Search Results (830)

Immune checkpoint inhibitors (ICIs) are approved in at least one line of therapy for most patients with advanced non-small cell lung cancer (NSCLC) without EGFR/ALK alterations and have improved survival for a subset of patients. Adjuvant, neoadjuvant, and perioperative therapy for resectable NSCLC carries the hope of more broadly increased cure rates for patients with resectable lung cancers. This review summarizes the current state of multimodality management, including ICIs, for resectable NSCLC. A literature search of PubMed and Scopus identified phase II and III clinical trials including ICIs in patients with resectable NSCLC. No level 1 evidence guides the clinician in choosing between the available neoadjuvant and perioperative approaches. Full article

Background: Tyrosine kinase inhibitors (TKIs) have significantly improved outcomes in non-small cell lung cancer (NSCLC), especially among patients with actionable genetic mutations. However, the influence of family and personal medical history (FPMH) on clinical and treatment outcomes with TKI therapy remains underexplored. Methods: We conducted a retrospective cohort study involving 136 NSCLC patients receiving TKIs, categorized into two groups based on the presence or absence of documented FPMH. Clinical variables assessed included demographic data, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status, tumor characteristics, genetic mutations (EGFR, ALK, ROS1), treatment responses, toxicity profiles, and survival outcomes. Statistical analyses included Chi-square tests, t-tests, Mann–Whitney U tests, Spearman correlation, and univariate logistic regression (p < 0.05 threshold for significance). Results: Patients with FPMH (n = 34) had a significantly higher burden of chronic diseases (58.8% vs. 15.7%), poorer ECOG scores (≥3: 8.8% vs. 1.0%), increased recurrence (41.2% vs. 20.6%), and greater chemotherapy-related toxicity (50.0% vs. 28.4%) compared to those without FPMH (n = 102). However, there were no significant differences in survival duration or mutation status between the two groups. Conclusions: FPMH may be a predictive factor for treatment complications and recurrence in NSCLC patients receiving TKIs, although it does not appear to influence survival or genetic mutation status. These findings support the need for personalized clinical monitoring strategies based on medical history. Full article

Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play an important role in vascular health and disease as well as in regulating Estrogen actions in many cell types. We hypothesize that E2 may mediate its vascular protective actions via the regulation of miRNAs. Following initial screening, we found that E2 downregulates the levels of miR-193a-3p in ECs. Moreover, miR-193a-3p downregulation by miR-193a-3p-antimir mimicked the effects as E2 on EC growth, migration, and capillary formation. Restoring miR-193a-3p levels with mimics after E2 treatment abrogated the vasculogenic actions of E2, suggesting a key role of miR-193a-3p in E2-mediated EC-growth-promoting effects. We further investigated the cellular mechanisms involved and found that miR-193a-3p inhibits angiogenesis by blocking phosphoinositide-3-kinase (PI3K)/Akt-vascular endothelial growth factor (VEGF) and Activin receptor-like kinase 1 (ALK1)/SMAD1/5/8 signaling in ECs, both pathways that are important in E2-mediated vascular protection. Additionally, using reverse transcription polymerase chain reaction (RT-PCR), we demonstrate that E2 downregulates miR-193a-3p in ECs via Estrogen Receptor (ER)α, but not ERβ or G protein-coupled estrogen receptor (GPER). Moreover, these actions occur post-transcriptionally, as the expression of pri-miR-193a-3p was not affected. The anti-angiogenic actions of miR-193a-3p were also observed in in vivo Matrigel implant-based capillary formation studies in ovariectomized mice where E2 induced capillary formation, and these effects were abrogated in the presence of miR-193a-3p, but not in the control mimic. Assessment of miR-193a-3p levels in plasma collected from in vitro fertilization (IVF) subjects with low and high E2 levels showed significantly lower miR-193a-3p levels in responders during the high E2 period. Hence, our findings provide the first evidence that miR-193a-3p mimic inhibits angiogenesis whereas its antimir is angiogenic. Importantly, E2 mediates its regenerative actions on ECs/capillary formation by downregulating endogenous miR-193a-3p expression. Both miR-193a-3p mimic or antimir may represent important therapeutic molecules to prevent or to induce endothelial function in treating pathophysiologies associated with capillary growth. Full article

The application of personalized medicine to lung adenocarcinoma has resulted in new therapies based on specific oncogenic drivers that have improved patient outcomes. However, oncogene-defined subsets of patients exhibit a significant heterogeneity of response to these agents. Defining the factors that mediate the varied depth and duration of response are critical to developing new therapeutic strategies. While the examination of patient samples can provide important correlations, definitive mechanistic studies require the use of relevant preclinical models. Based on a large body of data, interactions between cancer cells and the surrounding tumor microenvironment, comprised of inflammatory, immune, and vascular cells, represent a critical determinant of therapeutic response. In this review, we focus on preclinical models that can be used to explore these interactions, identify new therapeutic targets, and test combination therapies. In particular, we will describe the use of implantable orthotopic immunocompetent models employing a panel of murine lung adenocarcinoma cell lines with oncogenic drivers common to human lung adenocarcinoma as a powerful system to develop new treatment approaches. Full article

Various pretreatment methods for the valorization of sunflower husks (SHs) for H₂ gas generation through fermentation by Escherichia coli were investigated. We analyzed thermal treatment (TT), acid hydrolysis (AH), and alkaline hydrolysis (AlkH) at different substrate concentrations (50 g L⁻¹, 75 g L⁻¹, 100 g L⁻¹, and 150 g L⁻¹) and dilution levels (undiluted, 2× diluted, and 5× diluted). A concentration of 75 g L⁻¹ SH that was acid-hydrolyzed and dissolved twice in the medium yielded optimal microbial growth, reaching 0.3 ± 0.1 g cell dry weight (CDW) L⁻¹ biomass. The highest substrate level enabling effective fermentation was 100 g L⁻¹, producing 0.37 ± 0.13 (g CDW) × L⁻¹ biomass after complete fermentation, while 150 g L⁻¹ exhibited pronounced inhibitory effects. It is worth mentioning that the sole alkaline treatment was not optimal for growth and H₂ production. Co-fermentation with glycerol significantly enhanced both biomass formation (up to 0.42 ± 0.15 (g CDW) × L⁻¹)) and H₂ production. The highest H₂ yield was observed during batch growth at 50 g L⁻¹ SH hydrolysate with 5× dilution, reaching up to 5.7 mmol H₂ (g sugar)⁻¹ with glycerol supplementation. This study introduces a dual-waste valorization strategy that combines agricultural and biodiesel industry residues to enhance clean energy generation. The novelty lies in optimizing pretreatment and co-substrate fermentation conditions to maximize both biohydrogen yield and microbial biomass using E. coli, a widely studied and scalable host. Full article

Stargardt’s disease (STGD1) is an autosomal recessive juvenile macular degeneration caused by mutations in the ABCA4 gene, impairing clearance of toxic retinoid byproducts in the retinal pigment epithelium (RPE). This leads to lipofuscin accumulation, oxidative stress, photoreceptor degeneration, and central vision loss. Over 1200 pathogenic/likely pathogenic ABCA4 variants highlight the genetic heterogeneity of STGD1, which manifests as progressive central vision loss, with phenotype influenced by deep intronic variants, modifier genes, and environmental factors like light exposure. ABCA4 variants also show variable penetrance and geographical prevalence. With no approved treatment, investigational therapies target different aspects of disease pathology. Small-molecule therapies target vitamin A dimerization (e.g., ALK-001), inhibit lipofuscin accumulation (e.g., soraprazan), or modulate the visual cycle (e.g., emixustat hydrochloride). Gene therapy trials explore ABCA4 supplementation including strategies like RNA exon editing (ACDN-01) and bioengineered ambient light-activated OPSIN. RORA gene therapy (Phase 2/3) addresses oxidative stress, inflammation, lipid metabolism, and complement system dysregulation. Trials like DRAGON (Phase 3, tinlarebant), STARLIGHT (phase 2, bioengineered OPSIN) show promise, but optimizing efficacy remains challenging. With the key problem of establishing genotype–phenotype correlations, the future of STGD1 therapy may rely on approaches targeting oxidative stress, lipid metabolism, inflammation, complement regulation, and genetic repair. Full article

The enzyme ABH2, one of nine human DNA dioxygenases of the AlkB family, belongs to the superfamily of Fe(II)/α-ketoglutarate-dependent dioxygenases and plays a crucial role in the direct reversal repair of nonbulky alkyl lesions in DNA nucleobases. ABH2 has broad substrate specificity, directly oxidizing DNA damages such as N¹-methyladenine, N³-methylcytosine, 1,N⁶-ethenoadenine, 3,N⁴-ethenocytosine, and a number of others. In our investigation, we sought to uncover the subtleties of the mechanisms governing substrate specificity in ABH2 by focusing on several critical amino acid residues situated in its active site. To gain insight into the function of this enzyme, we performed a functional mapping of its active site region, concentrating on pivotal residues, participating in forming a damaged binding pocket of the enzyme (Val99 and Ser125), as well as the residues directly involved in interactions with damaged bases, namely Arg110, Phe124, Arg172, and Glu175. To support our experimental data, we conducted a series of molecular dynamics simulations, exploring the interactions between the ABH2 mutant forms, bearing corresponding substitutions and DNA substrates, and harboring various types of methylated bases, specifically N¹-methyladenine or N³-methylcytosine. The comparative studies revealed compelling data indicating that alterations in most of the studied amino acid residues significantly influence both the binding affinity of the enzyme for DNA and its catalytic efficiency. Intriguingly, the findings suggest that the mutations impact the catalytic activity of ABH2 to a greater extent than its ability to associate with DNA strands. Collectively, these results show how changes to the active site affect molecular dynamics and reaction kinetics, improving our understanding of the substrate recognition process in this pivotal enzyme. Full article

Some pancreatic ductal-type (PDADK) and lung adenocarcinomas (LADK) lacking other molecular drivers are reported to harbor NRG1 fusions as potential novel therapeutic targets. We investigated the feasibility of a fluorescent in situ hybridization (FISH)-based diagnosis of NRG1 fusions in a case series of PDADK and LADK lacking other identified oncogenic drivers. First, among a case series of PDADK, KRAS analyses (PCR followed in PCR-negative cases by RNA sequencing—RNAseq) found 27/162 (16.7%) KRAS wild-type cases, among which 1/162 (0.6%) NRG1 fusion was diagnosed using FISH. Secondly, among a case series of LDAK, 191/446 (42.8%) cases had no molecular alterations in EGFR, KRAS, BRAF, HER2, MET, ALK, ROS1 and RET according to NGS and FISH analyses and, among them, 4/446 (0.9%) cases had NRG1 fusions using FISH. Finally, four additional cases out of the two previously mentioned cases series (1 PDADK and 3 LADK) with NRG1 fusions diagnosed by first-line RNAseq were also concluded as NRG1 FISH-positive. The NRG1 FISH tests for the nine NRG1 FISH-positive cases resulted in 50% to 80% of positive tumor nuclei, all with single 3′-NRG1 FISH signals. In our series, of the 22 cases analyzed with both NRG1 FISH (positivity criterion of at least 15% of tumor nuclei with a split between the 5′- and the 3′- parts of the probes and/or isolated single 3′-NRG1 signal) and RNAseq, 17 cases were FISH– RNAseq– and 5 cases were FISH+ RNAseq+ (no FISH+ RNAseq– or FISH– RNAseq+ cases in our study) resulting in 100% sensibility and specificity for the NRG1 FISH test. In the case of no access to RNAseq, NRG1 FISH consists of a valuable tool searching for NRG1 fusions in patients with advanced cancers. Full article

Background/Objectives: The neurotrophic tropomyosin receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 encode tyrosine kinase receptors, and their fusion genes are known as the oncogenic driver genes for cancer. This study aimed to compare the diagnostic ability of NTRK fusion among five types of multi-cancer genome profiling tests (multi-CGP tests) and determine a useful multi-CGP test for NTRK fusion, recorded in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. This study aimed to compare the diagnostic results for NTRK fusions among the five different CGP tests. Methods: A total of 88,688 tumor cases were enrolled in the C-CAT profiling database from 2019 to 2024. The detection frequency of NTRK fusion genes was compared to the results for five multi-CGP tests: NCC Oncopanel, FoundationOne CDx (F1), FoundationOne Liquid (F1L), GenMineTOP (GMT), and Guardant360. Results: NTRK fusion genes were detected in 175 (0.20%) of the 88,688 total cases. GMT, which is equipped with RNA sequencing function, frequently detected NTRK fusion genes (20 of 2926 cases; 0.68%) in comparison with the other four multi-CGP tests that do not have RNA sequencing analysis. GMT showed significantly (p < 0.05) higher diagnostic ability for NTRK fusions compared with the other four multi-CGP tests. Especially, NTRK2 fusion was significantly (p < 0.001) more highly determined by GMT than it was by the other four multi-CGP tests. The detection rates for FGFR1 and FGFR3 were significantly higher in GMT than in other multi-CGP tests. In contrast, the detection rates of the ALK and RET fusion genes were significantly higher in F1L. Conclusions: GMT, which is equipped with RNA sequencing analysis, might show a useful diagnostic ability for NTRK fusions, especially for NTRK2 fusion genes. Full article

Background/Objectives: ALK+ Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma that is characterized by expression of the Anaplastic Lymphoma Kinase (ALK), which is induced by the t(2;5) chromosomal rearrangement, leading to the expression of the NPM-ALK fusion oncogene. Most previous preclinical models of ALK+ ALCL were based on overexpression of the NPM-ALK cDNA from heterologous promoters. Due to the enforced expression, this approach is prone to artifacts arising from synthetic overexpression, promoter competition and insertional variation. Methods: To improve the existing ALCL models and more closely recapitulate the oncogenic events in ALK+ ALCL, we employed CRISPR/Cas-based chromosomal engineering to selectively introduce translocations between the Npm1 and Alk gene loci in murine cells. Results: By inducing precise DNA cleavage at the syntenic loci on chromosome 11 and 17 in a murine IL-3-dependent Ba/F3 reporter cell line, we generated de novo Npm-Alk translocations in vivo, leading to IL-3-independent cell growth. To verify efficient recombination, we analyzed the expression of the NPM-ALK fusion protein in the recombined cells and could also show the t(11;17) in the IL-3 independent Ba/F3 cells. Subsequent functional testing of these cells using an Alk-inhibitor showed exquisite responsiveness towards Crizotinib, demonstrating strong dependence on the newly generated ALK fusion oncoprotein. Furthermore, a comparison of the gene expression pattern between Ba/F3 cells overexpressing the Npm-Alk cDNA with Ba/F3 cells transformed by CRISPR-mediated Npm-Alk translocation indicated that, while broadly overlapping, a set of pathways including the unfolded protein response pathway was increased in the Npm-Alk overexpression model, suggesting increased reactive changes induced by exogenous overexpression of Npm-Alk. Furthermore, we observed clustered expression changes in genes located in chromosomal regions close to the breakpoint in the new CRISPR-based model, indicating positional effects on gene expression mediated by the translocation event, which are not part of the older models. Conclusions: Thus, CRISPR-mediated recombination provides a novel and more faithful approach to model oncogenic translocations, which may lead to an improved understanding of the molecular pathogenesis of ALCL and enable more accurate therapeutic models of malignancies driven by oncogenic fusion proteins. Full article

The objective of this study was to identify the AlkB family genes in poultry using bioinformatics, and to explore their molecular characteristics, evolutionary relationships, and expression patterns to clarify their potential functions in poultry. (1) Methods: The study utilized the NCBI database to obtain chicken genome data, and screened and validated AlkB family members (ALKBH1-5, ALKBH8, and FTO) by hmmsearch and TBtools. MEGA 11.0 was used for phylogenetic analysis, PHYRE2 and I-TASSER predicted protein structures, and the String database was used to construct an interoperability network. Finally, the tissue expression profiles were analyzed by using The Human Protein Atlas online database and qRT-PCR. (2) Results: Phylogenetic analysis revealed distinct avian and mammalian clusters, with chicken AlkB proteins exhibiting low sequence homology but conserved 3D structures compared to mammals. Chromosomal synteny and conserved domains highlighted evolutionary divergence, with ALKBH4 lacking typical AlkB structural motifs. Protein interaction networks linked ALKBH1/2/3/5/8/FTO, underscoring functional coordination in poultry adaptation. Tissue-specific expression showed high AlkB levels in brain tissues, while ALKBH5 dominated in muscle. During differentiation, ALKBH3, ALKBH5, and FTO expression significantly increased during myoblast differentiation. (3) Conclusions: This study identified seven AlkB family genes in poultry, revealing their phylogenetic classification into two subfamilies, conserved structural domains, chromosomal synteny, and tissue-specific expression patterns. Full article

The large yellow croaker, or Larimichthys crocea, is highly prized for its golden color and nutritional content. The purpose of this study was to investigate the differences in body composition, mucus biochemical indices and body color in five strains of large yellow croakers (body weight: 347.01 ± 5.86 g). To conduct genetic diversity analyses of the populations, a total of 50 tailfin samples were randomly chosen from the following populations of large yellow croakers: wild (LYC1), Dai-qu population (LYC2), Yongdai 1 (LYC3), Min-yuedong population (LYC4), and Fufa 1 (LYC5). The findings demonstrated that the LYC3 group’s pigment contents, crude protein, crude lipid, and chromatic values were comparable to those of the LYC1 group (p > 0.05). There was no significant difference between the LYC1 and LYC5 groups’ mucus superoxide dismutase (SOD) and catalase (CAT) activities (p > 0.05). The alkaline phosphatases (ALP), acid phosphatases (ACP), and lysozyme (LYS) activities of the mucus in the LYC1 group were not significantly different from the LYC3 group (p > 0.05). The back skin mRNA expressions of tyrosinase (tyr), tyrosinase-related protein 1 (tyrp1), dopachrome tautomerase (dct), microphtalmia-associated transcription factor (mitf), and melanocortin 1 receptor (mc1r) were significantly up-regulated in the LYC2 and LYC4 groups compared to the LYC1, LYC3, and LYC5 groups (p < 0.05). Forkhead box d3 (foxd3), paired box 3 (pax3), purine nucleoside phosphorylase 4a (pnp4a), aristaless-like homeobox 4a (alx4a), cAMP dependent protein kinase (pka), anaplastic lymphoma kinase (alk), leukocyte receptor tyrosine kinase (ltk), and colony stimulating factor (fms) were among the mRNA expressions of the abdominal skin in the LYC1, LYC3, and LYC5 groups significantly higher than those in the LYC2 and LYC4 groups (p < 0.05). In conclusion, the LYC3 group’s crude protein, crude lipid, carotenoid, and lutein contents were most similar to those of the large yellow croaker found in the wild. Furthermore, the molecular mechanism underlying the variations in body color among the various strains of large yellow croakers was supplied for additional research. Full article

Choosing the optimal first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements can be challenging in daily practice. Although clinical trials with next-generation ALK-tyrosine kinase inhibitors (TKIs) have played a key role in evaluating their efficacy and safety, which patients benefit from a specific ALK-TKI may still be questioned. The methodological inconsistencies in these trials, which led to the inclusion of different patient populations, appear to have been inadequately addressed. ALK-rearranged NSCLC is a heterogeneous disease, and co-existing molecular alterations may affect the outcome. The questions explored in these trials appear insufficient to support a personalized approach to the first-line treatment, while defining long-term responders and early progressors would be clinically useful. This narrative review presents several considerations from oncologists’ and pathologists’ perspectives. We propose defining favorable and unfavorable features, such as histology, type of ALK fusion, co-existing molecular alterations, plasma circulating tumor DNA (ctDNA, performance status, and brain metastases, to help identify patients with lower and higher risk of progression. Consequently, the most potent ALK-TKI to date, Lorlatinib, may be considered as the first-line treatment for high-risk patients with unfavorable features, while sequencing of ALK-TKIs may be appropriate for low-risk patients with favorable features. Although ALK signal inhibition is critical in this disease, it may not be sufficient for clinical control due to de novo co-alterations. A more personalized approach to first-line therapy requires consideration of risk factors for each patient. Full article

Anaplastic Large Cell Lymphoma (ALCL) represents a diverse group of mature T-Cell Lymphomas unified by strong CD30 expression but with different molecular and clinical subtypes. This review summarizes recent molecular advances in ALCL, highlighting key discoveries that have refined its classification, diagnosis, and therapeutic strategies. ALCL comprises four major entities: systemic ALK-positive ALCL, systemic ALK-negative ALCL, Breast Implant-Associated ALCL (BIA-ALCL), and primary cutaneous ALCL. Each subtype exhibits unique phenotypes, along with cytogenetic and molecular alterations that affect clinical outcomes. Nevertheless, different oncogenic mechanisms mediate STAT3 activation. In ALK-positive ALCL, ALK fusion proteins drive oncogenesis via constitutive activation of STAT3 and other signaling pathways. ALK-negative ALCL comprises heterogeneous genetic subtypes, in which JAK/STAT3 pathway alterations and novel gene fusions are gaining recognition as potential therapeutic targets. This review emphasizes the need for integrative molecular diagnostics to improve stratification of ALCL subtypes and targeted treatment approaches. Future research should focus on elucidating the biological mechanisms underlying these alterations and on translating molecular insights into clinical practice. Full article

The increasing global oil consumption has led to significant soil contamination by hydrocarbons, notably diesel-range hydrocarbons. Soil bioremediation through bacterial bioaugmentation is an alternative to increase the degradation of organic pollutants such as petroleum products. Bioremediation is a sustainable practice that contributes to the Sustainable Development Goals (SDGs) because it is environmentally friendly, reduces the impact of human activities, and avoids the use of invasive and destructive methods in soil restoration. This study examines the bioremediation potential of hydrocarbonoclastic bacteria isolated from soil close to areas with a risk of spills due to pipelines carrying hydrocarbons. Among the isolated strains, Arthrobacter globiformis, Pantoea agglomerans, and Nitratireductor soli exhibited hydrocarbonoclast activity, achieving diesel removal of up to 90% in short-chain alkanes and up to 60% in long-chain hydrocarbons. The results from in silico studies, which included molecular docking and molecular dynamics simulations, suggest that the diesel removal activity can be explained by the bioavailability of the linear alkanes and their affinity for alkane monooxygenase AlkB present in the studied microorganisms, since long-chain hydrocarbons had lower enzyme affinity and lower aqueous solubility. The correlation of the experimental results with the computational analysis allows for greater insight into the processes involved in the microbial degradation of hydrocarbons with varying chain lengths. Furthermore, this methodology establishes a cost-effective approximation tool for the evaluation of the feasibility of using different microorganisms in bioremediation processes. Full article