CP) in 1958 and soon thereafter its isomer ifosfamide (IFO). The giant contributions of Professor Sir Alexander Haddow, Dr. Alfred Z. Gilman & Dr. Louis S. Goodman, Dr. George Gomori and Dr. Norbert Brock step by step led to this breakthrough in cancer chemotherapy. A developing understanding of the metabolic disposition of ifosfamide directed efforts to ameliorate its side-effects, in particular, ifosfamide-induced encephalopathy (IIE). This has resulted in several candidates for the encephalopathic metabolite, including 2-chloroacetaldehyde, 2-chloroacetic acid, acrolein, 3-hydroxypropionic acid and S-carboxymethyl-L-cysteine. The pros and cons for each of these, together with other IFO metabolites, are discussed in detail. It is concluded that IFO produces encephalopathy in susceptible patients, but CP does not, by a "perfect storm," involving all of these five metabolites. Methylene blue (MB) administration appears to be generally effective in the prevention and treatment of IIE, in all probability by the inhibition of monoamine oxidase in brain potentiating serotonin levels that modulate the effects of IFO on GABAergic and glutamatergic systems. This review represents the authors' analysis of a large body of published research.
Topics: Humans; Ifosfamide; Antineoplastic Agents; Cyclophosphamide; Brain Diseases; Methylene Blue
PubMed: 36842616
DOI: 10.1016/j.pharmthera.2023.108366 -
Toxicology Letters Jun 2021Sulfur mustard (SM) is a chemical warfare agent that has been used throughout recent history and remains a threat today. Exposed soldiers and civilians experience a... (Review)
Review
Sulfur mustard (SM) is a chemical warfare agent that has been used throughout recent history and remains a threat today. Exposed soldiers and civilians experience a variety of symptoms primarily in the respiratory system, skin, and eyes. The ocular tissues are highly sensitive to damage by SM and undergo unique manifestations of acute, chronic, and delayed complications that can persist for months and years after exposure. The mechanisms of this unique mustard gas keratopathy are still not fully understood and animal models for the study of this disease are discussed. Recent advances in mechanisms of injury are included in this review. Ophthalmic manifestations of SM injury including persistent epithelial defects, limbal stem cell deficiency, corneal neovascularization, dry eye, and corneal opacification have been reported. A wide variety of medical and surgical therapies have been studied and are reviewed here along with potential future therapies.
Topics: Chemical Warfare Agents; Drug Administration Schedule; Eye Diseases; Humans; Mustard Gas
PubMed: 33600921
DOI: 10.1016/j.toxlet.2021.02.007 -
Cells Jun 2023Sulfur mustard gas (SM) is a vesicating and alkylating agent used as a chemical weapon in many mass-casualty incidents since World War I. Ocular injuries were reported...
Sulfur mustard gas (SM) is a vesicating and alkylating agent used as a chemical weapon in many mass-casualty incidents since World War I. Ocular injuries were reported in >90% of exposed victims. The mechanisms underlying SM-induced blindness remain elusive. This study tested the hypothesis that SM-induced corneal fibrosis occurs due to the generation of myofibroblasts from resident fibroblasts via the SMAD2/3 signaling pathway in rabbit eyes in vivo and primary human corneal fibroblasts (hCSFs) isolated from donor corneas in vitro. Fifty-four New Zealand White Rabbits were divided into three groups (Naïve, Vehicle, SM-Vapor treated). The SM-Vapor group was exposed to SM at 200 mg-min/m3 for 8 min at the MRI Global facility. Rabbit corneas were collected on day 3, day 7, and day 14 for immunohistochemistry, RNA, and protein lysates. SM caused a significant increase in SMAD2/3, pSMAD, and ɑSMA expression on day 3, day 7, and day 14 in rabbit corneas. For mechanistic studies, hCSFs were treated with nitrogen mustard (NM) or NM + SIS3 (SMAD3-specific inhibitor) and collected at 30 m, 8 h, 24 h, 48 h, and 72 h. NM significantly increased TGFβ, pSMAD3, and SMAD2/3 levels. On the contrary, inhibition of SMAD2/3 signaling by SIS3 treatment significantly reduced SMAD2/3, pSMAD3, and ɑSMA expression in hCSFs. We conclude that SMAD2/3 signaling appears to play a vital role in myofibroblast formation in the cornea following mustard gas exposure.
Topics: Humans; Animals; Rabbits; Mustard Gas; Myofibroblasts; Chemical Warfare Agents; Cornea; Mechlorethamine; Signal Transduction; Smad2 Protein
PubMed: 37296653
DOI: 10.3390/cells12111533 -
Caspian Journal of Internal Medicine 2022Amongst the chemical warfare agents, blistering (vesicant) agents can be significant materials. The most important agent in this group is sulfur mustard (mustard gas)... (Review)
Review
BACKGROUND
Amongst the chemical warfare agents, blistering (vesicant) agents can be significant materials. The most important agent in this group is sulfur mustard (mustard gas) which is known as "King of chemical warfare (CW) agents ". Exposure to this agent, seriously causes damages in several organs, such as the eyes. This article reviews the ophthalmological aspects of sulfur mustard with reference of its management.
METHODS
A wide-ranging search in PubMed databases, Thomson Reuters and Scopus was done and different aspects of chemical properties of sulfur mustard, its mechanism of action and effects on eyes, clinical finding, diagnostic evaluation, initiate actions, pharmaceutical and surgical interventions was reported.
RESULTS
Sulfur mustard can alkylate DNA and RNA strands and break down structures of protein and lipid of cell membrane. This may impair cell energy production, and leads to cell death. Exposure to sulfur mustard, therefore, causes such problems for organs, including irreversible damage to the eyes.
CONCLUSION
Understanding the mechanism of the sulfur mustard effect and the early training in prevention injuries will cause fewer complications and damage to organs, including the eyes. Washing the eyes with tap water or eyewash solutions, using mydriatic drops, anti- inflammatory drugs, matrix metalloproteinase inhibitors and antibiotics may help to the management of poisoning. Surgical interventions including tarsorrhaphy, amniotic membrane transplantation, stem cell transplantation and corneal transplantation could reduce the harm to the victims.
PubMed: 35974928
DOI: 10.22088/cjim.13.3.458