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The initial saccade of experienced readers tends to land halfway between the beginning and the middle of words, at a position originally referred to as the preferred viewing location (PVL). This study investigated whether a simple physical manipulation-namely, increasing the saliency (brightness or color) of the letter located at the PVL-can positively influence saccadic targeting strategies and optimize reading performance. An eye-movement experiment was conducted with 25 adults and 24 s graders performing a lexical decision task. Results showed that this manipulation had no effect on initial landing positions in proficient readers, who already landed most frequently at the PVL, suggesting that PVL saliency is irrelevant once automatized saccade targeting routines are established. In contrast, the manipulation shifted the peak of the landing site distribution toward the PVL for a cluster of readers with immature saccadic strategies (with low reading-level scores and ILPs close to the beginning of words), but only in the brightness condition, and had a more compelling effect in a cluster with oculomotor instability (with flattened and diffuse landing position curves along with oculomotor and visuo-attentional deficits). These findings suggest that guiding the eyes toward the PVL may offer a novel way to improve reading efficiency, particularly for individuals with oculomotor and visuo-attentional difficulties. Show less

The incorporation of selenium into tacrine derivatives has been explored as a novel strategy to enhance therapeutic efficacy while minimizing toxicity in the treatment of neurodegenerative diseases such as Alzheimer's. This study utilized computational and experimental approaches, including Density Functional Theory (DFT), molecular docking, pharmacokinetic profiling, and toxicological predictions, to evaluate the potential of these derivatives. The selenium-modified compounds demonstrated improved electronic properties, such as narrower HOMO-LUMO gaps and optimized electronegativity, resulting in enhanced stability and reactivity. Pharmacokinetic analyses revealed favorable absorption, distribution, and blood-brain barrier penetration, while toxicological assessments indicated reduced hepatotoxicity and skin sensitization risks compared to tacrine. Molecular docking and dynamic simulations highlighted strong and stable interactions of the derivatives with critical enzymes, including acetylcholinesterase (AChE) and beta-secretases (BACE1 and BACE2). Compounds Show less

β-Amyloid (Aβ) is generated from the amyloid precursor protein (APP) through sequential cleavage by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase, where BACE1 acting as the rate-limiting enzyme. Elevated BACE1 levels in the brains of Alzheimer's disease (AD) patients implicate that dysregulated BACE1 expression is crucial to AD pathogenesis. However, the underlying regulatory mechanisms remain unclear. Here, we identified that the G protein subunit β5 gene (Gnb5), a component of the G protein-coupled receptor (GPCR) signaling pathway, is significantly downregulated in both human AD patients and AD mouse models. Conditional knockout of Gnb5 in excitatory neurons resulted in cognitive impairments, whereas adeno-associated virus (AAV)-mediated overexpression of Gnb5 in the hippocampus ameliorated cognitive deficits and reduced Aβ deposition in 5xFAD mice. Mechanistically, we demonstrated that Gnb5 interacts with BACE1, modulating its expression and potentially influencing Aβ generation. We further identify the first tryptophan-aspartate domain (WD domain) of Gnb5 and the Ser81 residue as crucial for this regulation. Expression of this WD domain alone is sufficient to reduce Aβ deposition in 5xFAD mice, whereas a point mutation at Ser81 (S81L) abolishes this effect. Overall, our findings establish Gnb5 as a negative regulator of the BACE1-APP processing axis and unveil mechanistic insights into its role in Aβ-mediated AD pathogenesis. Show less

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that affects the human blood glucose levels. Previous studies have confirmed the role of the gastric inhibitory polypeptide receptor (GIPR) gene in T2DM, obesity, and other human diseases. This study aimed to identify the molecular role of 5 SNPs (rs1800436, rs1800437, rs2302382, rs10423928, and rs34125392) in the GIPR gene in patients with T2DM in the Saudi population. This prospective case-control study enrolled 118 T2DM cases and 118 control participants based on the inclusion and exclusion criteria. Serum was collected from peripheral blood for biochemical tests, while EDTA blood was used for HbA1c and molecular analysis. In this study, T2DM cases were compared with control population to study the baseline characteristics along with molecular data. Genotyping and allelic association analysis showed that rs2302382, (OR-2.757 and OR-2.303) and rs10423928 (OR-3.859 and 2.206) are associated, while genotyping analysis alone showed rs34125392 (OR-1.776) is associated. The co-dominant model (OR-2.226) was associated with obese vs. non-obese participants among T2DM cases (p = 0.039). Females showed a positive association with rs2302382 (OR-3.701; p = 0.003) and rs10423928 (OR-2.343; p = 0.033) SNPs, while males showed a positive association with rs1800437 (OR-1.849; p = 0.040) rs2302382 (OR-2.418; p = 0.016), and rs10423928 (OR-3.641; p = 0.019) SNPs. ANOVA analysis and linkage disequilibrium exhibited a positive association along with gene-gene interaction in GMDR analysis. Linear regression, haplotype analysis and Frutcherman-Reingold, circle, and Kamada-Kawali models showed negative association. Our findings confirm a strong and significant association between rs2302382, rs10423928 and rs34125392 SNPs in T2DM. Additional analyses, such as ANOVA, haplotype analysis, gene-gene interaction, and graphical depiction models revealed genetic interactions among the studied SNPs. Show less

MicroRNA (miRNA), a conservatively evolved single-stranded non-coding RNA, exerts pivotal control over the appearance of target genes and several biological processes. This study conducted a comprehensive screening of candidate microRNAs (miRNAs) associated with Lipoprotein Lipase (LPL) in the large yellow croaker (Larimichthys crocea), utilizing sophisticated bioinformatics techniques across the species' muscular and hepatic tissues. The bioinformatics analysis facilitated the compilation and examination of miRNA datasets specific to these tissues. The investigation culminated in the identification of miR-84a and miR-1231-5p as key miRNAs that modulate fat hydrolysis, highlighting their potential roles in lipid metabolism. Subsequent in-depth analysis further implicated these miRNAs, along with miR-891a, as prospective targets of LPL, suggesting their integral involvement in the regulation of this critical enzyme. Validation of these bioinformatics predictions was conducted through the construction of double luciferase reporters concealing the LPL 3' untranslated region (3'UTR), substantiating that miR-84a and miR-1231-5p can modulate LPL expression via the LPL 3'UTR. Conversely, miR-891a was not concerned with this regulatory mechanism. Site-directed mutagenesis experiments elucidated the specificity of the interaction sequences. Quantitative PCR assays suggested that miR-84a and miR-1231-5p might influence LPL expression during the starvation phase, intimating the regulatory role of miRNA in fatty acid metabolism within hepatic and muscular tissue under starvation. These findings offer a nuanced understanding of LPL's molecular functionality under stress conditions in fish, emphasizing the regulatory dynamics of miRNA during metabolic stress. Show less

An association has been observed between alcohol and cheese intake and the onset of inflammatory bowel disease (IBD), necessitating further exploration from a genetic structural perspective. The present analysis was focused on the intake of alcohol and cheese in conjunction with IBD genome-wide association study (GWAS) data, with the objective of exploring genetic correlations and identifying common loci. Initially, overall genetic correlations were assessed employing two methodologies: linkage disequilibrium score regression (LDSC) and genetic covariance analyzer (GNOVA). Subsequently, local correlations were examined through the SUPERGNOVA method. A genetic overlap analysis between various traits was then conducted based on the statistical theory of conditional/conjunctional false discovery rate (cond/conjFDR). Ultimately, shared loci between the two traits were identified via conjFDR analysis and multi-trait analysis of GWAS (MTAG). Substantial overall correlations were noted at the genome-wide level between alcohol and cheese intake and both IBD and Crohn's disease (CD), whereas the association with ulcerative colitis (UC) was of lesser significance. In the local genetic analysis, chromosome 16 emerged as a key region implicated in the relationship between alcohol and cheese intake and IBD (including both CD and UC). The conjFDR analysis confirmed the genetic overlap between the two diseases. Furthermore, both conjFDR and MTAG analyses identified multiple shared genetic loci, with nine genes ( The present study provides genetic evidence supporting the comorbidity of alcohol and cheese intake with IBD, offering novel insights into potential strategies for the prevention and treatment of IBD through the modulation of alcohol and cheese consumption. Show less

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect in neonates. While there is compelling evidence of genetic contribution to the etiology of TOF, the contribution of noncoding variants to the development of the defect remains unexplored. Potentially damaging noncoding de novo variants (NC DNVs) were detected from 141 Chinese nonsyndromic TOF trios (CHN-TOF) and compared with those detected in the Pediatric Cardiac Genomics Consortium (PCGC). Bioinformatic analyses on noncoding and previously detected coding DNVs were performed to identify developmental pathways affected in TOF. Chinese but not PCGC-TOF patients showed a notably increased burden of putative damaging NC DNVs (n = 249). In Chinese, NC and coding DNVs were predominantly associated with cardiomyocyte differentiation and with chamber/valve/aorta development, respectively, producing a combined enrichment in NOTCH signaling (p = 1.1 × 10 Show less

Infantile epileptic spasms syndrome is a severe epilepsy of infancy that is often associated with focal malformations of cortical development. This study aimed to elucidate the genetic landscape and histopathologic aetiologies of infantile epileptic spasms syndrome due to focal malformations of cortical development requiring surgery. Fifty-nine children with a history of infantile epileptic spasms syndrome and focal malformations of cortical development on MRI were studied. Genetic testing of resected brain tissue was performed by high-coverage targeted panel sequencing or exome sequencing. Histopathology and MRI were reviewed, and integrated clinico-pathological diagnoses were established. A genetic diagnosis was achieved in 47 children (80% of cohort). Germline pathogenic variants were identified in 27/59 (46%) children, in Show less

Many factors involved in heparan sulfate (HS) biosynthesis and metabolism have been reported to play roles in viral infection. However, the detailed mechanisms are still not fully understood. In this study, we report that exostosin glycosyltransferase 1 (EXT1), the HS polymerase, is a critical regulatory factor for Zika virus (ZIKV) infection. Knocking out EXT1 dramatically restricts ZIKV infection, which is not due to the inhibition of virus entry resulting from HS deficiency, but mediated by the downregulation of autophagy. Induction of autophagy promotes ZIKV infection, and attenuated autophagy is found in distinct EXT1 knockout (EXT1-KO) cell lines. Induction of autophagy by rapamycin can relieve the ZIKV production defect in EXT1-KO cells. While over-expressing EXT1 results in the reduction of ZIKV production by targeting the viral envelope (E) protein and non-structural protein NS3 in a proteasome-dependent degradation manner. The different roles of EXT1 in ZIKV infection are further confirmed by the data that knocking down EXT1 at the early stage of ZIKV infection represses viral infection, whereas the increase of ZIKV infection is observed when knocking down EXT1 at the late stage of viral infection. This study discovers previously unrecognized intricate roles of EXT1 in ZIKV infection. Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated Show less

Lymphoplasmacytic lymphoma (LPL) is a B-cell lymphoproliferative disorder typically involving the bone marrow with infiltration by small lymphocytes and plasma cells. Studies have identified MYD88 L265P mutation as a diagnostic marker to distinguish LPL from other small B-cell lymphomas. Detection rates for this mutation have varied depending on the analytic methodology, with previous data suggesting that routine next-generation sequencing (NGS) does not demonstrate the required sensitivity to reliably detect MYD88 L265P. NGS has become part of routine clinical testing because it allows detection of variants across multiple genes. To study the utility of NGS in the detection of MYD88 L265P, we performed droplet digital PCR (ddPCR) and routine NGS on a cohort of 34 cases of lymphoid neoplasms (22 LPL, 4 CLL, 1 MCL, 1 MGUS, 2 plasma cell myeloma, and 4 negative bone marrow cases). We utilized manual review and BAMtools to assess MYD88 L265P in NGS cases. Limit of detection for ddPCR was determined to be 0.4 % variant allele frequency (VAF) with 10 ng DNA input. MYD88 L265P VAF detection by NGS and ddPCR was comparable down to 0.5 % VAF (R Show less

The fibroblast growth factor receptor family members, FGFR1-4, are frequently overexpressed in various solid tumors, including breast cancer and sarcomas. This overexpression highlights the potential of the family of FGFRs as promising targets for cancer therapy. However, conventional FGFR kinase inhibitors often encounter challenges such as limited efficacy or drug resistance. In this study, we pursue an alternative strategy by designing a conjugate of the FGFR ligand FGF1 with the radioisotope Show less

Aging is the greatest risk factor for Alzheimer's disease (AD), but the mechanisms connecting the two remain unclear. The mammalian target of rapamycin (mTOR) pathway, particularly its downstream effector S6 kinase 1 (S6K1), has emerged as a key regulator of aging and neurodegeneration. S6K1 controls translation, autophagy, and mitochondrial function-processes disrupted in both aging and AD. This review examines how S6K1 influences mitochondrial metabolism, autophagy, and metabolic dysfunction in aging. We also discuss its role in the nervous system, including effects on synaptic plasticity, memory, glial activation, and neuroinflammation. In AD, S6K1 contributes to amyloid and tau pathology by regulating translation of BACE1 and tau, and its hyperactivation is linked to synaptic deficits and cognitive decline. We further explore therapeutic strategies targeting S6K1, which have shown benefits for lifespan extension and neuroprotection in preclinical models. Finally, we consider the emerging link between S6K1 and necroptosis, a form of programmed cell death implicated in AD-related neuronal loss. Together, these findings highlight S6K1 as a promising target for interventions aimed at slowing aging and mitigating AD pathogenesis. Show less

Light therapy, using red and near-infrared (NIR) irradiation, is currently applied for the treatment of various neurodegenerative diseases, such as Alzheimer's disease (AD). Transcranial photobiomodulation therapy (tPBMT) can alleviate neurodegeneration, neuronal loss, and β-amyloid peptide plaque burden. Alternatively, potential early inhibition of oxidative stress, neuroinflammation, apoptosis, and amyloidogenic cellular pathways may constrain pathological changes with aging. In this research, we conduct an 808-nm tPBMT with a 30-day course of daily 1-hour sessions for mice and assess its influence on molecular mechanisms related to the potential onset of neurodegeneration. To comprehensively identify molecular mechanisms of tPBMT on the brain cells, the next-generation whole RNA sequencing of over 30,000 mRNA of the cortex and hippocampus of BALB/c mice is performed. After tPBMT, transcriptional alterations are found in 1,005 genes in the hippocampus and 1,482 genes in the cortex. Pathway-gene enrichment network analysis identifies genes associated with about 20 pathways of neurodegeneration, and a disease-gene network is constructed. Particularly, tPBMT alters the transcription and expression of the essential genes associated with oxidative stress (NF-κBIα, JUN, JUND, and PKC genes), inflammation (DOCK4/6, IL-1RAPL1, and TNFαIP6), and apoptosis (CASP3, TNFαIP6, AKT3, CDKN1A, CYP51, RASA2, and RESTAT). Additionally, 808-nm light modulates the main risk genes for AD (BACE1, BACE2, PSEN2, APH1B, GATA2, YY2, RELA, STAT3, JUN, JUND, ARNTL, CREB3L1, CELF2, E2F4, ELK3, and CEBPD), involved in APP processing supporting AD development. Moreover, the APP concentration is reduced after tPBMT. Hence, PBMT may help inhibit the development of different neurodegeneration types and maintain normal brain conditions. Show less

Osteosarcoma (OS) is an invasive and lethal malignancy showing a low 5 year survival rate, underscoring the need for identifying new therapeutic targets and their inhibitors to enhance prevention and treatment strategies. In this study, in vitro experiments including CCK-8 assay, anchorage-independent growth assays, and plate cloning assays were used to detect the anti-proliferation ability of natural compound tangeretin towards OS cells. An integrated approach was performed including WGCNA and network pharmacology to identify the key genes of tangeretin for the treatment of OS. Multigene diagnostic model, reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis along with molecular docking analysis were further conducted to validate the reliability of the targets obtained by bioinformatics methods. Single-cell and gene enrichment analyses were chosen to explore the mechanism of tangeretin in OS. Hub genes identified by the bioinformatics strategy included ABCC1, AKR1C3, BACE1, and CA12. RT-qPCR validation and molecular docking analysis confirmed that ABCC1 and BACE1 were the most likely potential targets. A multigene diagnostic model for OS demonstrated moderate accuracy of the hub genes. Single-cell sequencing results indicated that these two hub targets were closely related to OS and provided more potential mechanisms for targeting OS. Our research highlights the therapeutic potential of the natural compound tangeretin and its antineoplastic mechanisms in OS. It offers new insights into the molecular mechanisms of tangeretin, paving the way for the development of effective OS treatments. Show less

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), and neuroinflammation, leading to progressive cognitive decline. Research has increasingly emphasized the importance of a nutritious diet rich in phytochemicals that promotes brain health and potentially mitigates the risk or progression of neurodegenerative diseases, such as AD. Resveratrol (RSV), a natural polyphenol with known anti-inflammatory, antioxidant, antiapoptotic, and neuroprotective properties, has thus garnered significant attention. This review examines the potential of RSV in modulating AD pathophysiology, drawing from preclinical and clinical investigations. Preclinical studies demonstrate RSV reduces Aβ accumulation by modulating BACE1, enhancing neprilysin activity, inhibiting aggregation, and promoting clearance. RSV also attenuates Tau phosphorylation in animal models, suggesting its potential to target both hallmark AD pathologies. Furthermore, RSV exhibits anti-inflammatory properties by reducing microglial activation and proinflammatory markers. Clinical trials indicate that RSV may attenuate declines in CSF Aβ40 levels and reduce CSF MMP9 levels, indicating potential benefits in Aβ pathology and neuroinflammation in select studies. However, its impact on tau remains inconclusive. Some clinical studies have shown trends toward cognitive benefits, particularly in functional measures such as ADCS-ADL; however, these findings are inconsistent across different cognitive assessments (e.g., MMSE and ADAS-cog). Due to limited and inconsistent clinical evidence, RSV's therapeutic efficacy for AD or mild cognitive impairment (MCI) remains unproven, necessitating larger, well-powered clinical trials in diverse populations to evaluate its potential benefits. RSV holds promise as a potential therapeutic agent. Still, challenges such as poor bioavailability and rapid metabolism require optimized delivery systems and further research to establish clinical efficacy and optimal dosing. Show less

Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD. Show less

Cerebral amyloid angiopathy (CAA) is a common age-related small vessel disease characterized by amyloid-beta (Aβ) accumulation in cortical and leptomeningeal blood vessel walls. Reduced Aβ clearance in the vasculature elevates the risk of CAA, while increasing evidence indicates that enhanced Aβ production in neurons also contributes. The impact of Aβ on the diverse cell types of the neurovascular unit (NVU)-including endothelial cells (ECs), pericytes, neurons, vascular smooth muscle cells (VSMCs), and astrocytes-remains unclear. This narrative review proposes that Aβ accumulation in NVUs during CAA drives a transcriptional response that reduces Aβ clearance while activating a neuron-specific post- transcriptional response that enhances Aβ production. Specifically, Aβ in NVUs was found to initiate a transcriptional cascade that destabilizes endothelial cells, increases blood-brain barrier permeability, and damages pericytes, ultimately inducing inflammatory and dysfunctional changes in VSMCs. These changes cause mitochondrial dysfunction and TGFβ deregulation in neurons, activating profibrotic mechanisms. Post-transcriptional regulation by microRNA networks in neurons affects Aβ processing by controlling the balance between amyloidogenic and non-amyloidogenic pathways through BACE1 and ADAM10 expression respectively. This review improves our understanding of Aβ accumulation in neurovascular units in CAA, potentially leading to better diagnostics, early biomarkers, and tools for prognosis and treatment. Show less

Although primarily secreted by the liver, Fibroblast Growth Factor 21 (FGF21) is also expressed in the pancreas, where its function remains unclear. This study aims to elucidate the role of the glucagon-FGF21 interaction in the metabolic benefits of SGLT2 inhibition (SGLT2i) and hypothesizes it is key to enhancing glucose and lipid metabolism in individuals with glucose intolerance or type 2 diabetes (T2D). FGF21, FGF1R, and β-klotho expression in human pancreas was analysed by RNAscope, qPCR and immunofluorescent techniques. Glucose-stimulated insulin secretion (GSIS) assay was used to investigate the effects of recombinant FGF21 (rFGF21) on islets from donors with glucose intolerance or T2D. To explore the role of the glucagon-FGF21 axis in the benefits of SGLT2i, we used WT and Sglt2 knockout (KO) mice fed a chow diet (CD) or a high-fat diet (HFD) and chronically treated with vehicle or dapagliflozin. Chronic rFGF21 treatment enhanced GSIS in islets from donors with glucose intolerance, with increased FGFR1 expression, suggesting FGF21's greater efficacy in the early stages of disease. In diet-induced insulin-resistant mice, dapagliflozin reduced postprandial glycaemia and elevated plasma glucagon and FGF21 levels. Sglt2 KO mice on a CD showed increased fasting plasma glucagon without changes in FGF21. In diet-induced insulin-resistant Sglt2 KO mice, elevated glucagon and FGF21 levels paralleled chronic dapagliflozin treatment, indicating similar metabolic adaptations in both models. Our findings indicate FGF21 as a crucial mediator in liver-pancreas crosstalk, improving lipid and glucose metabolism, enhancing pancreatic function, and potentiating the therapeutic efficacy of SGLT2i, thereby representing a target for prediabetes treatment. Show less

Neurological disorders represent a significant burden on human health, particularly as global life expectancy continues to rise. Among these conditions, Alzheimer's disease is notably prevalent. Of greater concern, if left untreated or unaddressed, Alzheimer's disease can progress to dementia, leading to severe cognitive decline and a substantial reduction in quality of life. In this study, 15 novel benzofuran-azacyclic hybrids were designed and synthesized. The final compounds were evaluated for their inhibitory potency on AChE and BACE-1 enzymes, and in silico studies were performed to clarify their binding modes. Finally, structure-activity relationships (SARs) were proposed for future studies. The results indicated that the most promising compound is Show less

Comprehensive molecular assessment of cancers could open up new horizons for novel therapies. Fibroblast growth factor receptor 1 (FGFR1) gene amplification has been previously demonstrated in non-small cell lung cancer (NSCLC) patients. The current study aimed to evaluate the prevalence of FGFR1 gene amplification and its association with clinical and demographic data in a group of NSCLC patients. The present study was performed on eighty-eight NSCLC patients who underwent bronchoscopy or surgery in Qaem Hospital, Mashhad, between 2010 and 2016. FGFR1 gene amplification was detected using real-time PCR assay on DNA extracted from paraffin-embedded tissue blocks of patients. Also, patients' clinical and demographic data, such as their survival, were evaluated. Statistical analysis was carried out using SPSS software. Seventeen (19.31%) out of eighty-eight patients with NSCLC presented FGFR1 gene amplification. Besides, we found a significant association between FGFR1 amplification and cigarette smoking (p-value= 0.01; OR: 4.08). Although cases with squamous cell carcinoma (SCC) showed a higher prevalence of FGFR1 amplification compared to adenocarcinoma patients, the difference was not statistically significant (p-value> 0.05). In addition, our findings showed no relationship between FGFR1 gene amplification and other clinical and demographic factors, including age, sex, grade, tumor operability, and survival. The frequency of FGFR1 amplification is estimated at 20% in the current study (26% in SCC versus 11% in adenocarcinoma; p-value= 0.07). Moreover, we found a direct association between FGFR1 amplification and cigarette smoking. However, no significant relationship with survival or other factors was observed. Show less

Pheochromocytomas and paragangliomas (PPGLs) exhibit the highest degree of heritability among all human tumors, yet the genetics of urinary bladder paragangliomas (UBPGLs) remains poorly understood. The present study aims to examine the characteristics of a cohort of Chinese patients with UBPGLs, focusing particularly on genetics. The study included 70 Chinese patients with UBPGLs from 15 centers in China, 240 patients with non-head and neck PGLs (non-HNPGLs) outside the urine bladder, and 16 Caucasian patients with UBPGLs. Tumor DNA samples were sequenced by next generation sequencing. All identified pathogenic variants (PVs) were confirmed by Sanger sequencing. Among the 70 Chinese patients, PVs were identified in 38 cases: 23 in cluster 1 A (13 SDHB, 1 SDHD, 1 SDHA, 4 IDH1, 2 SLC25A11, and 2 FH), 4 in cluster 1B (3 EPAS1 and 1 EGLN1), and 11 in cluster 2 genes (7 HRAS, 1 FGFR1, 2 NF1, and 1 H3F3A). Compared with other non-HNPGLs, UBPGLs had more PVs in cluster 1 A genes (32.9% vs. 14.2%, p < 0.001), but fewer in cluster 1B (5.7% vs. 19.2%, p = 0.002) and cluster 2 genes (15.7% vs. 42.5%, p < 0.001). PVs in SDHB (18.6%) was the most common in Chinese patients with UBPGLs, followed by HRAS (10.0%). No PVs was found in 45.7% of all UBPGLs. PVs in HRAS, SLC25A11, EPAS1, and FH were also identified in Caucasians with UBPGLs. Chinese patients with UBPGLs have a diverse genetic profile. PVs in cluster 1 A genes underlie nearly 1/3 of patients, highlighting the importance of genetic testing. Diverse germline and somatic PVs are also present in Caucasian patients with UBPGLs. Show less

AXIN1 and AXIN2 are homologous proteins that inhibit the Wnt/β-catenin signaling pathway, which is frequently hyperactive in colorectal cancer. Stabilization of AXIN1 and AXIN2 by inhibiting their degradation through tankyrase (TNKS) allows the attenuation of Wnt signaling in cancer, attracting interest for potential targeted therapy. Here, we found that knockout or knockdown of AXIN2 in colorectal cancer cells increased the protein stability of AXIN1. The increase in AXIN1 overcompensated for the loss of AXIN2 with respect to protein levels; however, functionally it did not because loss of AXIN2 activated the pathway. Moreover, AXIN2 was highly essential in the context of TNKS inhibition because TNKS-targeting small-molecule inhibitors completely failed to inhibit Wnt signaling and to stabilize AXIN1 in AXIN2 knockout cells. The increased AXIN1 protein stability and the impaired stabilization by TNKS inhibitors indicated disrupted TNKS-AXIN1 regulation in AXIN2 knockout cells. Concordantly, mechanistic studies revealed that co-expression of AXIN2 recruited TNKS to AXIN1 and stimulated TNKS-mediated degradation of transiently expressed AXIN1 wild-type and AXIN1 mutants with impaired TNKS binding. Taken together, our data suggest that AXIN2 promotes degradation of AXIN1 through TNKS in colorectal cancer cells by directly linking the two proteins, and these findings may be relevant for TNKS inhibition-based colorectal cancer therapies. Show less

A 73-year-old woman was diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) with general fatigue and severe neutropenia. Although rituximab monotherapy was initiated, the neutrophil counts decreased within one week after rituximab administration. Subsequently, a combination of rituximab and bendamustine was initiated, and then her neutrophil counts became consistently within the normal range. The LPL/WM kept complete remission for two years. LPL/WM complicated with severe autoimmune neutropenia is rare. Rituximab and bendamustine brought strong lymphocyte depletion, leading to amelioration of autoimmune neutropenia. In this case, rituximab and bendamustine may have been active in patients with LPL/WM complicated with autoimmune disorders. Show less

Globally, colorectal cancer (CRC) is the third most common type of cancer, and its treatment frequently includes the utilization of drugs based on antibodies and small molecules. The development of CRC has been linked to various signaling pathways, with the Wnt/β-catenin pathway identified as a key target for intervention. We have explored the impact of imidazopyridine-tethered chalcone-C (CHL-C) in CRC models. To determine the influence of CHL-C on apoptosis and autophagy, Western blot analysis, annexin V assay, cell cycle analysis, acridine orange staining, and immunocytochemistry were performed. Next, the activation of the Wnt/β-catenin signaling pathway and the anti-cancer effects of CHL-C in vivo were examined in an orthotopic HCT-116 mouse model. We describe the synthesis and biological assessment of the CHL series as inhibitors of the viability of HCT-116, SW480, HT-29, HCT-15, and SNU-C2A CRC cell lines. Further biological evaluations showed that CHL-C induced apoptosis and autophagy in down-regulated β-catenin, Wnt3a, FZD-1, Axin-1, and p-GSK-3β (Ser9), and up-regulated p-GSK3β (Tyr216) and β-TrCP. In-depth analysis using structure-based bioinformatics showed that CHL-C strongly binds to β-catenin, with a binding affinity comparable to that of ICG-001, a well-known β-catenin inhibitor. Additionally, our in vivo research showed that CHL-C markedly inhibited tumor growth and triggered the activation of both apoptosis and autophagy in tumor tissues. CHL-C is capable of inducing apoptosis and autophagy by influencing the Wnt/β-catenin signaling pathway. Show less

Increasing evidence underscores the driving role of coding and non-coding variants in cancer development. Analyzing gene sets in biological processes offers deeper insights into the molecular mechanisms of carcinogenesis. Here, we developed geMER to identify candidate driver genes genome-wide by detecting mutation enrichment regions within coding and non-coding elements. We subsequently designed a pipeline to identify a core driver gene set (CDGS) that broadly promotes carcinogenesis across multiple cancers. CDGS comprising 25 genes for 25 cancers displayed instability in DNA aberrations. Variants within the TTN enrichment region may influence the folding of the I-set domain by altering local polarity or side-chain chemistry properties of amino acids, potentially disrupting its antigen-binding capacity in LUAD. Multi-omics analysis revealed that APOB emerged as a candidate oncogene in LIHC, whose genetic alterations within the enrichment region may activate key TFs, upregulate DNA methylation levels, modulate critical histone modifications, and enhance transcriptional activity in the HepG2 and A549 cell lines compared to Panc1. Additionally, CDGS mutation status was an independent prognostic factor for the pan-cancer cohort. High-risk patients tended to develop an immunosuppressive microenvironment and demonstrated a higher likelihood of responding to ICI therapy. Finally, we provided a user-friendly web interface to explore candidate driver genes using geMER ( http://bio-bigdata.hrbmu.edu.cn/geMER/ ). Show less

Asthma is a common chronic respiratory disease in children, the incidence rate of which has increased in recent years. Wilms tumour 1-associated protein (WTAP) is an N6-methyladenosine (m6A) methyltransferase. The purpose of this study was to explore the specific mechanism of WTAP in asthma progression, and clarify the intricate interplay between m6A modifications, WTAP, AXIN1, and their collective impact on airway smooth muscle cells (ASMCs) proliferation in asthma. Platelet-derived growth factor-BB (PDGF-BB)-treated ASMCs were used to establish an asthma model in vitro. The cell phenotype was tested using CCK-8, transwell, and wound healing assays. The expression of the Wnt signalling pathway was detected by western blotting. In addition, the relationship between WTAP/YTDHF2 and AXIN1 was assessed by a double luciferase reporter assay. Actinomycin D treatment and RT‒qPCR assays were performed to determine the mRNA stability of AXIN1. We found that WTAP was significantly increased in PDGF-BB-treated ASMCs. Knockdown of WTAP inhibited the excessive cell viability and migration of ASMCs induced by PDGF-BB. Furthermore, WTAP knockdown increased AXIN1 levels and inhibited the Wnt signalling pathway. Furthermore, WTAP knockdown decreased the m6A levels and enhanced the mRNA stability of AXIN1. WTAP overexpression showed the opposite effect. In addition, YTHDF2 was demonstrated to be the reader that recognizes the WTAP-mediated m6A modification of AXIN1. YTHDF2 knockdown enhanced the mRNA stability of AXIN1 and reversed the effect of WTAP overexpression on PDGF-BB-treated ASMCs. WTAP knockdown inhibited the excessive cell viability and migration of ASMCs by enhancing the m6A levels of AXIN1, which was further recognized by YTHDF2. The upregulation of AXIN1 mediated by the WTAP/YTHDF2 axis further inhibited the Wnt signalling pathway. Our study provides a new method for the treatment of asthma. This work not only deepens our understanding of the molecular underpinnings of asthma but also identifies potential therapeutic targets for the development of novel treatments aimed at inhibiting ASMC proliferation and alleviating asthma symptoms. Show less

The presence of low-grade inflammation has been reported in people with type 2 diabetes and related to the development of (macro)vascular complications. Whether systemic inflammation is present in type 1 diabetes and linked to long-term complications remains unknown. We used a targeted proteomics approach to compare inflammation in people with type 1 diabetes and type 2 diabetes with control subjects and linked these proteins to diabetes related characteristics and complications. We included 233 participants with type 1 diabetes, 387 participants with type 2 diabetes and 150 healthy controls. Plasma was collected and used to determine high sensitive C-reactive proteins (hs-CRP) and an additional 92 inflammatory proteins using the Olink proteomics platform. Compared to healthy controls, 41 circulating inflammatory proteins were higher in type 1 diabetes (FDR < 0.05) and 64 inflammatory proteins in type 2 diabetes (FDR < 0.05) (including CXCL5, IL-15RA, MCP-4 and AXIN1 for both groups). HbA Both type 1 diabetes and type 2 diabetes are associated with increased circulating inflammatory protein concentrations, but the increase is more pronounced in type 2 diabetes. These results suggest both differences in drivers of inflammation between type 1 diabetes and type 2 diabetes as well as potential similarities in pathways involved in the development of diabetes-associated complications. Show less