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Abstract Background Tumor necrosis factor α (TNF) is able to induce a variety of biological responses in the nervous system including inflammation and neuroprotection. Human astrocytoma cells U373 have been widely used as a model for inflammatory cytokine actions in the nervous system. Here we used cDNA microarrays to analyze the time course of the transcriptional response from 1 h up to 12 h post TNF treatment in comparison to untreated U373 cells. TNF activated strongly the NF-κB transcriptional pathway and is linked to other pathways via the NF-κB target genes JUNB and IRF-1. Part of the TNF-induced gene expression could be inhibited by pharmacological inhibition of NF-κB with pyrrolidine-dithiocarbamate (PDTC). NF-κB comprises a family of transcription factors which are involved in the inducible expression of genes regulating neuronal survival, inflammatory response, cancer and innate immunity. Results In this study we show that numerous genes responded to TNF (> 880 from 7500 tested) with a more than two-fold induction rate. Several novel TNF-responsive genes (about 60% of the genes regulated by a factor ≥ 3) were detected. A comparison of our TNF-induced gene expression profiles of U373, with profiles from 3T3 and Hela cells revealed a striking cell-type specificity. SCYA2 (MCP-1, CCL2, MCAF) was induced in U373 cells in a sustained manner and at the highest level of all analyzed genes. MCP-1 protein expression, as monitored with immunofluorescence and ELISA, correlated exactly with microarray data. Based on these data and on evidence from literature we suggest a model for the potential neurodegenerative effect of NF-κB in astroglia: Activation of NF-κB via TNF results in a strongly increased production of MCP-1. This leads to a exacerbation of neurodegeneration in stoke or Multiple Sclerosis, presumably via infiltration of macrophages. Conclusions The vast majority of genes regulated more than 3-fold were previously not linked to tumor necrosis factor α as a search in published literature revealed. Striking co-regulation for several functional groups such as proteasome and ribosomal proteins were detected.

Background: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene., Methods: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing., Results: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein., Conclusion: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition., (© 2024. The Author(s).)

As one of the frequent malignancies, breast cancer (BCa) is the foremost reason for cancer-related deaths among women. The role of Human papillomavirus (HPV) in chemoresistance has rarely been investigated in previous studies. The current study sets out to the possible role of HPV in BCa chemoresistance. In this research, 90 BCa tissue and 33 normal breast tissue were collected. We evaluated the presence of the HPV genome along with the viral (E2, E6, E7) and cellular gene expression associated with cell resistance to death. Statically significant differences in the prevalence of HPV between the BCa group (25.2% or 23/90) and the control group (21.8% or 7/32) were not found. HPV-16 and HPV-18 genotypes were the abundant HPV genotypes. Resistance to the Adriamycin-Cyclophosphamide (AC), paclitaxel regimen was elevated in the HPV- group (56/70) in comparison to the HPV+ group (14/70). Nevertheless, there was no significant difference in the prevalence of resistance to AC + paclitaxel + triple-negative breast cancer combination therapy between the HPV+ group (9/20) and in the HPV- group (11/20). In the BCa group in contrast to the control group, the expression level of Bcl-2, BCL-XL, and c-IAP2 demonstrated a significant decrease, while, the expression level of cytochrome C and caspase 3 was significantly increased. This study suggests that HPV infection might contribute to BCa chemoresistance through disrupt cellular genes involved in cell death., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: This pilot study aims to identify and functionally assess pharmacovariants in whole exome sequencing data. While detection of known variants has benefited from pharmacogenomic-dedicated bioinformatics tools before, in this paper we have tested novel deep computational analysis in addition to artificial intelligence as possible approaches for functional analysis of unknown markers within less studied drug-related genes., Methods: Pharmacovariants from 1800 drug-related genes from 100 WES data files underwent (a) deep computational analysis by eight bioinformatic algorithms (overall containing 23 tools) and (b) random forest (RF) classifier as the machine learning (ML) approach separately. ML model efficiency was calculated by internal and external cross-validation during recursive feature elimination. Protein modelling was also performed for predicted highly damaging variants with lower frequencies. Genotype-phenotype correlations were implemented for top selected variants in terms of highest possibility of being damaging., Results: Five deleterious pharmacovariants in the RYR1, POLG, ANXA11, CCNH, and CDH23 genes identified in step (a) and subsequent analysis displayed high impact on drug-related phenotypes. Also, the utilization of recursive feature elimination achieved a subset of 175 malfunction pharmacovariants in 135 drug-related genes that were used by the RF model with fivefold internal cross-validation, resulting in an area under the curve of 0.9736842 with an average accuracy of 0.9818 (95% CI: 0.89, 0.99) on predicting whether a carrying individuals will develop adverse drug reactions or not. However, the external cross-validation of the same model indicated a possible false positive result when dealing with a low number of observations, as only 60 important variants in 49 genes were displayed, giving an AUC of 0.5384848 with an average accuracy of 0.9512 (95% CI: 0.83, 0.99)., Conclusion: While there are some technologies for functionally assess not-interpreted pharmacovariants, there is still an essential need for the development of tools, methods, and algorithms which are able to provide a functional prediction for every single pharmacovariant in both large-scale datasets and small cohorts. Our approaches may bring new insights for choosing the right computational assessment algorithms out of high throughput DNA sequencing data from small cohorts to be used for personalized drug therapy implementation., (© 2023. The Author(s).)

Background: Substance use among medical students is a concern due to its relationship with students' health and the nature of the medical profession. Therefore, this study aimed to assess addiction potential and its relationship with health in medical students., Methods: This cross-sectional study was conducted on 200 medical students who were selected through convenience sampling. Students' demographic information, including age, gender, marital status, place of residence, educational level, and substance abuse in first-degree relatives (FDRs), as well as information obtained from the Duke Health Profile and Iranian Addiction Potential Scale (IAPS), were collected in person or online and analyzed using SPSS software (v. 26)., Findings: The mean age of the participants was 23.27±2.4 years and 57.5% of the participants were female. The results indicated a statistically significant relationship between addiction potential score and gender, family history of substance use, and educational level, but not with age, marital status, or place of residence. Moreover, a significant negative correlation was observed between addiction potential and physical, mental, social, and general health scores., Conclusion: This study demonstrated that paying special attention to the health of medical students and planning to improve their health indicators can effectively reduce addiction potential., Competing Interests: Competing Interests The authors declare no potential conflict of interest., (© 2023 Kerman University of Medical Sciences.)

Background: Steroid-5α-reductase-2 (SRD5A2) and 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) enzyme deficiencies are frequent causes of 46, XY disorder of sex development (46, XY DSD), where an infant with 46, XY has a female phenotype. We assessed the hydroxy-steroid-17β-dehydrogenase-3 (HSD17B3)and SRD5A2 genes in twenty Iranian phenotypic females with 46,XY DSD. Materials and methods: All exons in HSD17B3 and SRD5A2 genes were subjected to PCR amplification followed by sequencing. Results: Of 20 identified 46, XY DSD patients, one had a homozygous missense 17β-HSD3 mutation Ser65Leu (c.194C > T). We found 1 SRD5A2 novel homozygous missense mutation of Tyr242Asp (c.891T > G) in exon 5, which in-silico analyses revealed that this mutation may have deleterious impact on ligand binding site of SRD5A2 protein. Three other individuals harbored 17β-HSD3 deficiencies without identified mutations. Conclusions: SRD5A2 and 17β-HSD3 mutations are found in 10% of 46, XY DSD Iranian patients.

Epilepsy is a frequent chronic disorder of the brain characterized by intermittent epileptic seizures caused by hypersynchronous discharge of neurons in the brain. Studies have reported the role of cytokines in the pathogenesis of epilepsy, and a number of investigations have shown decreased levels of omega-3 fatty acids in epileptic patients. We investigated differences in serum levels of two cytokines, transforming growth factor (TGF)-β and interferon (IFN)-γ, in 40 epileptic cases prior to and after treatment with omega-3 fatty acids. IFN-γ levels were significantly increased after the 16-week treatment period (P < 0.001). However, TGF-β levels remained unchanged (P = 0.14). Omega-3 fatty acid treatment may alter the immune response in epileptic patients. This should be considered in prescription of omega-3 fatty acid supplements in these patients. Future studies with larger sample sizes should verify the results of the current study., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

An outbreak of Crimean-Congo haemorrhagic fever occurred in the county of Birjand in eastern Iran in November 2011. Four cases were involved in this outbreak. Two patients died after admission to hospital, one of whom was a nurse who acquired the infection nosocomially, and the others were treated successfully., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Dengue fever is one of the most important arthropod-borne viral diseases of public health significance. It is endemic in most tropical and subtropical parts of the world, many of which are popular tourist destinations. The presence of dengue infection was examined in Iranian patients who were referred to the Arboviruses and Viral Haemorrhagic Fevers Laboratory of the Pasteur Institute of Iran and tested negative for Crimean-Congo Haemorrhagic Fever (CCHF) between 2000 and 2012. Serum samples from these patients were tested for the presence of specific IgG and IgM and viral nucleic acid in blood. Of the 300 sera tested, 15 (5%) were seropositive, and 3 (1%) were both serologically and PCR positive. Of the 15 seropositive cases, 8 (53.3%) had travelled to endemic areas including Malaysia (5, 62.5%), India (2, 25%) and Thailand (1, 12.5%). In contrast, 7 (46.7%) of the cases had not reported travelling abroad. Of these, six cases were from the Sistan and Baluchistan province in southeast Iran and neighbouring Pakistan. Travellers play a key role in the epidemiology of dengue infection in Iran and it is recommended that travellers to endemic areas take precautionary measures to avoid mosquito bites., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The long bones of vertebrate limbs originate from cartilage templates and are formed by the process of endochondral ossification. This process requires that chondrocytes undergo a progressive maturation from proliferating to postmitotic prehypertrophic to mature, hypertrophic chondrocytes. Coordinated control of proliferation and maturation regulates growth of the skeletal elements. Various signals and pathways have been implicated in orchestrating these processes, but the underlying intracellular molecular mechanisms are often not entirely known. Here we demonstrated in the chick using replication-competent retroviruses that constitutive activation of Calcium/Calmodulin-dependent kinase II (CaMKII) in the developing wing resulted in elongation of skeletal elements associated with premature differentiation of chondrocytes. The premature maturation of chondrocytes was a cell-autonomous effect of constitutive CaMKII signaling associated with down-regulation of cell-cycle regulators and up-regulation of chondrocyte maturation markers. In contrast, the elongation of the skeletal elements resulted from a non-cell autonomous up-regulation of the Indian hedgehog responsive gene encoding Parathyroid-hormone-related peptide. Reduction of endogenous CaMKII activity by overexpressing an inhibitory peptide resulted in shortening of the skeletal elements associated with a delay in chondrocyte maturation. Thus, CaMKII is an essential component of intracellular signaling pathways regulating chondrocyte maturation.