Microorganisms. 2024 Dec 16;12(12):2602. doi: 10.3390/microorganisms12122602.

ABSTRACT

Toxoplasma gondii is a protozoan, and the etiologic agent of toxoplasmosis, a disease that causes high mortality in immunocompromised individuals and newborns. Despite the medical importance of toxoplasmosis, few drugs, which are associated with side effects and parasite resistance, are available for its treatment. Here, we show a screening of molecules present in COVID-Box to discover new hits with anti-T. gondii activity. COVID-Box contains 160 molecules with known or predicted activity against SARS-CoV-2. Our analysis selected 23 COVID-Box molecules that can inhibit the tachyzoite forms of the RH strain of T. gondii in vitro by more than 70% at 1 µM after seven days of treatment. The inhibitory curves showed that most of these molecules inhibited the proliferation of tachyzoites with IC50 values below 0.80 µM; Cycloheximide and (-)-anisomycin were the most active drugs, with IC50 values of 0.02 μM. Cell viability assays showed that the compounds are not toxic at active concentrations, and most are highly selective for parasites. Overall, all 23 compounds were selective, and for two of them (apilimod and midostaurin), this is the first report of activity against T. gondii. To better understand the effect of the drugs, we analyzed the effect of nine of them on the ultrastructure of T. gondii using transmission electron microscopy. After treatment with the selected drugs, the main changes observed in parasite morphology were the arrestment of cell division and organelle alterations.

PMID:39770804 | DOI:10.3390/microorganisms12122602

Pharmaceuticals (Basel). 2024 Nov 27;17(12):1601. doi: 10.3390/ph17121601.

ABSTRACT

Metformin is a commonly used drug for treating type 2 diabetes. Metformin is an inexpensive drug with low/no side effects and is well tolerated in human patients of different ages. Recent therapeutic strategies for human disease have considered the benefits of drug repurposing. This includes the use of the anti-diabetic drug metformin. Accordingly, the anti-inflammatory, anti-cancer, anti-viral, neuroprotective, and cardioprotective potentials of metformin have deemed it a suitable candidate for treating a plethora of human diseases. As results from preclinical studies using cellular and animal model systems appear promising, clinical trials with metformin in the context of non-diabetes-related illnesses have been started. Here, we aim to provide a comprehensive overview of the therapeutic potential of metformin in different animal models of human disease and its suggested relationship to epigenetics and ailments with epigenetic components.

PMID:39770443 | DOI:10.3390/ph17121601

Molecules. 2024 Dec 16;29(24):5932. doi: 10.3390/molecules29245932.

ABSTRACT

G-quadruplexes (G4s) are distinctive four-stranded nucleic acid structures formed by guanine-rich sequences, making them attractive targets for drug repurposing efforts. Modulating their stability and function holds promise for treating diseases like cancer. To identify potential drug candidates capable of interacting with these complex DNA formations, docking studies and molecular dynamics (MDs) simulations were conducted. Our analysis revealed kanamycin's ability to bind to various G4 structures, offering valuable insights into its potential as a modulator of G4 activity. Kanamycin exhibited favorable interactions with both parallel and hybrid G4 topologies in human structures, suggesting a broader mechanism of action for aminoglycosides. These findings may also shed light on aminoglycoside-associated toxicities, indicating that their effects might extend to binding non-ribosomal RNA structures. In summary, this research highlights kanamycin's potential as a promising tool for influencing G4 dynamics, paving the way for innovative therapeutic strategies targeting G4-related pathways.

PMID:39770021 | DOI:10.3390/molecules29245932

Int J Mol Sci. 2024 Dec 18;25(24):13573. doi: 10.3390/ijms252413573.

ABSTRACT

Finding an effective treatment for T-PLL patients remains a significant challenge. Alemtuzumab, currently the gold standard, is insufficient in managing the aggressiveness of the disease in the long term. Consequently, numerous efforts are underway to address this unmet clinical need. The rarity of the disease limits the ability to conduct robust clinical trials, making in silico, ex vivo, and in vivo drug screenings essential for designing new therapeutic strategies for T-PLL. We conducted a drug repurposing analysis based on T-PLL gene expression data and identified proteasome inhibitors (PIs) as a promising new class of compounds capable of reversing the T-PLL phenotype. Treatment of ex vivo T-PLL cells with Bortezomib and Carfilzomib, two PI compounds, supported this hypothesis by demonstrating increased apoptosis in leukemic cells. The current lack of a suitable in vitro model for the study of T-PLL prompted us to perform similar experiments in the SUP-T11 cell line, validating its potential by showing an increased apoptotic rate. Taken together, these findings open new avenues for investigating the molecular mechanisms underlying the efficacy of PI in T-PLL and expand the spectrum of potential therapeutic strategies for this highly aggressive disease.

PMID:39769335 | DOI:10.3390/ijms252413573

Biomolecules. 2024 Nov 27;14(12):1515. doi: 10.3390/biom14121515.

ABSTRACT

Neutrophil-mediated inflammation is a key feature of immune-mediated chronic skin disorders, but the mechanistic understanding of neutrophil involvement in these conditions remains incomplete. Dapsone, colchicine, and tetracyclines are established drugs within the dermatologist's therapeutic armamentarium that are credited with potent anti-neutrophilic effects. Anti-neutrophilic drugs have established themselves as versatile agents in the treatment of a wide range of dermatological conditions. Some of these agents are approved for the management of specific dermatologic conditions, but most of their current uses are off-label and only supported by isolated reports or case series. Their anti-inflammatory and immunomodulatory properties make them particularly valuable in managing auto-immune bullous diseases, neutrophilic dermatoses, eosinophilic dermatoses, interface dermatitis, and granulomatous diseases that are the focus of this review. By inhibiting inflammatory pathways, reducing cytokine production, and modulating immune responses, they contribute significantly to the treatment and management of these complex skin conditions. Their use continues to evolve as our understanding of these diseases deepens, and they remain a cornerstone of dermatological therapy.

PMID:39766222 | DOI:10.3390/biom14121515

Biomolecules. 2024 Nov 24;14(12):1497. doi: 10.3390/biom14121497.

ABSTRACT

Tuberculosis (TB) is one of the leading causes of death due to infectious disease. It is a treatable disease; however, conventional treatment requires a lengthy treatment regimen with severe side effects, resulting in poor compliance among TB patients. Intermittent drug use, the non-compliance of patients, and prescription errors, among other factors, have led to the emergence of multidrug-resistant TB, while the mismanagement of multidrug-resistant TB (MDR-TB) has eventually led to the development of extensively drug-resistant tuberculosis (XDR-TB). Thus, there is an urgent need for new drug development, but due to the enormous expenses and time required (up to 20 years) for new drug research and development, new therapeutic approaches to TB are required. Host-directed therapies (HDT) could be a most attractive strategy, as they target the host defense processes instead of the microbe and thereby may prevent the alarming rise of MDR- and XDR-TB. This paper reviews the progress in HDT for the treatment of TB using repurposed drugs which have been investigated in clinical trials (completed or ongoing) and plant-derived natural products that are in clinical or preclinical trial stages. Additionally, this review describes the existing challenges to the development and future research directions in the implementation of HDT.

PMID:39766204 | DOI:10.3390/biom14121497

Cancers (Basel). 2024 Dec 20;16(24):4253. doi: 10.3390/cancers16244253.

ABSTRACT

Despite significant progress in the field of clinical oncology in terms of diagnostic and treatment methods, the results of anticancer therapy are still not fully satisfactory, especially due to limited response and high toxicity. This has forced the need for further research to finding alternative ways to improve success rates in oncological treatment. A good solution to this problem in the context of rapidly obtaining an effective drug that works on multiple levels of cancer and is also safe is the global strategy of repurposing an existing drug. Research into other applications of an existing drug enables a precise assessment of its possible mechanisms of action and, consequently, the broadening of therapeutic indications. This strategy is also supported by the fact that most non-oncological drugs have pleiotropic effects, and most of the diseases for which they were originally intended are multifactorial, which in turn is a very desirable phenomenon due to the heterogeneous and multifaceted biology of cancer. In this review, we will mainly focus on the anticancer potential of H1 antihistamines, especially the new generation that were not originally intended for cancer therapy, to highlight the relevant signaling pathways and discuss the properties of these agents for their judicious use based on the characteristic features of cancer.

PMID:39766152 | DOI:10.3390/cancers16244253

Sensors (Basel). 2024 Dec 20;24(24):8142. doi: 10.3390/s24248142.

ABSTRACT

Poaching poses a significant threat to wildlife and their habitats, necessitating advanced tools for its prediction and prevention. Existing tools for poaching prediction face challenges such as inconsistent poaching data, spatiotemporal complexity, and translating predictions into actionable insights for conservation efforts. This paper presents PoachNet, a novel predictive system that integrates deep learning with Semantic Web reasoning to infer poaching likelihood. Using elephant GPS data extracted from an ontology-based knowledge graph, PoachNet employs a sequential neural network to predict future movements, which are semantically modelled and incorporated into the graph. Semantic Web Rule Language (SWRL) is applied to infer poaching risk based on these geo-location predictions and poaching rule-based logic. By addressing spatiotemporal complexity and integrating predictions into an actionable semantic rule, PoachNet advances the field, with its geo-location prediction model outperforming state-of-the-art approaches.

PMID:39771876 | DOI:10.3390/s24248142

Pharmaceutics. 2024 Dec 12;16(12):1585. doi: 10.3390/pharmaceutics16121585.

ABSTRACT

Background: Osteosarcoma is a rare disease, but it is the most frequent malignant bone tumor. Primary treatment consists of preoperative MAP (methotrexate (MTX), doxorubicin and cisplatin) chemotherapy followed by surgery and adjuvant chemotherapy. Pathological response to preoperative chemotherapy is one of the most important prognostic factors, but molecular biomarkers are lacking. Additionally, chemotherapy-induced toxicity might jeopardize treatment completion. We evaluated variants in genes involved in DNA repair and drug metabolism pathways as predictors of response to MAP-based treatment. Material and Methods: Germline polymorphisms in MTHFR, SLC19A1, ABCB1, ABCC2, ABCC3, ERCC1, ERCC2 and GSTP1 genes were determined for association studies in 69 patients diagnosed with localized osteosarcoma who enrolled in the prospective GEIS-33 trial. P-glycoprotein expression in tumor tissue was also analyzed. Results: In the multivariate analysis, the ABCC2 rs2273697 (odds ratio [OR] 12.3, 95% CI 2.3-66.2; p = 0.003) and ERCC2 rs1799793 (OR 9.6, 95% CI 2.1-43.2; p = 0.003) variants were associated with poor pathological response. P-glycoprotein expression did not correlate with pathological response. The ABCB1 rs1128503 (OR 11.4, 95% CI 2.2-58.0; p = 0.003) and ABCC3 rs4793665 (OR 12.0, 95% CI 2.1-70.2; p = 0.006) variants were associated with MTX grade 3-4 hepatotoxicity. Conclusions: Our findings add to the evidence that genetic variants in the ABC transporters and DNA-repair genes may serve as predictive biomarkers for MAP chemotherapy and contribute to treatment personalization.

PMID:39771563 | DOI:10.3390/pharmaceutics16121585

Molecules. 2024 Dec 16;29(24):5934. doi: 10.3390/molecules29245934.

ABSTRACT

Targeted metabolomics and lipidomics are increasingly utilized in clinical research, providing quantitative and comprehensive assessments of metabolic profiles that underlie physiological and pathological mechanisms. These approaches enable the identification of critical metabolites and metabolic alterations essential for accurate diagnosis and precision treatment. Mass spectrometry, in combination with various separation techniques, offers a highly sensitive and specific platform for implementing targeted metabolomics and lipidomics in clinical settings. Nevertheless, challenges persist in areas such as sample collection, quantification, quality control, and data interpretation. This review summarizes recent advances in targeted metabolomics and lipidomics, emphasizing their applications in clinical research. Advancements, including microsampling, dynamic multiple reaction monitoring, and integration of ion mobility mass spectrometry, are highlighted. Additionally, the review discusses the critical importance of data standardization and harmonization for successful clinical implementation.

PMID:39770023 | DOI:10.3390/molecules29245934

Int J Mol Sci. 2024 Dec 16;25(24):13464. doi: 10.3390/ijms252413464.

ABSTRACT

In open-angle glaucoma, the increase in intraocular pressure (IOP) is caused by an increased resistance to aqueous humour outflow in the trabecular meshwork. Since genetic variability of matrix metalloproteinase (MMP) genes may influence extracellular matrix remodelling, we investigated their association with glaucoma risk and/or response to treatment. The retrospective part of the study included patients with primary open-angle glaucoma and ocular hypertension (OHT); in the prospective part of the study, newly diagnosed patients with POAG or OHT were randomised to receive either latanoprost or selective laser trabeculoplasty (SLT) as the initial treatment. The reduction in IOP was measured 6 weeks after treatment. The following MMP single nucleotide polymorphisms were genotyped: MMP2 rs243865, rs243849, and rs7201; MMP3 rs3025058; MMP9 rs17576, rs17577, rs20544, and rs2250889; MMP14 rs1042704, rs1042704, and rs743257. Logistic regression was used to calculate odds ratios to assess the association between MMP polymorphism and risk of POAG or OHT, glaucoma phenotypes and response to treatment. Only carriers of the MMP3 rs3025058 TT genotype had a significantly higher risk of OHT, more advanced glaucoma, and a higher C/D ratio in the additive and dominant models. None of the investigated MMP polymorphisms were associated with response to treatment with latanoprost and SLT in our study population.

PMID:39769228 | DOI:10.3390/ijms252413464

Life (Basel). 2024 Nov 26;14(12):1555. doi: 10.3390/life14121555.

ABSTRACT

Alzheimer's disease (AD) is a complex/multifactorial brain disorder involving hundreds of defective genes, epigenetic aberrations, cerebrovascular alterations, and environmental risk factors. The onset of the neurodegenerative process is triggered decades before the first symptoms appear, probably due to a combination of genomic and epigenetic phenomena. Therefore, the primary objective of any effective treatment is to intercept the disease process in its presymptomatic phases. Since the approval of acetylcholinesterase inhibitors (Tacrine, Donepezil, Rivastigmine, Galantamine) and Memantine, between 1993 and 2003, no new drug was approved by the FDA until the advent of immunotherapy with Aducanumab in 2021 and Lecanemab in 2023. Over the past decade, more than 10,000 new compounds with potential action on some pathogenic components of AD have been tested. The limitations of these anti-AD treatments have stimulated the search for multi-target (MT) drugs. In recent years, more than 1000 drugs with potential MT function have been studied in AD models. MT drugs aim to address the complex and multifactorial nature of the disease. This approach has the potential to offer more comprehensive benefits than single-target therapies, which may be limited in their effectiveness due to the intricate pathology of AD. A strategy still unexplored is the combination of epigenetic drugs with MT agents. Another option could be biotechnological products with pleiotropic action, among which nosustrophine-like compounds could represent an attractive, although not definitive, example.

PMID:39768263 | DOI:10.3390/life14121555

Nutrients. 2024 Dec 14;16(24):4319. doi: 10.3390/nu16244319.

ABSTRACT

The gut microbiome is essential for children's normal growth and development, with its formation aligning closely with key stages of growth. Factors like birth method, feeding practices, and antibiotic exposure significantly shape the composition and functionality of the infant gut microbiome. Small intestinal bacterial overgrowth (SIBO) involves an abnormal increase in bacteria within the small intestine. This overgrowth can interfere with digestion, impair nutrient absorption, and lead to both local and systemic inflammation, potentially contributing to malnutrition. In this review, we provide a comprehensive overview of the current understanding of the relationship between SIBO and malnutrition, with a particular focus on the pediatric population. SIBO seems to play an important role in nutrient malabsorption through the gut microbiome imbalance, local inflammation, and disruption of the mucosal intestinal barrier. Additionally, SIBO is more prevalent in digestive disorders linked to malabsorption and malnutrition. Different therapeutic strategies for addressing malnutrition-related SIBO have been proposed. While antibiotics are the primary treatment for SIBO, their effectiveness in promoting weight gain among malnourished children remains uncertain. Hence, future research directed at the impact of microbiome imbalance on nutrient intake and absorption could bring to light new strategies for the effective prevention and treatment of malnutrition.

PMID:39770940 | DOI:10.3390/nu16244319

Microorganisms. 2024 Dec 9;12(12):2538. doi: 10.3390/microorganisms12122538.

ABSTRACT

Pseudomonas aeruginosa is a major cause of chronic respiratory infections in patients with cystic fibrosis (CF), with biofilm formation contributing to its persistence and antibiotic resistance. This study aimed to gain insights into the mechanistic action of succinic acid as a ciprofloxacin adjuvant against clinically relevant CF isolates, including small colony variants and mucoid strains, and a ciprofloxacin-resistant strain grown within CF dense mucus. Time-kill assays in artificial CF mucus, along with planktonic and surface-attached biofilm experiments, were used to assess the activity of succinic acid alone and in combination with sublethal ciprofloxacin concentrations. Succinic acid demonstrated an adjuvant effect of ciprofloxacin against P. aeruginosa grown within CF mucus at pH levels below pKa1 during the early bacterial growth stages. In examining planktonic growth and biofilms under these conditions, we found that succinic acid demonstrated strong antibacterial and antibiofilm properties. Conversely, succinic acid activity decreased at later growth stages, though it enhanced the ciprofloxacin effect, especially against mucoid biofilms. Moreover, we noted that, in dense CF mucus, succinic acid activity was attenuated compared to a non-CF environment, indicating diffusion challenges. These findings underscore the potential of succinic acid as a therapeutic adjuvant for improving antibiotic treatment outcomes and overcoming biofilm-associated resistance in CF.

PMID:39770741 | DOI:10.3390/microorganisms12122538

Pathogens. 2024 Nov 22;13(12):1030. doi: 10.3390/pathogens13121030.

ABSTRACT

The poor prognosis of infections associated with multidrug-resistant Pseudomonas aeruginosa can be attributed to several conditions of the patient and virulence factors of the pathogen, such as the type III secretion system (T3SS), which presents the ability to inject four effectors into the host cell: ExoS, ExoT, ExoU and ExoY. The aim of this study was to analyze the distribution of exo genes through multiplex polymerase chain reaction in P. aeruginosa strains isolated from patients at a third-level pediatric hospital and their relationships with clinical variables, e.g., the origin of the sample, susceptibility profile and outcome, through a multinomial logistic regression model. A total of 336 bacterial strains were obtained from cystic fibrosis (CF; n = 55) and bloodstream infection (BSI; n = 281) samples, and eleven presence (+)/absence (-) exo virulotype patterns were identified. The virulotype V3 (exoU-/exoS+/exoT+/exoY+) was observed in 64.28%, followed by V1 (exoU+/exoS-/exoT+/exoY+) with 11.60%. Additionally, V2 (exoU+/exoS-/exoT+/exoY-) was present in 11.60%, and V7 (exoU-/exoS+/exoT+/exoY-) was present in 4.17%. The remaining virulotypes (8.33%) identified were clustered in the other virulotype (OV) group (V4, V5, V6, V8, V9, V10 and V11). The clinical records of 100 patients and their outcomes were reviewed. Fifteen patients died (CF = 4; BSI = 11). V2 and V1 were the virulotypes most related to pandrug resistance (PDR), whereas the V1 relative risk of death was determined to be almost four-fold greater than that of V3, followed by V2 and OV. In summary, the virulotypes V1, V2 and CF are related to death. This study highlights the association of T3SS virulotypes with the susceptibility profile, clinical origin and their potential for predicting a poor prognosis.

PMID:39770290 | DOI:10.3390/pathogens13121030

Int J Mol Sci. 2024 Dec 11;25(24):13313. doi: 10.3390/ijms252413313.

ABSTRACT

Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is a rare disease that currently has no cure. It is caused by defects in the SGCB gene, mainly missense mutations, which cause the impairment of the sarcoglycan complex, membrane fragility, and progressive muscle degeneration. Here, we studied the fate of some β-sarcoglycan (β-SG) missense mutants, confirming that, like α-SG missense mutants, they are targeted for degradation through the ubiquitin-proteasome system. These data, collected using HEK-293 cells expressing either the I119F- or Y184C mutants of β-SG, were subsequently confirmed in primary myotubes derived from an LGMD2E/R4 patient carrying a homozygous I92T mutation. The knowledge that β-SG with an amino acid substitution shares a pathway of degradation with α-SG mutants, allowed us to explore the pharmacological approach successfully tested in LGMD2D/R3. Several CFTR correctors, particularly corrector C17, preserved β-SG mutants from degradation and promoted localization at the sarcolemma of the entire SG complex. The presence of the complex, despite containing a mutated subunit, improved sarcolemma integrity, as evidenced by the reduced creatine kinase release from myotubes under hypoosmotic stress. These results suggest that β-SG missense mutants undergo proteasomal degradation as α-SG mutants, and that CFTR correctors, particularly C17, may be used as a potential therapeutic option for recovering and stabilizing the SG complex in patients with sarcoglycanopathies.

PMID:39769077 | DOI:10.3390/ijms252413313

Life (Basel). 2024 Dec 18;14(12):1676. doi: 10.3390/life14121676.

ABSTRACT

The presence of bile acids in the cystic fibrosis patient's lungs contributes to an increase in the inflammatory response, in the dominance of pathogens, as well as in the decline in lung function, increasing morbidity. The aim of this study is to determine the effects of exposure of Pseudomonas aeruginosa to primary and secondary bile acids on the production of several virulence factors which are involved in its pathogenic power. The presence of bile acids in the bacterial culture medium had no effect on growth up to a concentration of 1 mM. However, a slight decrease in the adhesion index as well as a reduction in the virulence of the bacteria on the HT29 cell line could be observed. In this model, exposure of P. aeruginosa to bile acids showed a significant decrease in the production of LasB and AprA proteases due to the reduction in the expression of their genes. A decrease in pyocyanin production was also observed in relation to the effects of bile acids on the quorum sensing regulators. In order to have an effect on gene expression, it is necessary for bile acids to enter the bacteria. P. aeruginosa harbors two potential homologs of the eukaryotic genes encoding the bile acid transporters NTCP1 and NTCP2 that are expressed in hepatocytes and enterocytes, respectively. By carrying out a comparative BLAST-P between the amino acid sequences of the PAO1 proteins and those of NTCP1 and NTCP2, we identified the products of the PA1650 and PA3264 genes as the unique homologs of the two eukaryotic genes. Exposure of the mutant in the PA1650 gene to chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) showed a less significant effect on pyocyanin production than with the isogenic PAO1 strain. Also, no effect of CDCA on the PA3264 gene mutant was observed. This result indicated that CDCA should enter the bacteria by the transporter produced by this gene. The entry of LCA into bacteria seemed more complex and rather responded to a multifactorial system involving the product of the PA1650 gene but also the products of other genes encoding potential transporters.

PMID:39768382 | DOI:10.3390/life14121676

Diagnostics (Basel). 2024 Dec 19;14(24):2859. doi: 10.3390/diagnostics14242859.

ABSTRACT

BACKGROUND/OBJECTIVES: Recent studies indicate that sleep and sleep disorders differ between men and women, but corresponding data in people with chronic lung diseases are lacking. This study aims to answer the question of what the sex-specific differences in sleep profiles and responses to elexacaftor/tezacaftor/ivacaftor (ETI) therapy in people with cystic fibrosis (pwCF) are.

METHODS: Adult pwCF and a matched control group (adults with suspected sleep-disordered breathing undergoing in-laboratory polysomnography (PSG)) were included. PSG data at baseline and after 6 months' ETI therapy were compared between men (mwCF) and women (wwCF) with cystic fibrosis. PSG data at baseline and 6-month follow-up for mwCF/wwCF were compared with baseline PSG data for men/women in the control group. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS). Correlations between change in percentage predicted forced expiratory volume in 1 s from baseline to 6 months were correlated with corresponding changes in key sleep parameters. Changes in transferrin during ETI therapy were also documented.

RESULTS: Twenty-eight pwCF (12 wwCF, 16 mwCF) and 28 matched controls were included. Both mwCF (4 ± 5 vs. 9 ± 20 events/h, p = 0.028) and wwCF (3 ± 3 vs. 8 ± 9 events/h, p = 0.004) had fewer respiratory events during sleep versus male and female controls, but worse sleep efficiency (75 ± 11% vs. 84 ± 11%; p = 0.004 and 76 ± 10% vs. 83 ± 11%; p = 0.011. The baseline ESS score was significantly higher in wwCF versus female controls (8 ± 4 vs. 14 ± 8; p = 0.040). Although some sleep parameters normalized during ETI therapy in pwCF, sleep quality remained poor. The transferrin levels at baseline (2.7 ± 0.4 vs. 2.2 ± 0.5; p = 0.049) and 6 months (3.8 ± 0.4 vs. 2.6 ± 0.5; p < 0.001) were significantly higher in the wwCF versus the mwCF, and the change from baseline during ETI therapy was significantly greater in women versus men (1.1 ± 0.6 vs. 0.4 ± 0.4; p < 0.001).

CONCLUSIONS: These data suggest that wwCF and mwCF should be managed differently with respect to their sleep.

PMID:39767222 | DOI:10.3390/diagnostics14242859

Genes (Basel). 2024 Dec 5;15(12):1573. doi: 10.3390/genes15121573.

ABSTRACT

Background/Objectives: The FARSA gene encodes for the catalytic α subunit of Cytoplasmic phenylalanine-tRNA synthetase (FARS1), an essential enzyme for protein biosynthesis in transferring its amino acid component to tRNAs. Biallelic pathogenic variants have been associated with a multisystemic condition, characterized by variable expressivity and incomplete penetrance. Here, we report the case of an 11 year-old girl presenting interstitial lung disease, supratentorial leukoencephalopathy with brain cysts, hepatic dysfunction, hypoalbuminemia, skin and joint hyperlaxity, growth retardation, and dysmorphic features. In addition, our patient also developed two clinical features never reported before: hypergammaglobulinemia and myopic chorioretinitis. Methods: NGS analysis of the patient's skin-derived DNA revealed two novel biallelic variants in FARSA gene (NM_004461.3) never described before: the maternal nonsense variant, c.799C>T [p.(Gln267Ter)], and the paternal missense variant, c.737T>C [p.(Met246Thr)], both predicted as deleterious. Results: From a therapeutic perspective, this young girl has been enrolled in a clinical trial with Nintedanib, in order to treat the severe pulmonary fibrosis, with interesting initial results. Conclusions: Our findings expand the clinical and molecular spectrum of the FARSA-related phenotype and introduce new cues on lung fibrosis treatment in pediatric age.

PMID:39766840 | DOI:10.3390/genes15121573

Biology (Basel). 2024 Dec 16;13(12):1052. doi: 10.3390/biology13121052.

ABSTRACT

Adenoviral vectors (AdVs) are effective vectors for gene therapy due to their broad tropism, high capacity, and high transduction efficiency, which makes them actively used as oncolytic vectors and for creating vector vaccines. However, despite their numerous advantages, AdVs have not yet found their place in gene therapy for hereditary diseases. This review provides an overview of AdVs, their features, and clinical trials using them for gene replacement therapy in monogenic diseases and analyzes the reasons for the failures of these studies. Additionally, current research on the modification of AdVs to reduce immune responses and target delivery is discussed.

PMID:39765719 | DOI:10.3390/biology13121052