Search Results (28)

Resting myokine abundance cannot distinguish adaptive signaling from compensation, tissue injury, altered receptor availability, or non-muscle contribution. We conducted a targeted narrative review of PubMed/MEDLINE, Embase, Web of Science Core Collection, and Scopus through 30 June 2026 to examine ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine factor 1 (CLCF1), and muscle metabolism across basal, insulin-stimulated, exercise, recovery, and training states. CNTF has the better-established CNTFR$\alpha$–LIFR–gp130 receptor model, and pharmacological studies link it to AMPK activation, glucose uptake, ceramide handling, and insulin responsiveness. CLCF1 depends partly on CRLF1-associated extracellular availability, whereas its receptor usage and tissue source in skeletal muscle remain incompletely resolved. One recent study provides important preclinical and exploratory human evidence for exercise-responsive CLCF1, but direct human studies pairing CNTF/CLCF1 kinetics with muscle metabolomics or isotope-resolved flux are lacking. We, therefore, present neurotrophic secretory flexibility as a testable, hypothesis-generating construct rather than a validated biological system or biomarker. Its minimum evaluation requires synchronized measurements of extracellular ligand, receptor-proximal signaling, and metabolic output within the same physiological challenge. Targeted and untargeted metabolomics, lipidomics, quality-controlled annotation, paired tissue and plasma sampling, and stable isotope tracing can determine whether putative coupling is reproducible, muscle-relevant, and altered by aging. Full article

Background/Objectives: Liver fibrosis, a wound-healing response to chronic liver injury characterized by excessive extracellular matrix (ECM) accumulation, represents a major global health burden with no approved anti-fibrotic therapies. Pien Tze Huang (PZH), an officially approved traditional Chinese medicine (NMPA Drug Approval No. Z35020243), has demonstrated hepatoprotective effects, yet its epigenetic mechanisms in fibrosis treatment remain unexplored. Methods: We performed the first integrated methylome–transcriptome–proteome analysis to investigate PZH’s anti-fibrotic mechanisms in a CCl₄-induced mouse model using reduced representation bisulfite sequencing (RRBS), RNA-seq, and TMT-labeled LC-MS/MS. Results: We identified 10,974 differentially methylated loci (DMLs) and 773 differentially expressed genes (DEGs) modulated by PZH treatment. Integration analysis revealed ANXA3 and CORO1A as candidate therapeutic targets exhibiting significant inverse methylation-expression correlations validated at both transcriptomic and proteomic levels. Notably, PZH treatment modulated the CRLF-CLCF1 cytokine complex and the EGR-3 transcription factor network (42/44 genes enriched), suggesting broad transcriptional reprogramming in fibrotic liver. Protein–protein interaction (PPI) analysis highlighted key gene pairs such as Dnmt1-Uhrf1, Cbfb-Runx1, and Col4a1-Col4a2, implicating PZH in epigenetic maintenance, transcription factor regulation, and ECM remodeling. Conclusions: These findings suggest mechanistic insights into PZH’s multi-target anti-fibrotic effects and offer a rationale for developing potential therapeutic targets for liver fibrosis. Full article

Background: Cytokine-like receptor family 1 (CRLF1) has been implicated in tumor progression, yet its prognostic function and mechanistic actions in prostate cancer (PCa) remain elusive. Objective: This investigation sought to clarify the functional role, molecular mechanisms, and clinical relevance of CRLF1 in the progression of PCa. Methods: We conducted extensive bioinformatics analyses utilizing the protein interaction networks and the TCGA-PRAD dataset. CRLF1 and cartilage oligomeric matrix protein (COMP) expression were validated in clinical samples by qRT-PCR and Western blot (WB). Functional assessments, including Transwell invasion, flow cytometry, CCK-8, and wound healing, were conducted in vitro. An in vivo xenograft tumor model was used for further validation. Mechanistic investigations involved genetic perturbation (overexpression and inhibition) of CRLF1 and COMP. Results: Compared to benign tissues, the levels of CRLF1 and COMP were markedly elevated in PCa tissues. Bioinformatics assessments illustrated a robust positive relationship between CRLF1 and COMP, suggesting COMP may function as a downstream mediator. In vitro and in vivo investigations illustrated that silencing CRLF1 significantly suppressed PCa cell growth, invasion, and tumor progression, while enhancing apoptosis. Importantly, suppressing COMP counteracted the cancer-promoting effects triggered by CRLF1 overexpression. At the mechanistic level, CRLF1 facilitates tumor progression by modulating COMP to activate the FAK/PI3K/AKT signaling cascade. Conclusions: Our outcomes demonstrate that CRLF1 promotes PCa progression by targeting COMP to stimulate the FAK/PI3K/AKT signaling axis. This newly identified CRLF1/COMP/FAK/PI3K/AKT pathway underscores CRLF1 as a potential biomarker and therapeutic target for PCa. Full article

Background: Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by severe neonatal manifestations including paroxysmal muscle contractions, tendency for hyperthermia, and feeding and swallowing difficulties with high neonatal mortality. Pathogenic variants in the Cytokine Receptor-Like Factor 1 (CRLF1) gene have been associated with CS/CISS. These variants result in a loss of function of the encoded protein, which disrupts the formation of a functional heterodimer with Cardiotrophin-Like Cytokine Factor 1 (CLCF1). This complex is essential for the development of autonomic and sensory nervous systems, as well as for bone remodeling. We report two patients affected by CS harboring pathogenic variants in the CRLF1 gene. Methods—case reports: The first patient was diagnosed postnatally, presenting with non-epileptic paroxysmal events characterized by opisthotonus and orofacial contractions. He survived beyond infancy, later developing scoliosis and persistent episodes of hyperthermia. In the second patient, a prenatal ultrasound at 20 weeks of gestation revealed bilateral camptodactyly, also referred to as the ‘horn’s sign’, raising early suspicion of CS. The diagnosis was subsequently confirmed both clinically and genetically. After birth, the infant developed severe dysphagia, apnea, and paroxysmal events not associated with epileptiform activity on EEG. Sanger sequencing identified a homozygous c.708_709delinsT frameshift variant in the CRLF1 gene. The patient died at 30 days of age due to respiratory failure. Results and conclusions: With this manuscript, we aim to further delineate the phenotypic spectrum of this rare condition and propose the ‘horn’s sign’ as a targeted prenatal marker for early diagnosis in populations with known founder mutations or familial risk factors. Full article

Background: Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-cell ALL characterized by a gene expression profile similar to BCR::ABL1-positive leukemia, but lacking the BCR::ABL1 fusion gene. It is frequently associated with kinase-activating alterations, such as CRLF2 rearrangements, JAK-STAT pathway mutations, and ABL-class fusions. Patients with Ph-like ALL typically experience poor outcomes with conventional chemotherapy, underscoring the need for intensified and targeted therapeutic approaches. Methods: This review summarizes current evidence regarding the role of hematopoietic stem cell transplantation (HSCT) in patients with Ph-like ALL. We analyzed retrospective cohort studies, registry data, and ongoing clinical trials, focusing on transplant indications, molecular risk stratification, measurable residual disease (MRD) status, timing of transplant, and post-transplant strategies. Results: Retrospective data suggest that HSCT in first complete remission (CR1) may improve survival in patients with high-risk molecular lesions or MRD positivity at the end of induction. However, the lack of prospective data specific to Ph-like ALL limits definitive conclusions. Post-transplant relapse remains a challenge, and novel strategies, including the use of tyrosine kinase inhibitors or JAK inhibitors as post-HSCT maintenance therapy, are being explored. Emerging immunotherapies, such as chimeric antigen receptor (CAR) T cells, may reshape the therapeutic landscape and potentially alter the indications for transplantation. Conclusions: HSCT remains a crucial therapeutic option for selected patients with Ph-like ALL, particularly those with poor molecular risk features or persistent MRD. However, further prospective studies are needed to evaluate the indication for HSCT in CR1 and the potential integration of transplantation with targeted and immunotherapeutic strategies. Personalized treatment approaches based on genomic profiling and MRD assessment are essential to improve outcomes in this high-risk subset. Full article

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with cure rates exceeding 80% due to advancements in treatment protocols and supportive care. However, in children with Down syndrome (DS), ALL (DS-ALL) presents distinct genomic and clinical challenges. These include mutations in Janus kinase 2 (JAK2), neuroblastoma RAS viral oncogene homolog (NRAS), and E1A-binding protein p300 (EP300), as well as cytokine receptor-like factor 2 (CRLF2) rearrangements—such as P2RY8-CRLF2 fusion—and intrachromosomal amplification of chromosome 21 (iAMP21). These aberrations are associated with poor prognosis and increased risk of relapse. The objective of this study was to present a unique DS-ALL case with five concurrent high-risk genomic lesions and to contextualize its management in light of existing literature, emphasizing minimal residual disease (MRD)-guided therapy and supportive care. Case Report and Results: We present the case of a three-year-old boy with DS and B-cell ALL (B-ALL), in whom multiple high-risk genomic features co-occurred. Despite these adverse prognostic markers, the patient achieved complete remission following an intensive high-dose induction protocol. We also discuss therapeutic strategies that aim at balancing individualized treatment approaches with optimized supportive care to reduce toxicity and minimize relapse risk. Conclusions: This case underlines the importance of comprehensive molecular diagnostics, serial MRD monitoring, and personalized multidisciplinary care in DS-ALL. Full article

B-lineage acute lymphoblastic leukemia (B-ALL) is classified into more than 20 molecular subtypes, and next-generation sequencing has facilitated the identification of these with high sensitivity. Bulk RNA-seq analysis of bone marrow was realized to identify molecular subtypes in Mexican pediatric patients with B-ALL. High hyperdiploidy (27.3%) was the most frequent molecular subtype, followed by DUX4 (13.6%), TCF3::PBX1 (9.1%), ETV6::RUNX1 (9.1%), Ph-like (9.1%), ETV6::RUNX1-like (9.1%), PAX5alt (4.5%), Ph (4.5%), KMT2A (4.5%), and ZNF384 (4.5%), with one patient presenting both the PAX5alt and low hypodiploidy subtypes (4.5%). The genes TYK2, SEMA6A, FLT3, NRAS, SETD2, JAK2, NT5C2, RAG1, and SPATS2L harbor deleterious missense variants across different B-ALL molecular subtypes. The Ph-like subtype exhibited mutations in STAT2, ADGRF1, TCF3, BCR, JAK2, and NRAS with overexpression of the CRLF2 gene. The DUX4 subtype showed mutually exclusive missense variants in the PDGRFA gene. Here, we have demonstrated the importance of using RNA-seq to facilitate the differential diagnosis of B-ALL with successful detection of gene fusions and mutations. This will aid both patient risk stratification and precision medicine. Full article

Cytokine receptor-like factor 3 (CRLF3) has an extended evolutionary history, which has been conserved across metazoan species. It consists of several structural elements, notably including a fibronectin type 3 (FBNIII) domain containing a WSXWS motif that is synonymous with so-called class I cytokine receptors present throughout bilaterial species, and a proposed spl1 and ryanodine receptor (SPRY) domain that represents a widespread protein–protein interaction module. The function of CRLF3 has remained enigmatic, but several recent investigations have revealed critical insights into its biological roles. These studies suggest that CRLF3 principally functions in neural and hematopoietic cells, where it plays critical and diverse roles in the development and function of specific cell populations. Disruption of CRLF3 has also been associated with several human diseases, mainly associated with these same lineages but also including malignancy. The mechanisms by which CRLF3 exerts these diverse effects remain uncertain, although a number of potential options have emerged. Full article

Despite the excellent survival rate, relapse occurs in 20% of children with ALL. Deep analyses of cell signaling pathways allow us to identify new markers and/or targets promising more effective and less toxic therapy. We analyzed 61 diagnostic samples collected from 35 patients with B- and 26 with T-ALL, respectively. The expression of CK2, MYC and ERG genes using Sybr-Green assay and the comparative 2-ΔΔCt method using 20 healthy donors (HDs) was evaluated. We observed a statistically significant difference in CK2 expression in non-HR (p = 0.010) and in HR (p = 0.0003) T-ALL cases compared to HDs. T-ALL patients with PTEN-Exon7 mutation, IKZF1 and CDKN2A deletions showed high CK2 expression. MYC expression was higher in pediatric T-ALL patients than HDs (p = 0.019). Surprisingly, we found MYC expression to be higher in non-HR than in HR T-ALL patients. TLX3 (HOX11L2)-rearranged T-ALLs (27%) in association with CRLF2 overexpression (23%) showed very high MYC expression. In B-ALLs, we detected CK2 expression higher than HDs and MYC overexpression in HR compared to non-HR patients, particularly in MLL-rearranged B-ALLs. We observed a strong difference in ERG expression between pediatric T- and B-ALL cases. In conclusion, we confirmed CK2 as a prognostic marker and a therapeutic target. Full article

Recurrent fusions drive the pathogenesis of many hematological malignancies. Compared to routine cytogenetic/fluorescence in situ hybridization (FISH) studies, the RNA-based next-generation sequencing (NGS) fusion assay enables the identification of both known and novel fusions. In many cases, these recurrent fusions are crucial for diagnosis and are associated with prognosis, relapse prediction, and therapeutic options. The aim of this study is to investigate the application of the RNA-based NGS fusion assay in hematological malignancies. Our study included 3101 cases with available fusion results, and a fusion event was identified in 17.6% of cases. The discordant rate between the RNA-based NGS fusion assay and cytogenetic/FISH studies was 36.3%. Further analysis of discordant cases indicated that, compared to cytogenetic/FISH studies, the RNA-based NGS fusion assay significantly improved the identification of cryptic fusion genes, such as NUP98::NSD1, P2RY8::CRLF2, and KMT2A fusions involving different partners. Additionally, our study identified 24 novel fusions and 16 cases with the simultaneous presence of two fusions. These additional findings from the RNA-based NGS fusion assay resulted in improved risk stratification, disease targeting and monitoring. In conclusion, our study demonstrates the feasibility and utility of an RNA-based NGS fusion assay for patients with hematological malignancies, suggesting that it may be essential for the routine clinical workup of these patients. Full article

Papillary thyroid cancer (PTC) is one of the fastest-growing cancers worldwide, lacking established causal factors or validated early diagnostics. Human endogenous retroviruses (HERVs), comprising 8% of human genomes, have potential as PTC biomarkers due to their comparably high baseline expression in healthy thyroid tissues, indicating homeostatic roles. However, HERV regions are often overlooked in genome-wide association studies because of their highly repetitive nature, low sequence coverage, and decreased sequencing quality. Using targeted whole-genome sequence analysis in conjunction with high sequencing depth to overcome methodological limitations, we identified associations of specific HERV variants with PTC. Analyzing WGS data from 138 patients with PTC generated through The Cancer Genome Atlas project and 2015 control samples from the 1000 Genomes Project, we examined the mutational variation in HERVs within a 20 kb radius of known cancer predisposition genes (CPGs) differentially expressed in PTC. We discovered 15 common and 13 rare germline HERV variants near or within 20 CPGs that distinguish patients with PTC from healthy controls. We identified intragenic–intronic HERV variants within RYR2, LRP1B, FN1, MET, TCRVB, UNC5D, TRPM3, CNTN5, CD70, RYR1, RUNX1, CRLF2, and PCDH1X, and three variants downstream of SERPINA1 and RUNX1T1. Sanger sequencing analyses of 20 thyroid and 5 non-thyroid cancer cell lines confirmed associations with PTC, particularly for MSTA HERV-L variant rs200077102 within the FN1 gene and HERV-L MLT1A LTR variant rs78588384 within the CNTN5 gene. Variant rs78588384, in particular, was shown in our analyses to be located within a POL2 binding site regulating an alternative transcript of CNTN5. In addition, we identified 16 variants that modified the poly(A) region in Alu elements, potentially altering the potential to retrotranspose. In conclusion, this study serves as a proof-of-concept for targeted variant analysis of HERV regions and establishes a basis for further exploration of HERVs in thyroid cancer development. Full article

Feeding difficulties are constantly present in patients with Crisponi/cold-induced sweating syndrome type 1 (CS/CISS1). The aim of our study was to describe their prevalence and evolution from birth to adult age. We performed an observational study at the Department of Life Sciences and Public Health, Rome. Fourteen patients were included in this study (six M; mean age: 18 years; SD: 10.62 years; median age: 15 years; age range: 6–44 years); six were adults (43%). Data on oral motor abilities from birth were collected. Meal duration, presence of swallowing reflex, dysphagia symptoms, difficulty chewing, and drooling management were assessed. At birth, all patients needed enteral feeding. Introduction of solid food was postponed beyond the age of 18 months in 43% of patients. During childhood and adolescence, mealtime was characterized by increased duration (43%) accompanied by fatigue during chewing (43%), food spillage from the nasal cavities (21%), sialorrhea (86%), and poor/reduced appetite (57%). A mature rotatory chewing skill was never achieved. This report expands the phenotype description of CS/CISS1 and also improves the overall management and prevention of complications in this ultra-rare disease. Full article

B-cell lymphoblastic leukemia is a hematologic neoplasm that poses a serious health concern in childhood. Genetic aberrations, such as mutations in the genes IL-7, IL7R, JAK1, JAK2, TLSP, CRLF2, and KTM2A or gene fusions involving BCR::ABL1, ETV6::RUNX1, and PAX5::JAK2, often correlate with the onset of this disease. These aberrations can lead to malfunction of the JAK–STAT signaling pathway, which is implicated in various important biological processes, including those related to immunology. Understanding the mechanisms underlying the malfunction of the JAK–STAT pathway holds potential for research on drugs targeting its components. Available drugs that interfere with the JAK–STAT pathway include fludarabine, ruxolitinib, and fedratinib. Full article

Background: Since cytokine receptor-like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. Methods: The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow-derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno-associated virus (AAV) or AAV containing CRLF1 was determined by morphological, histological, and micro computer tomography (CT) analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were determined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes using real-time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. Results: Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondrogenic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and cardiotrophin-like Cytokine (CLC) stimulated catabolic events via STAT3 activation. Conclusion: A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells. Full article

The landscape of chromosomal aberrations in the tumor cells of the patients with B-ALL is diverse and can influence the outcome of the disease. Molecular karyotyping at the onset of the disease using chromosomal microarray (CMA) is advisable to identify additional molecular factors associated with the prognosis of the disease. Molecular karyotyping data for 36 patients with Ph-negative B-ALL who received therapy according to the ALL-2016 protocol are presented. We analyzed copy number alterations and their prognostic significance for CDKN2A/B, DMRTA, DOCK8, TP53, SMARCA2, PAX5, XPA, FOXE1, HEMGN, USP45, RUNX1, NF1, IGF2BP1, ERG, TMPRSS2, CRLF2, FGFR3, FLNB, IKZF1, RUNX2, ARID1B, CIP2A, PIK3CA, ATM, RB1, BIRC3, MYC, IKZF3, ETV6, ZNF384, PTPRJ, CCL20, PAX3, MTCH2, TCF3, IKZF2, BTG1, BTG2, RAG1, RAG2, ELK3, SH2B3, EP300, MAP2K2, EBI3, MEF2D, MEF2C, CEBPA, and TBLXR1 genes, choosing t(4;11) and t(7;14) as reference events. Of the 36 patients, only 5 (13.8%) had a normal molecular karyotype, and 31 (86.2%) were found to have various molecular karyotype abnormalities—104 deletions, 90 duplications or amplifications, 29 cases of cnLOH and 7 biallelic/homozygous deletions. We found that 11q22-23 duplication involving the BIRC3, ATM and MLL genes was the most adverse prognostic event in the study cohort. Full article