Search Results (76)

Glioblastoma multiforme (GBM) is a deadly disease known for its genetic heterogeneity. LTR12C is an endogenous retrovirus-derived regulator of pro-apoptotic genes and is normally silenced by epigenetic regulation. In this study, we found that the treatment of two glioblastoma cell lines, T98-G and U87-MG, with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors activated LTR12C expression. Combined treatment with these epigenetic drugs exerted a synergistic action on the LTR12C activation in both cell lines, while treatment with each drug as a single agent had a far weaker effect. A strong induction of the expression of the TP63 gene was seen in both cell lines, with the pro-apoptotic isoform GTA-p63 accounting for most of this increase. Coherently, downstream targets of p63, such as p21 and PUMA, were also induced by the combined treatment. Furthermore, we observed a significant reduction in the GBM cell growth and viability following the dual DNMT/HDAC inhibition. These findings reveal that the reactivation of LTR12C expression has the potential to modulate survival pathways in glioblastoma and provide information regarding possible epigenetic mechanisms that can be used to treat this deadly disease. Full article

Background/Objectives: The risk of post-transplantation lymphoproliferative disorder (PTLD) varies according to the type of transplanted organ. To investigate the factors contributing to PTLD development and treatment outcomes, we established a multicenter registry that included patients diagnosed with PTLD within a population of 13,263 kidney, liver, and lung transplant recipients (KTRs, LTRs, and LngTRs, respectively), observed in a period between 2000 and 2023. Methods: The chi-squared test was used to analyze differences in group composition. Univariate and multivariate Cox regression were applied to determine the impact of factors upon PTLD onset and patient survival. Results: Our registry included 58 out of 9432 KTRs, 40 out of 3500 LTRs, and 5 out of 331 LngTRs. The median time to PTLD onset was significantly longer among KTRs (117 months post-transplant) than among LTRs (49 months, p < 0.001) and LngTRs (5 months, p < 0.001). LTRs treated with tacrolimus developed PTLD later compared to LTRs treated with cyclosporin (p = 0.042). In multivariate analysis, older age at first transplantation correlated with earlier disease development in SOTRs (HR = 1.03, p = 0.006) and KTRs (HR = 1.04, p = 0.003). Older age at first transplantation was also associated with worse survival among KTRs (p = 0.045). Conclusions: We identified clear differences in the factors affecting PTLD onset and survival between KTRs and LTRs. Organ-specific analyses are needed to improve our understanding of PTLD risk factors, treatment choices, and clinical outcomes. Full article

Background: The COVID-19 pandemic highlighted the vulnerability of immunocompromised individuals, including liver transplant recipients (LTRs), who often exhibit reduced vaccine immunogenicity. While initial vaccine doses and subsequent boosters improved immune response, LTRs were prioritized for vaccination. Studies have shown increased antibody response after each booster dose. Vaccine hesitancy, defined as delayed or refused vaccination despite availability, poses a public health challenge, often fueled by misinformation. This study aimed to evaluate anti-spike antibody responses in vaccinated LTRs after two initial doses and at least one booster, also assessing adherence to subsequent doses. Methods: We conducted a retrospective observational study at a transplant center in Milan, Italy, between January 2021 and December 2023. LTRs who had received four or more doses of mRNA vaccines (Pfizer or Moderna) were included. Anti-spike antibody levels were measured 60–80 days after each dose. Data on vaccination status were collected in January 2024. Statistical analysis was performed to compare antibody responses and identify predictive factors. Results: LTRs showed a significant increase in anti-spike antibody responses after the first booster compared to the second dose with a trend versus a further increase following the fourth dose in a subgroup of the patients receiving two booster doses. However, adherence to booster doses decreased over time. In LTRs, predictors of a weaker response after the second dose were chronic kidney disease and metabolic etiology at transplant. Conclusions: The study highlighted that in LTRs, multiple doses of the COVID-19 vaccine led to a continuous increase in anti-spike antibody responses. The progressive decline in adherence of LTRs “to further booster doses” should be related to the fact that after the spread of vaccination programs worldwide, COVID-19 is still a current infection, but it is much less severe than before. Full article

The TGA (TGACG motif-binding factor) transcription factors are integral to root growth and development, and are pivotal in mediating plant responses to abiotic stresses. Nonetheless, their role in the nutrient absorption processes of banana plants has not been extensively investigated. This research conducted a comprehensive analysis of the MaTGA gene family, emphasizing their physicochemical characteristics, phylogenetic relationships, gene duplication events, promoter cis-regulatory elements and protein interaction networks. Furthermore, this study investigated the expression patterns of MaTGA family members under varying nitrogen conditions. A total of 18 MaTGA members were identified within the banana genome, each encoding proteins characterized by the presence of bZIP and DOG domains. These genes exhibited an uneven distribution across eight chromosomes. Phylogenetic analysis further classified the MaTGA family into four distinct subgroups (I–IV), consisting of three, seven, three, and five members, respectively. An analysis of promoter cis-elements indicated that over 50% of the MaTGA gene family members contain hormone-responsive elements associated with abscisic acid (ABRE), ethylene (ERE), and salicylic acid (SARE), in addition to stress-responsive elements related to drought (MBS) and low temperature (LTR). Regarding gene expression, MaTGA7, MaTGA8, and MaTGA15 exhibited significantly elevated expression levels in the leaves and roots relative to other tissues. Under varying nitrogen conditions, 13 members, including MaTGA7 and MaTGA8, demonstrated the highest expression levels under reduced nitrogen (70%) treatment, followed by low nitrogen (20%) conditions, and the lowest expression levels were observed under nitrogen-deficient conditions. These findings imply that MaTGA genes may play crucial roles in enhancing nitrogen use efficiency. Protein interaction predictions suggest that MaTGA7, MaTGA8, and MaTGA15 may interact with nitrogen-related proteins, including Nitrate Transporter 2 (NRT2.1 and NRT2.2), NIN-Like Protein 7 (NLP7), and Nitrate Transporter 1.1 (NPF6.3). In summary, MaTGA7, MaTGA8, and MaTGA15 are likely involved in the processes of nitrogen absorption and utilization in bananas. The present findings establish a basis for subsequent investigations into the functional roles of MaTGA genes in augmenting nutrient use efficiency and mediating responses to abiotic stresses in banana plants. Full article

Liver transplant recipients (LTRs) have been considered a population group that is vulnerable to COVID-19 as they are chronically immunosuppressed patients with frequent comorbidities. This study describes the course of the SARS-CoV-2 disease from February 2020 to December 2023 along seven pandemic “waves”. We carried out an observational study on 307 COVID-19 cases in a cohort of LTRs with the aim of evaluating the changes in the disease characteristics over time and determining the risk factors for severe COVID-19. An older age and serum creatinine level ≥ 2 mg/dL were found to be risk factors for hospital admission and respiratory failure. The use of calcineurin inhibitors was a protective factor for death, hospitalization, and respiratory failure from COVID-19. One hundred percent of patients who died (N = 12) were on mycophenolate mofetil, which was a determinant for respiratory failure. Azathioprine was associated with admission to the intensive care unit (ICU) and with invasive mechanical ventilation (IMV). Vaccination was a protective factor for hospitalization, respiratory failure, and mortality. The severe COVID-19 rate was higher during the first five waves, with a peak of 57.14%, and the highest mortality rate (21.43%) occurred in the fourth wave. The IMV and ICU admission rates did not show significant differences across the periods studied. Full article

Objectives: The aim of this study was to compare the efficacy and safety of thermal ablation, focusing on radiofrequency ablation (RFA) and microwave ablation (MWA), for hepatocellular carcinoma (HCC) using US-, CT-, and MR-guidance. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for studies comparing US, CT, and MR guidance in thermal ablation for HCC. Observational studies and randomized controlled trials (RCTs) were included. Overall survival (OS), local tumor recurrence (LTR), primary technique effectiveness (PTE), and major complications were assessed with network meta-analysis. Results: One RCT and 13 retrospective cohort studies reporting on 2349 patients were included. For OS at 3 years, compared to CT, US had hazard ratios (HRs) of 0.98 (95%CI: 0.77–1.26), and MR had HRs of 1.60 (95%CI: 0.51–5.00); For OS at 5 years, US had HRs of 0.80 (95%CI: 0.64–1.01), and MR had HRs of 1.23 (95%CI: 0.52–2.95) compared to CT. LTR rates, PTE, and major complications did not show statistical significance among the three guidance modalities (LTR: RR = 0.29 (95%CI: 0.08–1.14), p = 0.97 MR vs. CT; RR = 0.25 (95%CI: 0.06–1.02), p = 0.97 MR vs. US; PTE: RR = 1.06 (95%CI: 0.96–1.17), p = 0.90 MR vs. CT; RR = 1.08 (95%CI: 0.98–1.20), p = 0.90 MR vs. US. Major complications: RR = 0.27 (95%CI: 0.13–0.59), p = 0.94 MR vs. CT; RR = 0.41 (95%CI: 0.10–1.74), p = 0.94 MR vs. US). Conclusions: CT-, US-, and MR-guided RFA and MWA are equally effective and safe for HCC patients. Full article

We have previously shown that the hepatitis C virus (HCV) E1E2 envelope glycoprotein can regulate HIV-1 long-terminal repeat (LTR) activity through disruption to NF-κB activation. This response is associated with upregulation of the endoplasmic reticulum (ER) stress response pathway. Here, we demonstrate that the SARS-CoV-2 S, M, and E but not the N structural protein can perform similar downmodulation of HIV-1 LTR activation, and in a dose-dependent manner, in both HEK293 and lung BEAS-2B cell lines. This effect is highest with the SARS-CoV-2 Wuhan S strain and decreases over time for the subsequent emerging variants of concern (VOC), with Omicron providing the weakest effect. We developed pseudo-typed viral particle (PVP) viral tools that allowed for the generation of cell lines constitutively expressing the four SARS-CoV-2 structural proteins and utilising the VSV-g envelope protein to deliver the integrated gene construct. Differential gene expression analysis (DGEA) was performed on cells expressing S, E, M, or N to determine cell activation status. Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins. There were also differences observed in expression patterns of transcription factors, with both SP1 and MAVS upregulated in the presence of S, M, and E but not the N protein. Collectively, the results indicate that gene expression patterns associated with ER stress pathways can be activated by SARS-CoV-2 envelope glycoprotein expression. The results suggest the SARS-CoV-2 infection can modulate an array of cell pathways, resulting in disruption to NF-κB signalling, hence providing alterations to multiple physiological responses of SARS-CoV-2-infected cells. Full article

Corrosion is one of the main problems affecting reinforced concrete (RC) structures, yet there remains a lack of studies in which the electrochemical and structural behavior of corroded RC elements are studied together. In this work, four RC beams with and without corrosion were studied to evaluate their electrochemical and structural behavior via the variable of the diameter of the longitudinal tension steel reinforcement (LTR). The beams were initially tested to determine their initial structural behavior and then subjected to sustained loads and wetting and drying cycles by applying a NaCl solution. The beams were tested a second time to determine their final structural behavior. The variations in the corrosion potential and corrosion rate of the LTR with time, together with concrete resistivity, cracking patterns, and load–displacement curves of the RC beam, are presented. It was found that the electrochemical parameters of the beams with corrosion were similar regardless of the steel reinforcement diameter; these parameters indicated a high level of corrosion. The maximum flexural strength loss was observed for beams with an LTR of 10 mm compared to those with a 13 mm diameter. The maximum cross-sectional area loss associated with pitting corrosion was greater for the beam with an LTR of 10 mm. Full article

Background/Objectives: The efficacy of monovalent BNT162b2 Omicron XBB.1.5 booster vaccination in liver transplant recipients (LTRs) has yet to be described, particularly regarding the immune response to emerging variants like JN.1. Methods: This study evaluated humoral and cellular immune responses in 34 liver transplant recipients (LTRs) with varying SARS-CoV-2 immune histories before and after receiving a BNT162b2 Omicron XBB.1.5 booster vaccination. The assessment involved variant-specific serology, pseudovirus neutralization tests, and Interferon-γ release assays. Results: Participants had a median of four prior vaccinations, with 91.2% having a history of infection. Post-vaccination, significant increases in both Wuhan anti-S and Omicron-specific IgG antibodies and improved neutralization of B.1, XBB.1.5, and JN.1 pseudovirus particles were observed. Also, T-cell responses significantly increased post-vaccination. However, 17.6% of LTRs had no neutralizing antibodies against XBB.1.5 and JN.1, while 100% of healthy controls did. Shortly after vaccination, 18% of patients developed mild COVID-19. These LTRs had particularly low immune responses at baseline. Conclusions: The monovalent XBB.1.5 booster improved overall SARS-CoV-2-specific immunity. However, some LTRs still showed low or undetectable immune responses, indicating that ongoing monitoring and further booster doses are necessary in this high-risk group. Full article

The HIV integrase inhibitor, dolutegravir (DTG), in the absence of eliciting integrase (int) resistance, has been reported to select mutations in the virus 3′-polypurine tract (3′-PPT) adjacent to the 3′-LTR U3. An analog of DTG, cabotegravir (CAB), has a high genetic barrier to drug resistance and is used in formulations for treatment and long-acting pre-exposure prophylaxis. We examined whether mutations observed for DTG would emerge in vitro with CAB. HIV-1IIIB was cultured in paired experiments of continuous high (300 nM) CAB initiated 2 h or 24 h after infection. After eight months of CAB treatment, no int resistance was detected. Conversely, HIV RNA 3′-PPT mutants were detected within one month and were the majority virus by day 98. The appearance of 3′-PPT variants coincided with a rapid accumulation of HIV 1-LTR and 2-LTR circles. RNA amplification from the 3′-LTR TAR identified transcripts crossing 2-LTR circle junctions, which incorporated the adjacent U5 sequence identical to the 3′-PPT mutants. 3′-PPT variants were only identified in LTR circles and transcripts. Additionally, we found evidence of linear HIV and LTR circle recombination with human DNA at motifs homologous to 3′-PPT sequences. HIV persistence under CAB was associated with transcription and recombination of LTR circle sequences. Full article

Drug abuse continues to pose a significant challenge in HIV control efforts. In our investigation, we discovered that cocaine not only upregulates the expression of the DNA-dependent protein kinase (DNA-PK) but also augments DNA-PK activation by enhancing its phosphorylation at S2056. Moreover, DNA-PK phosphorylation triggers the higher localization of the DNA-PK into the nucleus. The finding that cocaine increases the nuclear localization of the DNA-PK provides further support to our observation of enhanced DNA-PK recruitment at the HIV long terminal repeat (LTR) following cocaine exposure. By activating and facilitating the nuclear localization of the DNA-PK, cocaine effectively orchestrates multiple stages of HIV transcription, thereby promoting HIV replication. Additionally, our study demonstrates that the cocaine-induced DNA-PK promotes the hyper-phosphorylation of the RNA polymerase II (RNAP II) carboxyl-terminal domain (CTD) at Ser5 and Ser2 sites, enhancing both the initiation and elongation phases, respectively, of HIV transcription. The cocaine-mediated enhancement of transcriptional initiation is supported by its activation of cyclin-dependent kinase 7 (CDK7). Additionally, the induction of transcriptional elongation is marked by higher LTR recruitment and the increased phosphorylation of CDK9, which indicates the stimulation of positive transcriptional elongation factor b (P-TEFb). We demonstrate for the first time that cocaine, through DNA-PK activation, promotes the specific phosphorylation of TRIM28 at serine 824 (p-TRIM28, S824). This modification converts TRIM28 from a transcriptional inhibitor to a transactivator for HIV transcription. Additionally, we observed that the phosphorylation of TRIM28 (p-TRIM28, S824) promotes the transition from the pausing phase to the elongation phase of HIV transcription, thereby facilitating the production of full-length HIV genomic transcripts. This finding corroborates the previously observed enhanced RNAP II CTD phosphorylation at Ser2, a marker of transcriptional elongation, following cocaine exposure. Accordingly, upon cocaine treatment, we observed the elevated recruitment of p-TRIM28-(S824) at the HIV LTR. Overall, our results unravel the intricate molecular mechanisms underlying cocaine-induced HIV transcription and gene expression. These findings hold promise for the development of highly targeted therapeutics aimed at mitigating the detrimental effects of cocaine in individuals living with HIV. Full article

Homologous recombination events take place between the 5′ and 3′ long terminal repeats (LTRs) of ERVs, resulting in the generation of solo-LTR, which can cause solo-LTR-associated polymorphism across different genomes. In the current study, specific criteria were established for the filtration of solo-LTRs, resulting in an average of 5630 solo-LTRs being identified in 21 genomes. Subsequently, a protocol was developed for detecting solo-LTR polymorphisms in the pig genomes, resulting in the discovery of 927 predicted solo-LTR polymorphic sites. Following verification and filtration processes, 603 highly reliable solo-LTR polymorphic sites were retained, involving 446 solo-LTR presence sites (solo-LTR⁺) and 157 solo-LTR absence sites (solo-LTR⁻) relative to the reference genome. Intersection analysis with gene/functional regions revealed that 248 solo-LTR⁻ sites and 23 solo-LTR⁺ sites overlapped with genes or were in the vicinity of genes or functional regions, impacting a diverse range of gene structures. Moreover, through the utilization of 156 solo-LTR polymorphic sites for population genetic analysis, it was observed that these solo-LTR loci effectively clustered various breeds together, aligning with expectations and underscoring their practical utility. This study successfully established a methodology for detecting solo-LTR polymorphic sites. By applying these methods, a total of 603 high-reliability solo-LTR polymorphic sites were pinpointed, with nearly half of them being linked to genes or functional regions. Full article

Background/Objectives: Neutropenia is a frequent complication among solid organ transplant (SOT) recipients receiving immunosuppressive therapy and antimicrobial prophylaxis. However, there are limited studies analysing the frequency and impact of neutropenia in lung transplant recipients (LTRs). Our aim was to analyse the frequency of neutropenia, the need for granulocyte colony-stimulating factor (GCSF) treatment within the first 18 months post-transplant and its association with acute rejection, chronic lung allograft dysfunction (CLAD), overall survival and the development of infections. Methods: This observational and retrospective study recruited 305 patients who underwent lung transplantation between 2009 and 2019, with outpatient quarterly follow-up during the first 18 months post-surgery.Results: During this period, 51.8% of patients experienced at least one episode of neutropenia. Neutropenia was classified as mild in 50.57% of cases, moderate in 36.88% and severe in 12.54%. GCSF treatment was indicated in 23.28% of patients, with a mean dose of 3.53 units. No statistically significant association was observed between neutropenia or its severity and the development of acute rejection, CLAD or overall survival. However, the patients who received GCSF treatment had a higher mortality rate compared to those who did not. Sixteen patients (5.25%) developed infections during neutropenia, with bacterial infections being the most common. Conclusions: Neutropenia is common in the first 18 months after lung transplantation and most episodes are mild. We did not find an association between neutropenia and acute rejection, CLAD, or mortality. However, the use of GCSF were associated with worse post-transplant survival. Full article

Human endogenous retroviruses (HERVs) are retroviral sequences integrated into 8% of the human genome resulting from ancient exogenous retroviral infections. Unlike endogenous retroviruses of other mammalian species, HERVs are mostly replication and retro-transposition defective, and their transcription is strictly regulated by epigenetic mechanisms in normal cells. A significant addition to the growing body of research reveals that HERVs’ aberrant activation is often associated with offsetting diseases like autoimmunity, neurodegenerative diseases, cancers, and chemoresistance. Adult T-cell leukemia/lymphoma (ATLL) is a very aggressive and chemoresistant leukemia caused by the human T-cell leukemia virus type 1 (HTLV-1). The prognosis of ATLL remains poor despite several new agents being approved in the last few years. In the present study, we compare the expression of HERV genes in CD8⁺-depleted PBMCs from HTLV-1 asymptomatic carriers and patients with acute ATLL. Herein, we show that HERVs are highly upregulated in acute ATLL. Our results further demonstrate that the oncoprotein Fra-2 binds the LTR region and activates the transcription of several HERV families, including HERV-H and HERV-K families. This raises the exciting possibility that upregulated HERV expression could be a key factor in ATLL development and the observed chemoresistance, potentially leading to new therapeutic strategies and significantly impacting the field of oncology and virology. Full article

Transposable elements (TEs) comprise a substantial portion of the mammalian genome, with potential implications for both embryonic development and cancer. This study aimed to characterize the expression profiles of TEs in embryonic stem cells (ESCs), cancer cell lines, tumor tissues, and the tumor microenvironment (TME). We observed similarities in TE expression profiles between cancer cells and ESCs, suggesting potential parallels in regulatory mechanisms. Notably, four TE RNAs (HERVH, LTR7, HERV-Fc1, HERV-Fc2) exhibited significant downregulation across cancer cell lines and tumor tissues compared to ESCs, highlighting potential roles in pluripotency regulation. The strong up-regulation of the latter two TEs (HERV-Fc1, HERV-Fc2) in ESCs has not been previously demonstrated and may be a first indication of their role in the regulation of pluripotency. Conversely, tandemly repeated sequences (MSR1, CER, ALR) showed up-regulation in cancer contexts. Moreover, a difference in TE expression was observed between the TME and the tumor bulk transcriptome, with distinct dysregulated TE profiles. Some TME-specific TEs were absent in normal tissues, predominantly belonging to LTR and L1 retrotransposon families. These findings not only shed light on the regulatory roles of TEs in both embryonic development and cancer but also suggest novel targets for anti-cancer therapy. Understanding the interplay between cancer cells and the TME at the TE level may pave the way for further research into therapeutic interventions. Full article