Toxicology is a branch of pharmacology concerned with the study of adverse effects of chemical, biological and physical agents on biological systems to establish the extent of damage. Determination of relationship between dose levels and its effects on the living organisms attain great significance in clinical studies. The Journal of Toxicology is an open access, peer-reviewed international journal that publishes studies including Environmental toxicology, Chemical toxicology, Industrial toxicology, Toxicogenomics, Reproductive toxicology, etc.

Toxic Effects of Pesticides

DNA materials have emerged as potential nanocarriers for targeted cancer therapy to precisely deliver cargos with specific purposes. The short half‐life and low bioavailability of DNA materials due to their interception by the reticuloendothelial system and blood clearance further limit their clinical translation. This study employs an HER2‐targeted DNA‐aptamer‐modified DNA tetrahedron (HApt‐tFNA) as a drug delivery system, and combines maytansine (DM1) to develop the HApt‐DNA tetrahedron/DM1 conjugate (HApt‐tFNA@DM1, HTD, HApDC) for targeted therapy of HER2‐positive cancer. To optimize the pharmacokinetics and tumor‐aggregation of HTD, a biomimetic camouflage is applied to embed HTD. The biomimetic camouflage is constructed by merging the erythrocyte membrane with pH‐responsive functionalized synthetic liposomes, thus with excellent performance of drug delivery and tumor‐stimulated drug release. The hybrid erythrosome‐based nanoparticles show better inhibition of HER2‐positive cancer than other drug formulations and exhibit superior biosafety. With the strengths of precise delivery, increased drug loading, sensitive tumor probing, and prolonged circulation time, the HApDC represents a promising nanomedicine to treat HER2‐positive tumors. Notably, this study developsa dual‐targeting nanoparticle by combining pH‐sensitive camouflage and HApDC, initiating an important step toward the development and application of DNA‐based medicine and biomimetic cell membrane materials in cancer treatment and other potential biological applications.

Biomimetic Nanoerythrosome‐Coated Aptamer–DNA Tetrahedron/Maytansine Conjugates: pH‐Responsive and Targeted Cytotoxicity for HER2‐Positive Breast Cancer

While Nature harnesses RNA and DNA to store, read and write genetic information, the inherent programmability, synthetic accessibility and wide functionality of these nucleic acids make them attractive tools for use in a vast array of applications. In medicine, antisense oligonucleotides (ASOs), siRNAs, and therapeutic aptamers are explored as potent targeted treatment and diagnostic modalities, while in the technological field oligonucleotides have found use in new materials, catalysis, and data storage. The use of natural oligonucleotides limits the possible chemical functionality of resulting technologies while inherent shortcomings, such as susceptibility to nuclease degradation, provide obstacles to their application. Modified oligonucleotides, at the level of the nucleobase, sugar and/or phosphate backbone, are widely used to overcome these limitations. This review provides the reader with an overview of non-native modifications and the challenges faced in the design, synthesis, application and outlook of novel modified oligonucleotides.

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Recent progress in non-native nucleic acid modifications.

Beyond traditional needs of biosensors such as high sensitivity and selectivity for analyte detection, newly emerging requirements including a real-time detection ability and in-field applicability have been gradually emphasized to address clinical and environmental availability. Highly programmable, synthetic aptamers that can specifically recognize a broad range of targets have the potential to fulfill these requirements; cooperative binding to target molecules achieves a significant increase in sensitivity, and binding-induced structure-switching enables target detection even in complex mixtures. Due to the availability of chemical synthesis and functional modifications, these artificial ligand materials are easily installed in many devices, and the amenability to modularization allows the aptamer-based biosensors to diversify detectable targets and signaling processes. In this review, we highlight current progress in the development of aptamer-based, next-generation biosensors including new types of field-effect transistors, electrochemical detectors, and microfluidic devices. As the nucleic acid aptamers have been rapidly generated by various in vitro selection techniques, the use of the versatile nanostructures is expected to expand further to include in-field and real-time biosensors.

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Detection and beyond: challenges and advances in aptamer-based biosensors

The arrival of the monoclonal antibody (mAb) technology in the 1970s brought with it the hope of conquering cancers to the medical community. However, mAbs, on the whole, did not achieve the expected wonder in cancer therapy although they do have demonstrated successfulness in the treatment of a few types of cancers. In 1990, another technology of making biomolecules capable of specific binding appeared. This technique, systematic evolution of ligands by exponential enrichment (SELEX), can make aptamers, single-stranded DNAs or RNAs that bind targets with high specificity and affinity. Aptamers have some advantages over mAbs in therapeutic uses particularly because they have little or no immunogenicity, which means the feasibility of repeated use and fewer side effects. In this review, the general properties of the aptamer, the advantages and limitations of aptamers, the principle and procedure of aptamer production with SELEX, particularly the undergoing studies in aptamers for cancer therapy, and selected anticancer aptamers that have entered clinical trials or are under active investigations are summarized.

Aptamers, the Nucleic Acid Antibodies, in Cancer Therapy

Soon after they were first described in 1990, aptamers were largely recognized as a new class of biological ligands that can rival antibodies in various analytical, diagnostic, and therapeutic applications. Aptamers are short single-stranded RNA or DNA oligonucleotides capable of folding into complex 3D structures, enabling them to bind to a large variety of targets ranging from small ions to an entire organism. Their high binding specificity and affinity make them comparable to antibodies, but they are superior regarding a longer shelf life, simple production and chemical modification, in addition to low toxicity and immunogenicity. In the past three decades, aptamers have been used in a plethora of therapeutics and drug delivery systems that involve innovative delivery mechanisms and carrying various types of drug cargos. However, the successful translation of aptamer research from bench to bedside has been challenged by several limitations that slow down the realization of promising aptamer applications as therapeutics at the clinical level. The main limitations include the susceptibility to degradation by nucleases, fast renal clearance, low thermal stability, and the limited functional group diversity. The solution to overcome such limitations lies in the chemistry of aptamers. The current review will focus on the recent arts of aptamer chemistry that have been evolved to refine the pharmacological properties of aptamers. Moreover, this review will analyze the advantages and disadvantages of such chemical modifications and how they impact the pharmacological properties of aptamers. Finally, this review will summarize the conjugation strategies of aptamers to nanocarriers for developing targeted drug delivery systems.

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Aptamers Chemistry: Chemical Modifications and Conjugation Strategies.

Background An increased incidence of non-Hodgkin’s lymphoma (NHL) has been reported in farmers and other occupational groups working with pesticides. In these individuals, an increased prevalence of the chromosomal translocation t(14;18)(q32;q21), one of the most common chromosomal abnormalities in NHL, has been detected in peripheral blood lymphocytes. This translocation juxtaposes the antiapoptotic BCL2 protein to the immunoglobulin heavy chain gene locus (IGH) leading to overexpression of BCL2. This causes an increase in cell survival, paving the way for malignant transformation. Aim of the study The present study aimed to evaluate the association between the occurrence of the chromosomal translocation t(14;18) and occupational exposure to pesticides among a group of Jordanian farmers. Methods A total of 192 male subjects including 96 agricultural workers and 96 control subjects participated in this study. BCL2-IGH t(14;18) fusions were detected by a nested polymerase chain reaction (PCR) assay targeting the major breakpoint region (MBR). Results We found that occupational exposure to pesticides in open-field farming and insecticide used on animals increased the frequency of the chromosomal translocation t(14;18). Farmers occupationally exposed to pesticides and insecticide were 13.5 times more likely to harbor t(14;18). 63.5% (61 of 96) of farmers compared to 11.5% (11 of 96) of controls carried the translocation (odds ratio: 13.5; 95% confidence interval (CI) = 6.3–28.6). We ruled out the influence of possible confounding factors such as age, duration of sun exposure, alcohol intake, smoking, and use of personal protective equipment. Conclusion Our results indicate that pesticides increased the frequency of chromosomal translocation in the 14q32 region. Accordingly, the presented data agrees with previous suggestions from the literature that pesticides might be involved in the development of NHL through the t(14;18) pathway.

Occupational exposure to pesticides and occurrence of the chromosomal translocation t(14;18) among farmers in Jordan

The t(14;18) translocation is the most distinguishing molecular finding in follicular lymphoma (FL). However, the reported frequencies of t(14;18) in FL show significant variation, which is often attributed to geographical and/or methodological factors. The methods used to detect t(14;18) include Southern blotting, conventional cytogenetics, fluorescent in situ hybridization, and polymerized chain reaction (PCR). Because of its practicality and superior sensitivity, PCR is becoming the more commonly used method in clinical laboratories. The identification of the main breakpoint regions on chromosome 18, including the major breakpoint region (MBR), the minor cluster region (mcr), and the newly defined intermediate cluster region (icr), increased the detection frequency of PCR. In our study, using a highly sensitive nested PCR strategy with primers for MBR, mcr and icr regions, we were able to detect t(14;18) in 95% of FL patients, which is one of the highest reported frequencies using PCR. We screened 58 FL patient samples collected retrospectively from different hospitals in Jordan. DNA was extracted from archival paraffin-embedded samples, some of which were >10 years old. The respective breakpoint distributions were, 47 for MBR (81%), two for mcr (3.5%) and six for icr (10.3%). In this report, we analyze this high frequency of t(14;18) detection in a general review of the recent literature, in an attempt to assess the geographical vs. methodological influences on the reported frequencies.

Frequency of t(14;18) in follicular lymphoma patients: geographical or technical variation.

Coronavirus disease 2019 (COVID-19) pandemic control measures rely on the accurate and timely diagnosis of infected individuals. Real-time polymerase chain reaction (qPCR) remains the gold-standard method for laboratory diagnosis of the disease. Delayed diagnosis due to challenges that face laboratories performing COVID-19 testing can hinder public health control measures. Such challenges may be related to shortages in staff, equipment or materials, improper inventory management, flawed workflow, or long turnaround time (TAT). The aim of the current study was to assess the overall COVID-19 molecular testing capacity in Jordan as of April 2021. In addition, the study’s objectives included the identification of potential defects that could comprise the utility of the COVID-19 molecular testing capacity in the country. All laboratories certified by the Ministry of Health (MoH) in Jordan to conduct molecular testing for SARS-CoV-2 were invited to participate in this study. Data were obtained from the participating laboratories (those which agreed to participate) by either telephone interviews or a self-reported written questionnaire with items assessing the key aspects of COVID-19 molecular testing. The full molecular testing capacity in each laboratory was self-reported considering 24 working hours. The total number of participating laboratories was 51 out of 77 (66.2%), with the majority being affiliated with MoH (n = 17) and private laboratories (n = 20). The total molecular COVID-19 testing capacity among the participating laboratories was estimated at 574,441 tests per week, while the actual highest number of tests performed over a single week was 310,047 (54.0%, reported in March 2021). Laboratories affiliated with the MoH were operating at a level closer to their maximum capacity (87.2% of their estimated full capacity for COVID-19 testing) compared to private hospital laboratories (41.3%, p = 0.004), private laboratories (20.8%, p < 0.001), and academic/research laboratories (14.7%, p < 0.001, ANOVA). The national average daily COVID-19 molecular testing was 349.2 tests per 100,000 people in April 2021. The average TAT over the first week of April 2021 for COVID-19 testing was 932 min among the participating laboratories, with the longest TAT among MoH laboratories (mean: 1959 min) compared to private laboratories (mean: 333 min, p < 0.001). Molecular COVID-19 testing potential in Jordan has not been fully utilized, particularly for private laboratories and those belonging to academic/research centers. Supply-chain challenges and shortages in staff were identified as potential obstacles hindering the exploitation of full molecular testing capacity for COVID-19 in the country.

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Assessment of COVID-19 Molecular Testing Capacity in Jordan: A Cross-Sectional Study at the Country Level

BACKGROUND
Propofol is the most commonly used general anesthetic drug in many countries, including Jordan. However, there is a wide variation in the propofols' dose and response among the patients. Genetic variation in the cytochrome (CYP) 2B6 gene affects propofol metabolism and might affect propofol dose and response.


AIMS
This study aimed to determine the influence of major genetic alleles of the CYP2B6 gene, CYP2B6*2A, *6A, *3, *4A, and *5A, on the required propofol dose and response among Jordanian Arabic patients attending The University of Jordan Hospital.


METHODS
A total of 155 patients were administrated propofol. The propofol response was evaluated by monitoring the time to reach the bispectral index of 60 (BIS60) for every patient. The CYP2B6 genetic variants were genotyped by polymerase chain reaction followed by restriction through specific enzymes for CYP2B6 variants.


RESULTS
It is found that patients with variant CYP2B6*2A and *4A alleles required significantly (P < 0.05) lower propofol doses, while patients with variant CYP2B6*6A, *3, and *5A alleles required higher propofol doses in comparison with patients carrying the wild CYP2B6 alleles. Patients with variant CYP2B6*2A and *3 alleles needed a significantly (P < 0.05) shorter while patients with variant CYP2B6*5A allele needed longer time of BIS60 than patients with wild CYP2B6*2A, *3, and *5A alleles.


CONCLUSION
It is concluded that CYP2B6 genetic variants affect propofol dose and can explain, at least partly, the inter-individual variation in the propofol response. Further clinical studies with a larger sample size are needed to confirm the findings of this study.

Bara’a M. Qaqish

Papers

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies.

Occupational exposure to pesticides and occurrence of the chromosomal translocation t(14;18) among farmers in Jordan

Frequency of t(14;18) in follicular lymphoma patients: geographical or technical variation.

Assessment of COVID-19 Molecular Testing Capacity in Jordan: A Cross-Sectional Study at the Country Level

Effects of CYP2B6 Genetic Variants on the Propofol Dose and Response among Jordanian Arabic Patients Undergoing General Anesthesia.