Search Results (592)

Precision medicine approaches rely on accurate somatic variant detection, where the DNA input into genomic workflows is a key variable. However, there are no gold standard methods for total DNA quantification. In this study, a pentaplex reference gene panel using digital PCR (dPCR) was developed as a candidate reference method. The multiplex approach was compared between two assay chemistries, applied to healthy donor genomic DNA and plasma cell-free DNA (cfDNA) to measure the ERBB2 (HER2) copy number variation in cancer cell line DNA. The multiplex approach demonstrated robust performance with the two assay chemistries, demonstrating comparable results and a wide dynamic range. Ratios of reference genes were close to the expected 1:1 in healthy samples; however, some small but significant differences (<1.2-fold) were observed in one of the five targets. Expanded relative measurement uncertainty was 12.1–19.8% for healthy gDNA and 9.2–25.2% for cfDNA. The multiplex approach afforded lower measurement uncertainty compared to the use of a single reference for total DNA quantification, which is an advantage for its potential use as a calibration method. It avoided potential biases in the application to CNV quantification of cancer samples, where cancer genome instability may be prominent. Full article

Plantsterol esters (PSEs) exert beneficial effects on animal product quality, indicating their potential as a nutritional intervention strategy. This study investigated the effects of dietary PSE supplementation on lactation performance and lipid metabolism in Tarim Bactrian camels (Camelus bactrianus) to establish a scientific basis for its application in their husbandry. Thirty-two mid-lactation female camels were randomly allocated to four groups (n = 8): CON (basal diet), L (200 mg/kg PSE), M (400 mg/kg PSE), and H (800 mg/kg PSE). Since lactation performance is closely linked to metabolic status, biochemical and lipidomic analyses were conducted on serum and milk samples. Analysis revealed that the H group showed significantly increased milk yield, lactose yield, and milk fat yield compared to other groups. Serum cholesterol levels decreased progressively with higher PSE supplementation, while serum urea levels rose dose-dependently. Blood Glu was lower in the L group but higher in the H group relative to CON. Lipidomic profiling identified 644 and 257 differential metabolites in milk and serum, respectively. Milk metabolites were enriched in the EGFR inhibitor resistance, MAPK, and ErbB signaling pathways; serum metabolites were linked to glycerophospholipid, arachidonic acid, and linoleic acid metabolism. These findings indicate that PSE-modulated metabolites in serum and milk significantly influence lactation performance and glucolipid metabolism in Tarim Bactrian camels, supporting further investigation into precision nutrition strategies. Full article

Precision oncology is witnessing an increasing number of molecular targets fueled by the continuous improvement of cancer genomics and drug development. Tumor genomic profiling is nowadays (August 2025) part of routine cancer patient care, guiding therapeutic decisions day by day. Nevertheless, implementing and distilling the increasing number of potential gene targets and possible precision drugs into therapeutically relevant actions is a challenge. The availability of prescreening programs for clinical trials has expanded the description of the genomic landscape of gastrointestinal tumors. The selection of the genomic test to use in each clinical situation, the correct interpretation of the results, and ensuring clinically meaningful implications in the context of diverse geographical drug accessibility, economic cost, and access to clinical trials are daily challenges of personalized medicine. In this context, well-established negative predictive biomarkers, such as extended RAS extended mutations for anti-EGFR therapy in colorectal cancer, and positive predictive biomarkers, such as MSI status, BRAF p.V600E hotspot mutation, ERBB2 amplification, or even NTRK1, NTRK2, NTRK3, RET, and NRG1 fusions across gastrointestinal cancers, are mandatory to provide tailored clinical care, improve patient selection for treatment and clinical trials, maximize therapeutic benefit, and minimize unnecessary toxicity. In this review, we provide an updated overview of actionable genomic alterations in GI cancers and discuss their implications for clinical decision making. Full article

The adult heart has a limited ability to regenerate, which is partly due to the structural and metabolic specialization that cardiomyocytes (CMs) acquire during postnatal maturation. In this review, we explore how cytoskeletal remodeling, metabolic reprogramming, and interactions with the extracellular matrix (ECM) regulate CM maturation, proliferation, and the potential for regeneration. We describe how the assembly of microtubules, actin filaments, and sarcomeric structures is essential for developing contractile function, but also creates structural barriers that prevent cell division. Recent studies show that disassembling these cytoskeletal components, along with activating signaling pathways such as Hippo-YAP, Wnt, and NRG1/ErbB4, can promote CM dedifferentiation and re-entry into the cell cycle. Metabolic shifts also play a critical role. A return from oxidative phosphorylation to glycolysis also leads to CM dedifferentiation and proliferation. In addition, changes in ECM composition and mechanical signaling affect cytoskeletal dynamics and regenerative capacity. Understanding how these structural, metabolic, and signaling networks work together opens the door to new approaches for restoring heart function after injury. Full article

Chronic inflammation conducts an irreplaceable role in the aging process. More importantly, the impact is particularly significant in scenarios involving cardiac arrest and cardiopulmonary resuscitation (CA/CPR), where elderly individuals are inclined to suffer from more severe inflammatory injuries when compared to younger counterparts. Network pharmacology demonstrated a tight correlation between epicatechin (EC), aging, and the NRG1-NF-κB signaling pathway. With an aim to investigate whether EC suppressing inflammatory aging and alleviating post-CA/CPR brain injury is associated with the inhibition of the NRG1-NF-κB pathway, we established a model of naturally aged 21-month-old rats subjected to CA/CPR. A network pharmacology method was employed to pinpoint possible pathways that connect EC to neuroinflammation associated with aging. Sixty rats were randomly divided into three groups for feeding: a control group (pure water) and EC groups (EC was administered by gavage at doses of 1 mg/kg and 2 mg/kg respectively from the 12th month). Those groups underwent a CA/CPR procedure. At 24-h post-resuscitation, neurological scores, cortical pathology staining and assessments of neural injury were conducted. Expression levels of NRG1-NF-κB pathway-relevant inflammatory factors and proteins underwent systematic investigation by carrying out ELISA, RT-PCR, and Western blotting. In comparison with the 21-month-old groups treated with water, the 21-month-old groups treated with EC at 1 mg/kg and 2 mg/kg demonstrated decreased β-galactosidase staining, aging-correlated proteins and pro-inflammatory factors and NF-κB pathway-relevant proteins, as well as reinforced NRG1-ErbB4 expression. EC lessened inflammatory aging and mitigates post-CA/CPR brain injury in aged rats, associated with the inhibition of the NRG1-NF-κB pathway. Full article

Breast cancer (BC) is associated with multiple molecular factors such as overexpression of the beta-2 adrenergic receptor (ADRB2) and the overproduction of its agonists (norepinephrine and epinephrine). The role of adrenergic signaling in BC highlights the therapeutic potential of non-selective beta-blockers (nsBBs) as inhibitors of well-established protumor signaling pathways related to ADRB2 and their possible affinity for other important protumoral receptors. Our aim was to identify how nsBBs currently prescribed may also interact with receptors other than ADRB2, which are related to the pathophysiology of BC, using bioinformatic intracellular pathway analysis (BIPA). Subsequently, the affinity of nsBBs for both ADRB2 and the targets identified by BIPA was evaluated. We found that, beyond ADRB2, both receptor tyrosine kinase 2 (ERBB2) and neuropeptide Y receptor (NPYR) are promising targets for nsBBs in the adjuvant treatment of BC, according to BIPA. Docking studies showed that the nsBB with the highest binding affinity (ΔG) was carvedilol (−10.5 kcal/mol), followed by propranolol (−8.5 kcal/mol). These in silico findings suggest previously unrecognized pharmacological mechanisms for nsBBs in the possible treatment for BC. Notably, differences in receptor affinity were observed among the nsBBs, with carvedilol exhibiting the strongest binding affinity values on ADRB2, ERBB2, and NPYR as biological targets against BC cells. These promising results require future experimental validation. Full article

Background: Blood-based comprehensive genomic profiling (CGP), a form of liquid biopsy, is often used for biliary tract cancer (BTC) when tissue-based CGP (tissue CGP) is unavailable, despite lower detection rates. This study explored factors linked to detecting actionable genomic alterations to optimize its use. Methods: We retrospectively analyzed BTC cases in Japan’s C-CAT (June 2019–January 2025), restricting panel comparisons to FoundationOne^® CDx (F1; n = 5019) and FoundationOne^® Liquid CDx (F1L; n = 1550). Missing covariates were handled by multiple imputations (m = 20). Between-panel balance used 1:1 propensity-score matching (caliper 0.2). Outcomes were modeled with logistic regression. Targets included MSI-H, TMB-H, FGFR2/RET/NTRK fusions, BRAF V600E, KRAS G12C, IDH1 mutations, and ERBB2 amplification. An exploratory analysis stratified results by the number of prespecified enrichment factors (0–4). Liquid biopsy was performed using plasma-based comprehensive genomic profiling assays (FoundationOne^® Liquid). Results: Missingness was low; after matching (n = 1549 per group) covariates were well balanced (all|SMD|≤0.05). Detection of any actionable alteration was lower with F1L than F1 (16.8% vs. 24.8%; OR 0.61, 95% CI 0.49–0.75; p < 0.001). F1L also had lower TMB-H (OR 0.62, 0.43–0.90; p = 0.01) and ERBB2 amplification (OR 0.42, 0.31–0.57; p < 0.001), with no significant differences for MSI-H, IDH1, KRAS G12C, or BRAF V600E. Within F1L, non-perihilar location (OR 2.05), liver (1.90), lymph-node (1.41), and lung metastases (1.52) predicted detection of actionable genomic alterations. F1L detection increased from 5.8% (zero factors) to 32.8% (four factors), approximating tissue at three factors. Conclusions: The utility of liquid biopsy can be maximized by carefully selecting samples on the basis of conditions that increase the detection rate. Full article

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer. miRNAs play an essential role in TNBC pathogenesis and prognosis. Obesity is linked with an increased risk for several cancers, including breast cancer. Obesity is also related to the dysregulation of miRNA expression in adipose tissues. However, there is limited knowledge about race- and obesity-specific differential miRNA expression in TNBC. We performed miRNA sequencing of 48 samples (24 tumor and 24 adjacent non-tumor tissues) and RNA sequencing of 24 tumors samples from Black (AA) and White (EA) TNBC patients with or without obesity. We identified 55 miRNAs exclusively associated with tumors in obese EA patients and 33 miRNAs in obese AA patients, each capable of distinguishing tumor tissues from obese from lean individuals within their respective racial groups. In EA, we detected 41 significant miRNA–mRNA correlations. Notably, miR-181b-5p and miR-877-5p acted as negative regulators of tumor-suppressor genes (e.g., HEY2, MCL2, HAND2), while miR-204-5p and miR-143-3p appeared to indirectly target oncogenes (e.g., RAB10, DR1, PTBP3, NCBP1). Among AA patients, we found 28 significant miRNA–mRNA interactions. miR-195-5p, miR-130a-3p, miR-130a-5p, miR-424-5p, miR-148a-3p, miR-374-5p, and miR-30a-5p each potentially downregulated two or more genes (e.g., CLCN4, PLCB1, CDC25B, AEBP2, ERBB4). Pathway enrichment analysis highlighted KRAS, ESR1, ESR2, RAB10, TNRC6C, and NCAN as the most commonly differentially expressed in EA, whereas ERBB4, PLCB1, and SERPINE1 were most frequently in AA. These findings highlight the importance of considering race-specific miRNA–mRNA signatures in understanding TNBC in the context of obesity, offering insights into biomarker-driven patient stratification for targeted therapeutic strategies. Full article

Background: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy arising from the biliary epithelium, with an increasing incidence and poor prognosis worldwide. Recent advances in next-generation sequencing have revealed a variety of genomic alterations―such as FGFR2 fusions, IDH1 mutations, and ERBB2 amplification―that may serve as therapeutic targets. However, the influence of underlying etiologic factors, including chronic liver and biliary diseases, on the molecular landscape of CCA remains unclear. Objective: This review aimed to synthesize the current knowledge on the genomic and molecular alterations of CCA in the context of diverse etiologic factors, including hepatitis B virus, hepatitis C virus, primary sclerosing cholangitis (PSC), primary biliary cholangitis, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and liver fluke infection. Main findings: Certain backgrounds, such as PSC and liver fluke infection, are associated with distinct molecular signatures (e.g., TP53, SMAD4, KRAS, and ERBB2 alterations), whereas others, such as MASLD or ALD, show limited and inconsistent genomic data. Targetable alterations―including FGFR2 fusions, IDH1 mutations, and ERBB2 amplification―are heterogeneously distributed across etiologies and anatomical subtypes. Molecular targeted therapies such as FGFR and IDH1 inhibitors have shown clinical benefits in selected patients. Conclusions: A better understanding of how chronic liver and biliary diseases shape the genomic landscape of CCA will inform the development of personalized treatments, surveillance strategies, and preventive approaches. Large-scale etiology-stratified genomic studies integrating multiomics and real-world clinical data are urgently needed to advance precision oncology in CCA. Full article

Colorectal cancer (CRC) remains a major global challenge, with growing attention to its pathogenesis as mediated by the gut microbiome and epigenetic regulation. Despite therapeutic progress, clinical management remains difficult. CRC accounts for ~10% of cancers and is the second leading cause of cancer death worldwide. Romania bears a substantial burden, with many diagnoses at advanced stages. Etiology—Integrated Genetic, Environmental, and Microbial Determinants. Hereditary syndromes explain 10–15% of cases; most are sporadic, with hypermutated MSI/POLE (~15%), non-hypermutated chromosomal instability (~85%), and a CpG island methylator phenotype (~20%). GWAS implicate loci near SMAD7, TCF7L2, and CDH1; in Romania, SMAD7 rs4939827 associates with risk. Lifestyle exposures—high red/processed meat, low fiber, adiposity, alcohol, and smoking—shape susceptibility. Microbiome–Epigenome Interactions. Dysbiosis promotes carcinogenesis via genotoxins (e.g., colibactin), hydrogen sulfide, activation of NF-κB/STAT3, barrier disruption, and epigenetic remodeling of DNA methylation and microRNAs. Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and pks⁺ Escherichia coli exemplifies these links. Population-Specific Risk—Romania within Lifestyle–Microbiome Evidence. Incidence is rising, including early-onset disease. Romania lacks CRC-specific microbiome datasets. However, metabolic cohorts show loss of butyrate producers, enrichment of pathobionts, and SCFA imbalance—patterns that mirror European CRC cohorts—and exhibit regional heterogeneity. Beyond Fusobacterium nucleatum. Additional oncobacteria shape tumor biology. Peptostreptococcus stomatis activates integrin α6/β4→ERBB2–MAPK and can bypass targeted inhibitors, while Parvimonas micra enhances WNT/β-catenin programs and Th17-skewed immunity. Together, these data support a systems view in which microbial cues and host epigenetic control jointly drive CRC initiation, progression, metastasis, and treatment response. Full article

The bombesin (Bn) receptor family [Gastrin-releasing peptide (GRPR/BB2R) and Neuromedin B receptors (NMBR/BB1R)] are G-protein coupled receptors (GPCR’s) with potent growth effects on normal tissues/numerous cancers, often by transactivating the ErbB receptor-tyrosine kinase (RTK) family. Whereas GRPR stimulation transactivates ErbB RTKs EGFR, HER2, and HER3 in non-small cell lung-cancer (NSCLC) cells, its effects on HER4 are unknown. This study was designed to address this question. Of 12 NSCLC’s studied, 75% had HER4 mRNA expression and Western-Blotting. NCI-H522 and NCI-H661-cells had high levels of GRPR, HER4, and the HER4-ligand neuregulin (NRG1). Adding GRP to NCI-H522/NCI-H661-cells activated HER4, shown by its increased phosphorylation (P-HER4). The GRPR antagonists PD176252/BW2258U89 inhibited this increase. In NCI-H661-cells, GRP stimulated the formation of HER4-homodimers and HER2-HER4-heterodimers. Adding GRP to these NSCLC-cells increased P-ERK/P-AKT, which was inhibited by siRNA-HER4, PD176252, and ibrutinib, as well as N-acetylcysteine and Tiron, which reduce reactive-oxygen species (ROS). GRP increased secretion of NRG1 from NSCLC-cells, and NRG1 increased P-HER4 and P-ERK, which were impaired by ibrutinib. GRP and NRG1 stimulated proliferation of NSCLC-cells, which was inhibited by PD176252, siRNA-HER4, or ibrutinib and which was mediated by MAPK, not AKT/PI3K, activation. These results show GRPR activation results in HER4 transactivation in a ROS-dependent manner, which stimulates NSCLC-growth through a MAPK-mediated mechanism. Full article

Purpose: Preclinical studies suggest that interleukin-1β (IL-1β) influences tumor behavior in non-small cell lung cancer (NSCLC). While the CANTOS trial demonstrated reduced lung cancer incidence with IL-1β inhibition, the CANOPY trials failed to show survival benefit when combined with chemoimmunotherapy. The role of IL-1β in NSCLC with oncogenic mutations remains unclear. We evaluated the prognostic and predictive significance of IL-1β expression across NSCLC subtypes. Methods: We analyzed 21,698 NSCLC tumors profiled by Caris Life Sciences using DNA and RNA next-generation sequencing. IL-1β expression was stratified into quartiles (Q1: lowest 25%, Q4: highest 25%). Real-world overall survival (OS) and time on treatment (TOT) were obtained from insurance claims. Statistical comparisons used Chi-square, Fisher’s exact, or Mann–Whitney U tests. Survival outcomes were assessed with Cox models. Results: Across unselected NSCLC patients, low IL-1β expression (Q1) was associated with modestly longer OS versus high expression (Q4) (median OS 19.5 vs. 17.4 months; HR 0.94; p < 0.0001). This effect was more pronounced in EGFR-mutant adenocarcinoma (36.7 vs. 27.2 months; HR 0.76; p < 0.001) and ALK fusion-positive NSCLC (53.0 vs. 35.2 months; HR 0.62; p = 0.002). In NSCLC without targetable mutations, IL-1β expression was not prognostic. In KRAS-mutant adenocarcinoma, high IL-1β expression was associated with modestly longer TOT on immunotherapy (7.4 vs. 6.4 months; HR 1.15; p = 0.041), but not OS. High IL-1β expression correlated positively with TP53 mutation, TMB-high, and PD-L1 expression and inversely with EGFR, KRAS, BRAF, ERBB2, KEAP1, and STK11 mutations. Conclusions: IL-1β expression is a potential prognostic and predictive biomarker in NSCLC, associated with survival outcomes in defined molecular subsets. These findings suggest that IL-1β-targeted strategies may be particularly relevant in EGFR- or ALK-altered tumors. Full article

Background: In Kazakhstan, there is a notable demand for fat-tail sheep breeds in both domestic and international markets, which has led to the prioritization of certain breeds for breeding purposes. Among the various sheep breeds raised in the desert and semi-desert regions of Kazakhstan, the Kazakh fat-tailed coarse-wool sheep is particularly valued for its production of high-quality mutton. Objective: This study aimed to identify genomic regions and candidate genes associated with body conformation traits in this breed using a genome-wide association study (GWAS). Methods: A GWAS was performed on 295 Kazakh fat-tailed coarse-wool using OvineSNP50 Genotyping BeadChip (Illumina, San Diego, CA, USA). Results: After quality control, 41,912 single-nucleotide polymorphisms (SNPs) remained for analysis. Several loci showed suggestive associations (p < 1 × 10⁻⁵) with growth traits. These included s23127.1 and OAR6_56152225.1 for live weight; s08490.1 for chest width; s22731.1 for oblique length; OAR10_1168444.1 for cannon bone circumference; and s58409.1 for both rump height and withers height. Candidate genes near these loci encompassed VCAN, NEK1, NRG1, ADAM12, ERBB4, RUNX1T1, and PDGFD. Conclusion: Thus, these genetic variations have the potential to serve as candidate markers for MAS targeting body conformation traits in Kazakh fat-tailed coarse-wool sheep. Full article

Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not random but rather driven by a complex network of molecular alterations that sustain tumor growth independent of EGFR signaling. These include amplification of ERBB2 (HER2) and MET, activation of the PI3K and AKT pathways, EGFR extracellular domain mutations, and rare kinase fusions. The concept of negative hyperselection has emerged as a powerful strategy to refine patient selection by excluding tumors with these resistance drivers. Multiple clinical trials have consistently shown that patients who are hyperselected based on comprehensive molecular profiling achieve significantly higher response rates and improved survival compared to those selected by RAS and BRAF status alone. Liquid biopsy through circulating tumor DNA has further transformed this landscape, offering a noninvasive tool to capture tumor heterogeneity, monitor clonal evolution in real time, and guide rechallenge strategies after resistance emerges. Together, negative hyperselection, ctDNA-guided monitoring, and emerging therapeutics define a precision-oncology framework for identifying, tracking, and overcoming resistance to anti-EGFR therapy in mCRC, moving the field toward more effective and individualized care. Looking ahead, the development of innovative therapeutics such as bispecific antibodies, antibody drug conjugates, and RNA-based therapies promises to further expand in this challenging clinical scenario. These advances move precision oncology in colorectal cancer from concept to clinical reality, reshaping the standard of care through molecular insights. Full article

Background: Young-onset colorectal cancer (YO-CRC) has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, the molecular and clinical underpinnings of YO-CRC remain underexplored. This study aims to characterize the clinical and molecular features of YO-CRC and to evaluate their impact on OS. Methods: We reviewed 110 patients diagnosed with YO-CRC at our institution who underwent next-generation sequencing. Demographic, clinical, and molecular data, including age, gender, race, tumor location, cancer stage, and mutation status (KRAS, NRAS, BRAF, POLE, ERBB-2/HER2, microsatellite status), were collected by reviewing electronic medical records. For OS analysis, we focused on patients diagnosed with de novo stage IV. Cox proportional hazards regression and Kaplan–Meier survival analysis were utilized to assess the association of these factors with OS, with statistical significance determined by a p-value threshold of <0.05. Results: Among 110 patients, n = 44 (40%) presented with local disease (stage 1–3), while n = 66 (60%) presented with de novo metastatic disease at the time of diagnosis. The median age at diagnosis was 44.5 years. The cohort consisted of 64% males and 36% females, with 84% of patients identified as White. Most tumors were left-sided (77%), including the distal colon/sigmoid (44%) and rectum (33%). KRAS and BRAF mutations were present in 36% and 5.5%, respectively. ERBB-2/HER2 amplification and microsatellite instability were observed in 4.5% and 6.4%, respectively. Tumor mutation burden (TMB) was <10 in 57% of patients, with 14% having TMB > 20. CNV analysis revealed that 14% of patients had copy gains, 12% had concurrent gains/losses, and 31% had copy losses. Among 66 patients with de novo metastatic disease, 44% had died by the time of analysis, with a median overall survival (OS) of 43.6 months (95% CI, 28.7—not reached). KRAS mutations were found to be significantly associated with worse survival outcomes. Cox regression analysis reveals the prognostic significance of KRAS status, with a hazard ratio (HR) of 3.52 (95% CI: 1.59–7.76, p = 0.002), indicating a significantly higher risk of death for KRAS-mutant YO-CRC patients. Conclusions: Patients with YO-CRC are more likely to present with de novo metastatic disease and left-sided tumors with distinct molecular characteristics. KRAS mutations are a key prognostic factor in YO-CRC, highlighting the need for therapeutic interventions to improve outcomes in this high-risk group. Full article