Search Results (1,115)

Background: This study was aimed to comprehensively investigate the clinical and molecular characteristics, treatments, and outcomes of young patients with lung cancer in the new era of cancer treatment. Methods: Clinical data from patients aged 18 to 45 with lung cancer, treated at our hospital from January 2014 through January 2024, were systematically collected and analyzed. Results: This study enrolled a total of 343 patients, with a predominance of females, never-smokers, and those diagnosed at an advanced stage. Adenocarcinoma was the most common histology (72.0%), and rare tumors could also be seen in young patients, such as pulmonary sarcomatoid carcinoma and pulmonary mucoepidermoid carcinoma. The mutation rate of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in NSCLC patients were 35.9% (111/309) and 14.2% (44/309), respectively. PD-L1 expression was assessed in 55 patients, with 14 showing high expression (≥50%) and 24 showing negative expression (<1%). The median overall survival (mOS) for the entire cohort was 80.2 months, with a 5-year survival rate of 55.7%. For patients with stage I, II, and III disease, the mOS had not yet been reached, whereas the mOS for stage IV patients was 39.7 months. Targeted therapy, particularly second-generation ALK tyrosine kinase inhibitors (TKIs), significantly improved the prognosis of patients with driver gene mutations. Chemotherapy combined with immunotherapy was beneficial for patients with progressive disease or driver gene negativity in NSCLC and was associated with improved OS in small cell lung cancer (SCLC). Female, family history of lung cancer, positive driver genes, and first-line use of second-generation ALK-TKIs are independent prognostic factors in young patients with advanced NSCLC. Conclusions: Our findings highlight the importance of early diagnosis, targeted therapy, and immunotherapy in improving outcomes for young patients with lung cancer. Full article

Insertion sequence (IS) elements are key drivers of bacterial genome plasticity, yet the overall regulation of their transposition remains poorly understood. This is especially true for the multiple-layer regulation at the donor site, which has been largely overlooked. Using multiple mutation assays, genetic manipulations and reporter genes, this study focuses on characterizing how endogenous DNA sequences, transcriptional and translational factors, and genomic context regulate IS1 transposition from its donor site. Out of six elements within the chromosome of E. coli strain BW25113, IS1A and IS1E (both with the consensus sequence) contribute to over 99.9% of the overall IS1 transposition within the genome while the other four elements without the non-consensus sequence are essentially incapable of transposing. Inducing a ribosomal -1 frameshift at the A₆C motif increases transposition over 1000-fold, but this enhancement is largely reversed by restoring InsA-mediated transcriptional regulation. Strikingly, genomic sequences flanking IS1 elements appreciably modulate transposition by promoting transcription or facilitating formation of transpososomes, a phenomenon that remains under-studied. Finally, IS1 was confirmed to undergo replicative transposition intramolecularly, a mechanism shown here to be independent of transposase levels in the cell. These findings contribute to our understanding of mobile genetic element regulation and potentially offer strategies for mitigating their potentially harmful effects. 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

Ecological drought in terrestrial systems is a vegetation-functional degradation phenomenon triggered by the long-term imbalance between ecosystem water supply and demand. This process involves nonlinear coupling of multiple climatic factors, ultimately forming a compound ecological stress mechanism characterized by spatiotemporal heterogeneity. Based on meteorological and remote sensing datasets from 1982 to 2022, this study identified the spatial distribution and temporal variability of ecological drought in China, elucidated the dynamic evolution and return periods of typical drought events, unveiled the scale-dependent effects of climatic factors under both univariate dominance and multivariate coupling, as well as deciphered the response mechanisms of ecological drought to meteorological drought. The results demonstrated that (1) terrestrial ecological drought in China exhibited a pronounced intensification trend during the study period, with the standardized ecological water deficit index (SEWDI) reaching its minimum value of −1.21 in February 2020. Notably, the Alpine Vegetation Region (AVR) displayed the most significant deterioration in ecological drought severity (−0.032/10a). (2) A seasonal abrupt change in SEWDI was detected in January 2003 (probability: 99.42%), while the trend component revealed two mutation points in January 2003 (probability: 96.35%) and November 2017 (probability: 43.67%). (3) The drought event with the maximum severity (6.28) occurred from September 2019 to April 2020, exhibiting a return period exceeding the 10-year return level. (4) The mean values of gridded trend eigenvalues ranged from −1.06 in winter to 0.19 in summer; 87.01% of the area exhibited aggravated ecological drought in winter, with the peak period (88.51%) occurring in January. (5) Evapotranspiration (ET) was identified as the dominant univariate driver, contributing a percentage of significant power (POSP) of 18.75%. Under multivariate driving factors, the synergistic effects of ET, soil moisture (SM), and air humidity (AH) exhibited the strongest explanatory power (POSP = 19.21%). (6) The response of ecological drought to meteorological drought exhibited regional asynchrony, with the maximum correlation coefficient averaging 0.48 and lag times spanning 1–6 months. Through systematic analysis of ecological drought dynamics and driving mechanisms, a dynamic assessment framework was constructed. These outcomes strengthen the scientific basis for regional drought risk early-warning systems and spatially tailored adaptive management strategies. Full article

Since the emergence of SARS-CoV-2, the interplay of human behavior, environmental factors, viral evolution, and public health interventions has resulted in unexpected changes in the timing, intensity, and geography of respiratory virus outbreaks. For example, respiratory syncytial viruses (RSV) exhibited a surge during atypical summer months in several countries. Influenza, on the other hand, nearly vanished in the early years of the pandemic, but returned with unusual strength and altered seasonal patterns. Concurrently, new variants of concern in coronaviruses have demonstrated increased airborne transmissibility, greater resilience to environmental conditions, and the ability to evade both natural and vaccine-induced immunity. In this review article, we have synthesized the current understanding of the aerobiology of respiratory infectious viruses, with a particular emphasis on the paradoxical trends observed in recent years. We examined various aspects, including viral morphology and environmental survivability, shifts in seasonality, the drivers of mutation and resistance, and the impact of environmental and climatic factors. Key issues we explored include viral morphology adaptation in response to airborne selective pressures and climate variability influence on the ecology of airborne viruses. Lastly, we investigated future risks and proposed an interdisciplinary framework for monitoring and mitigating airborne viral threats in an ever-changing world. Full article

Uterine fibroids are benign smooth muscle tumors that affect ~70% of women, with Black women being affected at a disproportionate rate. The growth of these tumors is driven by estrogen and progesterone. Driver mutations in genes such as MED12, HMGA2, and FH also play roles in the development and growth of fibroids. Despite their high prevalence, the pathogenesis of fibroids remains largely unknown, leading to a lack of effective therapeutic options. Non-coding RNAs (ncRNAs), including miRNAs (e.g., miR-21, miR-29, miR-200), lncRNAs (e.g., H19, MIAT, XIST), and circRNAs, are important regulatory RNAs that are becoming increasingly implicated in the aberrant expression of protein-coding genes functionally associated with ECM production, cell proliferation, apoptosis, and inflammation in fibroids. Race/ethnicity, MED12 mutations, and ovarian steroids influence the expression of ncRNA expression, further implicating their relevance to fibroid pathogenesis. Therapeutic targeting of these dysregulated ncRNAs in fibroids could enable more precise and individualized non-hormonal-based treatment for this common gynecologic tumor. Full article

Multiple myeloma (MM) is a malignant plasma cell disorder that evolves from precursor conditions including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Understanding the biological continuum and the molecular drivers of disease progression is crucial for early diagnosis and risk-adapted therapy. Recent advances in next-generation sequencing have identified recurrent mutations in the RAS/MAPK, TP53, and MYC pathways, along with epigenetic alterations that contribute to clonal evolution and therapeutic resistance. Novel diagnostic tools including minimal residual disease (MRD) assessment, gene expression profiling, and advanced imaging have improved risk stratification. Therapeutically, the integration of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies has dramatically improved patient outcomes. In parallel, emerging immunotherapies such as CAR-T cells, bispecific T-cell engagers, and antibody–drug conjugates are expanding treatment options, especially in relapsed or refractory settings. Future directions aim to personalize treatment using genomics, target the tumor microenvironment, and leverage synthetic lethality and epigenetic vulnerabilities. This review highlights the evolving landscape of plasma cell disorders from molecular pathogenesis to cutting-edge therapeutic innovations, emphasizing the need for precision medicine approaches to improve survival and quality of life for patients with MM and its precursors. Full article

Globally, the mutations around forest landscapes continue to draw significant scientific interest, despite fragmented evidence on the socio-ecological outcomes linked to this process. This knowledge gap is evident in the Congo Basin—one of the world’s major ecosystems. To contribute towards addressing the knowledge gap, this study analyzed two decades of forest landscape mutations and the socio-ecological transformation-cum-outcomes linked to the process in Cameroon. A mixed-methods approach was employed, combining remote sensing-based land use/land cover (LULC) analysis (using multi-date Landsat imagery at 30 m resolution) with household surveys involving 100 randomly selected forest-dependent households across three forest blocks: Ebo, Ndokbou, and Makombé for ground truthing. Survey data were analyzed using descriptive statistics and combined spatial analysis to reveal the following. Firstly, forest cover has significantly increased within the 20-year period; this involved a 104.01% increase between 2004 and 2014, and an additional 47.27% between 2014 and 2024. In that vein, agricultural land declined by more than 20%, whereas settlement and water bodies increased by 226.4% and 376.2%, respectively. Secondly, forest landscape mutations in the Yabassi Forest Area were primarily driven by a convergence of social (notably population growth at 57% and livelihood diversification), economic (agricultural expansion and timber exploitation), political (tenure ambiguity and development-driven land conversion), and environmental (climate variability at 36% and ecological restoration efforts) forces. These interwoven drivers shaped the land use change process, revealing how the human-environment feedback defines landscape trajectories in complex and non-linear ways. Thirdly, while the ecological outcomes of forest mutations were largely positive—with significant gains in forest cover, the social outcomes were skewed towards the negative. Communities experienced both improvements in livelihoods and infrastructure (66%), but also faced land conflicts (67%), the loss of traditional access (69%), and resource-based insecurity. By applying the socio-ecological systems (SES) framework, this study provides novel insights on how governance, ecological processes, and human behavior co-evolve in forest landscapes. The findings do not only edify the SES framework but also challenge the mainstream position about forest decline by highlighting areas of recovery. The evidence informs adaptive forest governance processes in the Congo Basin and similar contexts. Further research should investigate the institutional and adaptive mechanisms that influence these dynamics across the Congo Basin. Full article

Pancreatic neuroendocrine tumors (pNETs) are rare malignancies, accounting for 1–2% of pancreatic cancers, with an incidence of ≤1 case per 100,000 individuals annually. Originating from pancreatic endocrine cells, pNETs display significant clinical and biological heterogeneity. Traditional classification based on proliferative grading does not fully capture the complex mechanisms involved, such as oxidative stress, mitochondrial dysfunction, and tumor-associated macrophage infiltration. Recent advances in molecular profiling have revealed key oncogenic drivers, including MEN1 (menin 1), DAXX (death domain–associated protein), ATRX (alpha thalassemia/mental retardation syndrome X-linked), CDKN1B (cyclin-dependent kinase inhibitor 1B) mutations, chromatin remodeling defects, and dysregulation of the mTOR pathway. Somatostatin receptors, particularly SSTR2, play a central role in tumor biology and serve as important prognostic markers, enabling the use of advanced diagnostic imaging (e.g., Gallium-68 DOTATATE PET/CT) and targeted therapies like somatostatin analogs and peptide receptor radionuclide therapy (PRRT). Established biomarkers such as Chromogranin A and the Ki-67 proliferation index remain vital for diagnosis and prognosis, while emerging markers, like circulating tumor DNA and microRNAs, show promise for enhancing disease monitoring and diagnostic accuracy. This review summarizes the molecular landscape of pNETs and highlights genomic, transcriptomic, proteomic, and epigenomic factors that support the identification of novel diagnostic, prognostic, and therapeutic biomarkers, ultimately advancing personalized treatment strategies. Full article

Lung cancer (LC), with non-small-cell lung cancer (NSCLC) as its predominant subtype, remains the leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors (ICIs) have redefined the therapeutic paradigm in advanced NSCLC, durable responses are confined to a limited subset of patients. A major clinical challenge persists: the inability to accurately predict which patients will derive meaningful benefit, which will exhibit primary resistance, and which are at risk for severe immune-related toxicities. The imperative to individualize ICI therapy necessitates robust, dynamic, and accessible biomarkers. Liquid biopsy has emerged as a transformative, minimally invasive tool that enables real-time molecular and immunologic profiling. Through analysis of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and peripheral blood immune components, liquid biopsy offers a window into both tumor intrinsic and host-related determinants of ICI response. These biomarkers not only hold promise for identifying predictive signatures—such as tumor mutational burden, neoantigen landscape, or immune activation states—but also for uncovering mechanisms of acquired resistance and guiding treatment adaptation. Beyond immunotherapy, liquid biopsy plays an increasingly central role in the landscape of targeted therapies, allowing early detection of actionable driver mutations and resistance mechanisms (e.g., EGFR T790M, MET amplification, and ALK fusion variants). Importantly, serial sampling via liquid biopsy facilitates longitudinal disease monitoring and timely therapeutic intervention without the need for repeated tissue biopsies. By guiding therapy selection, monitoring response, and detecting resistance early, liquid biopsy has the potential to significantly improve outcomes in NSCLC. Full article

Targeted therapies against specific driver gene mutations have become the standard first-line treatment for most patients with advanced non-small cell lung cancer (NSCLC). While these therapies significantly prolong survival, the entire cancer treatment journey remains challenging and distressing. To better understand these experiences, this study employed a qualitative descriptive approach, conducting semi-structured interviews with 18 advanced NSCLC patients receiving targeted therapy, supplemented by patient journey logs. The resulting journey map delineated five stages: diagnosis, initial treatment, maintenance therapy, disease progression, and end-of-life. The analysis identified four key themes characterizing patient experiences at each stage. These findings enable healthcare professionals to identify risk situations and determine optimal timing for support interventions. Similarly, preparing patients for the processes they must undergo and the side effects of medical treatment helps reduce their uncertainty and anxiety, thereby improving their quality of life. Full article

Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies. Full article

Coronavirus disease 2019 (COVID-19) causes cardiovascular complications, which contributes to the high mortality rate of the disease. Emerging evidence indicates that aberrant vascular smooth muscle cell (SMC) function is a key driver of vascular disease in COVID-19. While antivirals alleviate the symptoms of COVID-19, it is not known whether these drugs directly affect SMCs. Accordingly, the present study investigated the ability of three approved COVID-19 antiviral drugs to influence SMC function. Treatment of SMCs with remdesivir (RDV), but not molnupiravir or nirmatrelvir, inhibited cell proliferation, DNA synthesis, and migration without affecting cell viability. RDV also stimulated an increase in heme oxygenase-1 (HO-1) expression that was not observed with molnupiravir or nirmatrelvir. The induction of HO-1 by RDV was abolished by mutating the antioxidant responsive element of the promoter, overexpressing dominant-negative NF-E2-related factor-2 (Nrf2), or treating cells with an antioxidant. Finally, silencing HO-1 partly rescued the proliferative and migratory response of RDV-treated SMCs, and this was reversed by carbon monoxide and bilirubin. In conclusion, the induction of HO-1 via the oxidant-sensitive Nrf2 signaling pathway contributes to the antiproliferative and antimigratory actions of RDV by generating carbon monoxide and bilirubin. These pleiotropic actions of RDV may prevent occlusive vascular disease in COVID-19. Full article

Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and gut microbiota in liver cancer development and progression. This review aims to integrate emerging knowledge on the interplay between host genomic changes and gut microbial dynamics in the pathogenesis and treatment of hepatic cancers. Methods: We conducted a comprehensive review of current literature on genetic and epigenetic drivers of HCC and CCA, focusing on commonly mutated genes such as TP53, CTNNB1, TERT, IDH1/2, and FGFR2. In parallel, we evaluated studies addressing the gut–liver axis, including the roles of dysbiosis, microbial metabolites, and immune modulation. Key clinical and preclinical findings were synthesized to explore how host–microbe interactions influence tumorigenesis and therapeutic response. Results: HCC and CCA exhibit distinct but overlapping genomic landscapes marked by recurrent mutations and epigenetic reprogramming. Alterations in the gut microbiota contribute to hepatic inflammation, genomic instability, and immune evasion, potentially enhancing oncogenic signaling pathways. Furthermore, microbiota composition appears to affect responses to immune checkpoint inhibitors. Emerging therapeutic strategies such as probiotics, fecal microbiota transplantation, and precision oncology based on mutational profiling demonstrate potential for personalized interventions. Conclusions: The integration of host genomics with microbial ecology provides a promising paradigm for advancing diagnostics and therapies in liver cancer. Targeting the gut–liver axis may complement genome-informed strategies to improve outcomes for patients with HCC and CCA. Full article

Replication timing (RT), the temporal order of DNA replication during S phase, influences regional mutation rates, yet the mechanistic basis for RT-associated mutagenesis remains incompletely defined. To identify drivers of RT-dependent mutation biases, we analyzed whole-genome sequencing data from cells with disruptions in DNA replication/repair genes or exposed to mutagenic compounds. Mutation distributions between early- and late-replicating regions were compared using bootstrapping and statistical modeling. We identified 14 genes that exhibit differential effects in early- or late-replicating regions, encompassing multiple DNA repair pathways, including mismatch repair (MLH1, MSH2, MSH6, PMS1, and PMS2), trans-lesion DNA synthesis (REV1) and double-strand break repair (DCLRE1A and PRKDC), DNA polymerases (POLB, POLE3, and POLE4), and other genes central to genomic instability (PARP1 and TP53). Similar analyses of mutagenic compounds revealed 19 compounds with differential effects on replication timing. These results establish replication timing as a critical modulator of mutagenesis, with distinct DNA repair pathways and exogenous agents exhibiting replication timing-specific effects on genomic instability. Our systematic bioinformatics approach identifies new DNA repair genes and mutagens that exhibit differential activity during the S phase. These findings pave the way for further investigation of factors that contribute to genome instability during cancer transformation. Full article