Special Issue:
Challenges and Opportunities in Toxicology
Yunfeng Zhao
Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
Annapoorna Sreedhar
Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
Chunjing Zhang
Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA; School of Basic Medicine, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, China
Noel Jacquet
Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
Abstract
Upregulation of uncoupling protein 2 (UCP2) is considered a prosurvival mechanism for cancer cells. This prosurvival function is thought to be mediated by UCP2’s uncoupling activity which reduces the production of superoxide in the mitochondria. However, exactly how highly expressed UCP2 regulates cell proliferation, cell cycle, and cell death during the early stage of tumorigenesis has not been studied thoroughly. For this purpose, we generated UCP2 stably overexpressed JB6 Cl-41 cells (a skin cell transformation model) and performed studies to answer the above questions. Our results demonstrated that UCP2 overexpression enhanced cell proliferation, activation of the oncoprotein Fra-1, anchorage-independent growth, 3D spheroids growth, and glucose uptake during skin cell transformation. Next, our results demonstrated that UCP2 overexpression resulted in marked decreases in the proportion of the cells in the G1 phase and an increase of cells in the S phase of the cell cycle, which was accompanied by increased expression of Cyclin E and Cdk2. Lastly, UCP2 overexpression did not enhance or suppress apoptosis during skin cell transformation, as indicated by Annexin V and active caspase 3/7 staining. Taken together, these data suggest that UCP2 upregulation mainly enhances the Fra-1 oncogenic pathway which drives cell proliferation, without inhibiting apoptosis during skin cell transformation.
Kuldeep Kumar
Pt BD Sharma PGIMS, Rohtak, Haryana, INDIA
Vinod Kumar
Pt BD Sharma PGIMS, Rohtak, Haryana, INDIA
Naveen Sharma
Maharishi Markandeshwar College of Medical Sciences and Research, Sadopur, Ambala, Haryana
Kunal Gaba
Adesh Institute of Medical Sciences & Research, Bathinda
Rahul Kaushik
Pt BD Sharma PGIMS, Rohtak
Abstract
Medicolegal autopsies are routinely done by forensic pathologist to fulfil the objectives of autopsy and to solve the dilemma of investigating agencies. But the medicolegal autopsy is not always concluding the main objective of it which is cause of death and such autopsies are categorised as obscure and negative autopsy. Acknowledgement of incidence of negative autopsy to the practicing forensic pathologist is necessary. We are discussing here some autopsies conducted by the author(s) after which the final scientific cause of death could not be ascertained. The algorithm-based approach toward the determination of cause of death and importance of other circumstantial evidences has been discussed.
Scott A. Barman
Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia
Stephen Haigh
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia
David J.R. Fulton
Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, Georgia; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia
Abstract
Pulmonary Hypertension is a progressive vascular disease resulting from the tapering of pulmonary arteries causing high pulmonary arterial blood pressure and ultimately right ventricular failure. A defining characteristic of Pulmonary Hypertension is the excessive remodeling of pulmonary arteries that includes increased proliferation, vascular fibrosis and inflammation. There is no outward cure for Pulmonary Hypertension nor are there interventions that effectively impede or reverse pulmonary arterial remodeling, and pulmonary vascular research over the past several decades has sought to identify novel molecular mechanisms to target for therapeutic benefit. Galectin-3 is a carbohydrate binding lectin that is unique for its chimeric structure, comprised of an N-terminal oligomerization domain and a C-terminal carbohydrate-recognition domain. Galectin-3 is a regulator of modifications in cell behavior that contribute to aberrant pulmonary arterial remodeling including cell proliferation, inflammation, and fibrosis, but its role in Pulmonary Hypertension is poorly understood. In this review, we define Galectin-3 and summarize specific topics regarding the role of Galectin-3 expression in the development of Pulmonary Hypertension by providing evidence which supports the ability of Galectin-3 to influence reactive oxygen species production, NADPH enzyme expression, vascular inflammation and vascular fibrosis, all phenomena which contribute to pulmonary arterial remodeling and the development of Pulmonary Hypertension.
Kenneth Blum
The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX., USA.; Division of Addiction Research & Education, Center for Sports, Exercise & Psychiatry, Western University Health Sciences, Pomona, CA., USA.; Institute of Psychology, ELTE Eötvös Loránd University, Budapest, Hungary.; Department of Psychiatry, School of Medicine, University of Vermont, Burlington, VT.,USA.; Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Centre, Dayton, OH, USA.; Division of Nutrigenomics Research, TranspliceGen Therapeutics, Inc., Austin, Tx., 78701, USA; Department of Nutrigenomic Research, Victory Nutrition International, Inc., Bonita Springs, FL, USA.; Division of Personalized Medicine, Cross-Cultural Research and Educational Institute, San Clemente, CA., USA; Sunder Foundation, Palm Springs, CA, USA; Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel, Israel.
Mark S Gold
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO., USA.
Jean Lud Cadet
Molecular Neuropsychiatry Research Branch, National Insti-tute on Drug Abuse, National Institutes of Health, Bethesda, MD., USA
Marjorie C. Gondre-Lewis
Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washing-ton, DC., USA.
Thomas McLaughlin
Division of Nutrigenomics Re-search, TranspliceGen Thera-peutics, Inc., Austin, Tx., 78701, USA
Eric R Braverman
The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX., USA.
Igor Elman
Center for Pain and the Brain (P.A.I.N Group), Department of Anesthesiology, Critical Care & Pain Medicine, Boston Chil-dren’s Hospital, Boston, MA., USA.
B. Paul Carney
Division Pediatric Neurology, University of Missouri ,School of Medicine, Columbia, MO., USA
Rene Cortese
Department of Child Health – Child Health Research Institute, & Department of Obstetrics, Gynecology and Women’s Health School of Medicine, Uni-versity of Missouri, MO., USA.
Tomilowo Abijo
Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washing-ton, DC., USA.
Debasis Bagchi
Department of Pharmaceutical Sciences, Texas Southern Uni-versity College of Pharmacy and Health Sciences, Houston, TX, USA
John Giordano
Division of Personalized Mental Illness Treatment & Research, Ketamine Infusion Clinics of South Florida, Pompano Beach, Fl., USA
Catherine A. Dennen
Department of Family Medi-cine, Jefferson Health North-east, Philadelphia, PA, USA.
David Baron
Institute of Psychology, ELTE Eötvös Loránd University, Bu-dapest, Hungary.
Panayotis K Thanos
Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.; Department of Psychology, State University of New York at Buffalo, Buffalo, NY 14203, USA.
Diwanshu Soni
College of Osteopathic Medi-cine of the Pacific, Western University of Health Sciences, Pomona, CA., USA.
Milan T. Makale
Department of Radiation Medi-cine and Applied Sciences, UC San Diego, 3855 Health Sci-ences Drive, La Jolla, CA 92093-0819, USA.
Miles Makale
Department of Psychology, UC San Diego, Health Sciences Drive, La Jolla, CA, 92093, USA
Kevin T. Murphy
Peak Logic, San Diego, CA., USA
Nicole Jafari
Department of Human Devel-opment, California State Uni-versity at long Beach, Long Beach, CA., USA ; Division of Personalized Medi-cine, Cross-Cultural Research and Educational Institute, San Clemente, CA., USA
Keerthy Sunder
Department of Psychiatry, Me-nifee Global Medical Center, Palm Desert, CA., USA; Sunder Foundation, Palm Springs, CA, USA
Foojan Zeine
Awareness Integration Institute, San Clemente, CA., USA.; Department of Health Science, California State University at Long Beach, Long Beach, CA., USA.
Mauro Ceccanti
Società Italiana per il Tratta-mento dell’Alcolismo e le sue Complicanze (SITAC), ASL Ro-ma1, Sapienza University of Rome, Rome, Italy
Abdalla Bowirrat
Department of Molecular Biol-ogy and Adelson School of Medicine, Ariel University, Ariel, Israel.
Rajendra D. Badgaiyan
Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Medical Center, San Antonio, TX., USA.; Department of Psychiatry, Mt Sinai University School of Medicine, New York, NY., USA
Abstract
Addiction, albeit some disbelievers like Mark Lewis [1], is a chronic, relapsing brain disease, resulting in unwanted loss of control over both substance and non- substance behavioral addictions leading to serious adverse consequences [2]. Addiction scientists and clinicians face an incredible challenge in combatting the current opioid and alcohol use disorder (AUD) pandemic throughout the world. Provisional data from the Centers for Disease Control and Prevention (CDC) shows that from July 2021-2022, over 100,000 individuals living in the United States (US) died from a drug overdose, and 77,237 of those deaths were related to opioid use [3]. This number is expected to rise, and according to the US Surgeon General it is highly conceivable that by 2025 approximately 165,000 Americans will die from an opioid overdose. Alcohol abuse, according to data from the World Health Organization (WHO), results in 3 million deaths worldwide every year, which represents 5.3% of all deaths globally [4].
Cécile F Rousseau, PhD
Voisin Consulting Life Sciences, Boulogne (Paris), France
Arnaud Beurdeley, MSc
Voisin Consulting Life Sciences, Boulogne (Paris), France.
Déborah Revaud, PhD
Voisin Consulting Life Sciences, Boulogne (Paris), France.
Emmanuelle M. Voisin, PhD
Voisin Consulting Life Sciences, Boulogne (Paris), France.
Carlo Chiavaroli, PhD
Voisin Consulting Life Sciences, Lausanne, Switzerland.
Abstract
As it is often the case with innovative technologies, regulatory agencies are highly demanding in product safety demonstration from those pioneering breakthrough therapy products. Since the first historically approved gene therapy medicinal product (Gencidine in 2003) by the Chinese National Medicinal Products Administration, gene therapy medicinal products have slowly been emerging in other regions, as illustrated by the first European-approved gene therapy medicinal product (Glybera in 2012) and the first US-approved product (Imlygic in 2015). From then, with the rise of new molecular technologies (e.g., non-viral and viral vector systems), an exponential growth of gene therapies development could be gauged with, for example, the approval of more than thirty gene therapies between 2016-2022.
Using a method based on Preferred Reporting Items for Systematic reviews and Meta-Analyses principle, throughout different literature databases, this review is restricted to the evaluation of viral vector-based gene therapy medicinal products (VV-GTMPs). It also considered relevant guidelines and public assessment reports issued by the EMA and / or the FDA on the products these agencies approved. Then, a benchmark was performed to help stakeholders to identify regulatory trends and to design appropriate nonclinical programs establishing the benefit / risk ratio for patients to be enrolled in clinical trials. The analysis was focused on the nonclinical activities (pharmacology, biodistribution / persistence / shedding, and toxicology) performed by Applicants / Sponsors.
As of 30 March 2023, 18 VV-GTMPs have been authorized by the EMA and 14 by the FDA to treat either orphan diseases or limited number of oncology patients. The majority of these therapies are based on adeno-associated or retroviral viruses (often lentiviruses able to transfect hematopoietic CD34+ cells or T-cells). Based on an analysis of the ongoing clinical trials, there is now a trend for developing gene therapies for larger patient populations.
In conclusion, given the VV-GTMPs diversity and targeted indications, a “one-size fits all” nonclinical development plan cannot be considered by default. Instead, individual, risk-based, tailored nonclinical development programs appear more appropriate to assess such products, taking into consideration the lessons learned from the past. In such fast-evolving environment, regulatory agencies need to adapt their evaluation process very rapidly.
Angelo Gianni Casalini, MD
Unit of Pulmonology and Thoracic Endoscopy, University Hospital of Parma, Italy.
Pier Anselmo Mori, MD
Unit of Pulmonology and Thoracic Endoscopy, University Hospital of Parma, Italy.
Roberta Pisi, BSc
Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, Italy.
Federico Maria Maniscalco, MD
Department of Medicine and Surgery, University of Parma, Italy
Massimo Corradi, MD
Centre for Research in Toxicology (CERT), University of Parma, Italy
Matteo Goldoni, PhD
Department of Medicine and Surgery, University of Parma, Italy
Abstract
A pleural effusion is defined as eosinophilic when eosinophils represent ≥ 10% of the total nucleated cell count, and accounts for approximately 10% of all pleural effusions. The diagnostic significance of eosinophilic pleural effusion has yet to be determined.
Objective and Methods: A retrospective study was conducted on 65 patients with eosinophilic pleural effusion to evaluate the correlation between the percentage of eosinophils present in the pleural fluid and the benign or malignant nature of the effusion. An original aspect of current study was the evaluation of other variables in association with pleural eosinophilia, in particular pleural fluid lymphocytosis (≥ 50%), and the presence or absence of fever.
Results: Data showed the trend towards a decrease in neoplastic incidence with increasing percentages of eosinophilic counts, although this correlation was not statistically significant. The presence of fever correlated with low incidence of neoplasms (10% of neoplastic effusions in patients with fever) and was the most significant variable (p=0.001), with a Negative Predictive Value of neoplastic disease of 90%, with sensitivity 92.6% and specificity 47.4%.
When evaluated together with fever, eosinophils increased their discriminating sensitivity to the benign or malignant nature of the effusion but lost in specificity.
When evaluated as absence or presence of lymphocytosis (≥50% lymphocytes), associated with eosinophilia, lymphocytes were significantly associated with the neoplastic nature of the effusion.
Conclusions: the study showed that the finding of eosinophilic pleural effusion should not be considered an indicator of benignity of the effusion; the association of other parameters with eosinophilia, lymphocytosis of the pleural fluid and fever can provide more precise prognostic indications; a high percentage of eosinophils, the absence of lymphocytosis and the presence of fever would seem to be associated with a low probability of a neoplastic nature of the effusion.
