Search Results (26,245)

This review focuses on the pivotal roles of nuclear receptors (NRs) in driving endocrine resistance in prostate and breast cancers. In prostate cancer (PCa), androgen receptor (AR) amplification, mutations, and altered coactivator interactions sustain tumor growth under androgen deprivation therapy (ADT), leading to castration-resistant prostate cancer (CRPC). Orphan NRs like RORβ, TLX, and COUP-TFII further contribute to CRPC by regulating stemness and therapeutic resistance mechanisms. In breast cancer, NRs, including estrogen receptor alpha (ERα), androgen receptor (AR), glucocorticoid receptor (GR), and liver receptor homolog-1 (LRH-1), modulate estrogen signaling pathways and alternative survival mechanisms like PI3K/AKT/mTOR and NFκB, promoting resistance to endocrine therapies such as tamoxifen. Understanding these NR-mediated mechanisms is critical for developing targeted therapies to overcome endocrine resistance and improve patient outcomes in hormone-dependent cancers. Full article

Since the first reported case of COVID-19 in December 2019, several SARS-CoV-2 variants have evolved, and some of them have shown higher transmissibility, becoming the prevalent strains. Genomic epidemiological investigations into strains from different time points, including the early stages of the pandemic, are very crucial for understanding the evolution and transmission patterns. Using whole-genome sequences, our study describes the early landscape of SARS-CoV-2 variants in central India retrospectively (including the first known occurrence of SARS-CoV-2 in Madhya Pradesh). We performed amplicon-based whole-genome sequencing of randomly selected SARS-CoV-2 isolates (n = 38) collected between 2020 and 2022 at state level VRDL, ICMR-NIRTH, Jabalpur, from 11899 RT-qPCR-positive samples. We observed the presence of five lineages, namely B.1, B.1.1, B.1.36.8, B.1.195, and B.6, in 19 genomes from the first wave cases and variants of concern (VOCs) lineages, i.e., B.1.617.2 (Delta) and BA.2.10 (Omicron) in the second wave cases. There was a shift in mutational pattern in the spike protein coding region of SRAS-CoV-2 strains from the second wave in contrast to the first wave. In the first wave of infections, we observed variations in the ORF1Ab region, and with the emergence of Delta lineages, the D614G mutation associated with an increase in infectivity became a prominent change. We have identified five immune escape variants in the S gene, P681R, P681H, L452R, Q57H, and N501Y, in the isolates collected during the second wave. Furthermore, these genomes were compared with 2160 complete genome sequences reported from central India that encompass 109 different SARS-CoV-2 lineages. Among them, VOC lineages Delta (28.93%) and Omicron (56.11%) were circulating predominantly in this region. This study provides useful insights into the genetic diversity of SARS-CoV-2 strains over the initial course of the COVID-19 pandemic in central India. Full article

Background/Objective: Medullary thyroid carcinoma (MTC) is a rare yet aggressive form of thyroid cancer comprising a disproportionate share of thyroid cancer-related mortalities, despite its low prevalence. MTC differs from other differentiated thyroid malignancies due to its heterogeneous nature, presenting complexities in both hereditary and sporadic cases. Traditional management guidelines, which are designed primarily for papillary thyroid carcinoma (PTC), fall short in providing the individualized care required for patients with MTC. In recent years, the sheer volume of data generated from clinical evaluations, radiological imaging, pathological assessments, genetic mutations, and immunological profiles has made it humanly impossible for clinicians to simultaneously analyze and integrate these diverse data streams effectively. This data deluge necessitates the adoption of advanced technologies to assist in decision-making processes. Holomics, which is an integrated approach that combines various omics technologies, along with artificial intelligence (AI), emerges as a powerful solution to address these challenges. Methods: This article reviews how AI-driven precision oncology can enhance the diagnostic workup, staging, risk stratification, management, and follow-up care of patients with MTC by processing vast amounts of complex data quickly and accurately. Articles published in English language and indexed in Pubmed were searched. Results: AI algorithms can identify patterns and correlations that may not be apparent to human clinicians, thereby improving the precision of personalized treatment plans. Moreover, the implementation of AI in the management of MTC enables the collation and synthesis of clinical experiences from across the globe, facilitating a more comprehensive understanding of the disease and its treatment outcomes. Conclusions: The integration of holomics and AI in the management of patients with MTC represents a significant advancement in precision oncology. This innovative approach not only addresses the complexities of a rare and aggressive disease but also paves the way for global collaboration and equitable healthcare solutions, ultimately transforming the landscape of treatment and care of patients with MTC. By leveraging AI and holomics, we can strive toward making personalized healthcare accessible to every individual, regardless of their economic status, thereby improving overall survival rates and quality of life for MTC patients worldwide. This global approach aligns with the United Nations Sustainable Development Goal 3, which aims to ensure healthy lives and promote well-being at all ages. Full article

Crigler–Najjar Syndrome (CNS) is a rare genetic disorder caused by mutations in the UGT1A1 gene, leading to impaired bilirubin conjugation and severe unconjugated hyperbilirubinemia. CNS presents in the following forms: CNS type 1 (CNS1), the more severe form with the complete absence of UGT1A1 activity, and CNS type 2 (CNS2), with partial enzyme activity. This narrative review aims to provide a detailed overview of CNS, highlighting its clinical significance and the need for new, more effective treatments. By summarizing current knowledge and discussing future treatments, this article seeks to encourage further research and advancements that can improve outcomes for CNS patients. The literature analysis showed that CNS1 requires aggressive management, including phototherapy and plasmapheresis, but liver transplantation (LT) remains the only definitive cure. The timing of LT is critical, as it must be performed before the onset of irreversible brain damage (kernicterus), making early intervention essential. However, LT poses risks such as graft rejection and lifelong immunosuppression. CNS2 is milder, with patients responding well to phenobarbital and having a lower risk of kernicterus. Recent advancements in gene therapy and autologous hepatocyte transplantation offer promising alternatives to LT. Gene therapy using adeno-associated virus (AAV) vectors has shown potential in preclinical studies, though challenges remain in pediatric applications due to liver growth and pre-existing immunity. Autologous hepatocyte transplantation avoids the risk of rejection but requires further research. These emerging therapies provide hope for more effective and less invasive treatment options, aiming to improve the quality of life for CNS patients and reduce reliance on lifelong interventions. Full article

Peste des petits ruminants virus (PPRV), which is the only member of the Morbillivirus caprinae species and belongs to the genus Morbillivirus within the Paramyxoviridae family, causes the highly contagious viral sickness “Peste des petits ruminants (PPR).” PPR is of serious economic significance for small ruminant production, particularly in Africa. Control of this critical disease depends highly on successful vaccination against the PPRV. An in-depth understanding of the genetic evolution of the live-attenuated PPR vaccine Nigeria 75/1 strain used in Africa is essential for the successful eradication of this disease by 2030. Therefore, this study investigated the possible genetic evolution of the PPR vaccine produced by various African laboratories compared with the master seed available at AU-PANVAC. RT-PCR was performed to amplify a segment of the hypervariable C-terminal part of the nucleoprotein (N) from commercial batches of PPR vaccine Nigeria 75/1 strain. The sequences were analyzed, and 100% nucleotide sequence identity was observed between the master seed and vaccines produced. The results of this study indicate the genetic stability of the PPR vaccine from the Nigeria 75/1 strain over decades and that the vaccine production process used by different manufacturers did not contribute to the emergence of mutations in the vaccine strain. Full article

NRAS belongs to the RAS family of GTPases. In colorectal cancer (CRC), NRAS mutations are rare compared to KRAS, but may lead to worse outcomes. We report the functional characterization of the novel NRAS mutants—G48C, Q43K, and E37K—identified in Filipino young-onset CRC patients. Unlike previously characterized NRAS mutants with no apparent effects on cell proliferation, these mutants enhanced proliferation of both HCT116 and NIH3T3 cells. This was confirmed in 3D spheroid assays to mimic the spatial organization of cells. G48C and E37K showed apoptosis resistance in both cell lines, and Q43K showed resistance in HCT116 cells. All three showed no effect on cellular migration in NIH3T3, but G48C enhanced the migration rate of HCT116 cells. Actin staining of NIH3T3 cells expressing the mutants showed a shrunken cytoplasm and transient structures associated with motility and invasiveness. Docking simulations show that GDP is only able to bind fully within the binding pocket of wild-type NRAS, but not in the mutants. Further, G48C, Q43K, and E37K all have less negative ΔG values, indicating a weaker GDP-binding affinity compared to wild-type NRAS. Taken together, the results suggest that oncogenic readouts of NRAS mutants are codon- and mutation-specific, with potential repercussions on the aggressiveness, resistance, and therapeutic response. Full article

Background: Rosette-Forming Glioneuronal Tumors (RGNTs) are rare, typically benign central nervous system tumors primarily located in the fourth ventricle and pineal region. Despite being classified as WHO grade I with generally favorable prognoses, RGNTs present complexities in their molecular mechanisms, occasional malignant transformation, and epidemiological characteristics that require further investigation. Method: This study systematically reviews the existing literature to analyze the epidemiological patterns, MRI characteristics, pathological features, diagnostic challenges, and molecular mechanisms associated with RGNTs, aiming to provide a comprehensive theoretical foundation for clinical practice and future research. Results: Through an in-depth review of recent studies, key molecular mechanisms, including mutations in FGFR1, PIK3CA, TERT, and IDH1/2, are highlighted. Additionally, the challenges in accurate diagnosis and the potential for misdiagnosis are discussed, emphasizing the importance of thorough molecular analysis in clinical settings. The literature indicates that RGNTs predominantly affect young adults and adolescents, with a slight female predominance. MRI typically reveals mixed cystic–solid lesions, often accompanied by hydrocephalus. Pathologically, RGNTs are characterized by a combination of neuronal and glial components, with immunohistochemical staining showing positivity for Synaptophysin and GFAP. High frequencies of FGFR1 and PIK3CA mutations underscore the significance of these pathways in RGNT pathogenesis and progression. Although RGNTs generally exhibit low malignancy, the TERT mutations identified in some cases suggest a risk of malignant transformation. Conclusions: This study concludes that while current treatment strategies focus on surgical resection, integrating molecular diagnostics and targeted therapies may be essential for managing recurrent or refractory RGNTs. Future research should explore the impact of various gene mutations on tumor behavior and their correlation with clinical outcomes, to optimize individualized therapeutic strategies and improve patient survival and quality of life. Full article

Autoimmune polyglandular syndrome (APS) comprises a complex association of autoimmune pathological conditions. APS Type 1 originates from loss-of-function mutations in the autoimmune regulator (AIRE) gene. APS2, APS3 and APS4 are linked to specific HLA alleles within the major histocompatibility complex, with single-nucleotide polymorphisms (SNPs) in non-HLA genes also contributing to disease. In general, variability in the AIRE locus and the presence of heterozygous loss-of-function mutations can impact self-antigen presentation in the thymus. In this study, whole-exome sequencing (WES) was performed on a sixteen-year-old female APS3A/B patient to investigate the genetic basis of her complex phenotype. The analysis identified two variants (p.Arg111Trp and p.Thr101Ile) of the hepatitis A virus cell receptor 2 gene (HAVCR2) encoding for the TIM-3 (T cell immunoglobulin and mucin domain 3) protein. These variants were predicted, through in silico analysis, to impact protein structure and stability, potentially influencing the patient’s autoimmune phenotype. While confocal microscopy analysis revealed no alteration in TIM-3 fluorescence intensity between the PBMCs isolated from the patient and those of a healthy donor, RT-qPCR showed reduced TIM-3 expression in the patient’s unfractionated PBMCs. A screening conducted on a cohort of thirty APS patients indicated that the p.Thr101Ile and p.Arg111Trp mutations were unique to the proband. This study opens the pathway for the search of TIM-3 variants possibly linked to complex autoimmune phenotypes, highlighting the potential of novel variant discovery in contributing to APS classification and diagnosis. Full article

The most common causes of morbidity and mortality in the myeloproliferative neoplasms (MPNs), with the exception of myelofibrosis, are venous and arterial thrombosis, as well as more recently discovered cardiovascular disease (CVD). Clonal hematopoiesis of indeterminate potential (CHIP) is the subclinical finding in an individual of somatic mutations that are also found in clinically overt MPNs and other myeloid malignancies. The prevalence of “silent” CHIP increases with age. CHIP can transform into a clinically overt MPN at an estimated rate of 0.5 to 1% per year. It is likely, therefore, but not proven, that many, if not all, MPN patients had antecedent CHIP, possibly for many years. Moreover, both individuals with asymptomatic CHIP, as well as clinically diagnosed patients with MPN, can develop thrombotic complications. An unexpected and remarkable discovery during the last few years is that even CHIP (as well as MPNs) are significant, independent risk factors for CVD. This review discusses up-to-date information on the types of thrombotic and cardiovascular complications that are found in CHIP and MPN patients. A systemic inflammatory state (that is often subclinical) is most likely to be a major mediator of adverse reciprocal bone marrow–cardiovascular interplay that may fuel the development of progression of MPNs, including its thrombotic and vascular complications, as well as the worsening of cardiovascular disease, possibly in a “vicious cycle”. Translating this to clinical practice for hematologists and oncologists who treat MPN patients, attention should now be paid to ensuring that cardiovascular risk factors are controlled and minimized, either by the patient’s cardiologist or primary care physician or by the hematologist/oncologist herself or himself. This review is intended to cover the clinical aspects of thrombosis and cardiovascular complications in the MPN, accompanied by pathobiological comments. Full article

Melanoma is a highly aggressive type of skin cancer. Metastatic melanoma tumors have historically featured a particularly poor prognosis and have often been considered incurable. Recent advances in targeted therapeutic interventions have radically changed the landscape in metastatic melanoma management, significantly increasing the overall survival of patients. Hyperactive BRAF is the most common mutational event found in metastatic melanoma and its inhibition has proven to be a successful approach in a number of patients. Unfortunately, initial tumor retreat is followed by relapse in most cases, highlighting the elusiveness of finding a widely effective treatment. Melanoma tumors often carry a particularly high number of mutations in what is known as a high level of inter- and intra-patient tumor heterogeneity, driving resistance to treatment. The various mutations that are present in these tumors, in addition to impacting the root cause of the malignancy and the potential for therapeutic interventions, have also been known to arise during tumor clonal evolution leading to the establishment of drug resistance, a major issue in melanoma management. Full article

Influenza A virus (IAV) causes highly contagious respiratory disease worldwide, so prevention and control of IAV is extremely important. However, overuse of neuraminidase inhibitor (NAI) drugs leads to drug resistance. To explore the up-to-date geographical distribution and evolution of drug-resistant mutations (DRMs) in the NA protein of IAV, 81,492 near full-length NA sequences downloaded from NCBI and GISAID databases, including 34,481 H1N1 and 46,622 H3N2, were processed and analyzed. Our results showed the annual number of NA sequences from 2011 to 2019 continuously increased. Meanwhile, almost 85% of sequences were from developed countries in North America, Europe and Asia. Clustering analysis demonstrated H3N2 varied more than H1N1. Notably, H3N2 exhibited a higher frequency of DRMs than H1N1, with prevailing DRMs mainly located at non-active sites within the NA protein. Phylogenetic analyses showed NA harboring DRMs collected in the same year and from the same location clustered together, which may be related to the local economic level, clinical monitoring of DRMs and research level. Consequently, it is imperative to enhance global surveillance targeting drug resistance in IAV infections which can mitigate the transmission of drug-resistant strains. In summary, our research provides valuable insights for clinical medication while establishing a robust scientific basis for IAV prevention and treatment strategies to improve overall efficacy. Full article

Deleterious variations in STXBP1 are responsible for early infantile epileptic encephalopathy type 4 (EIEE4, OMIM # 612164) because of its dysfunction in the central nervous system. The clinical spectrum of the neurodevelopmental delays associated with STXBP1 aberrations is collectively defined as STXBP1 encephalopathy (STXBP1-E), the conspicuous features of which are highlighted by early-onset epileptic seizures without structural brain anomalies. A girl was first diagnosed with unexplained disorders of movement and cognition, which later developed into STXBP1-E with unexpected leukoaraiosis and late onset of seizures. Genetic screening and molecular tests alongside neurological examinations were employed to investigate the genetic etiology and establish the diagnosis. A heterozygous mutation of c.37+2dupT at the STXBP1 splice site was identified as the pathogenic cause in the affected girl. The de novo mutation (DNM) did not result in any truncated proteins but immediately triggered mRNA degradation by nonsense-mediated mRNA decay (NMD), which led to the haploinsufficiency of STXBP1. The patient showed atypical phenotypes characterized by hypomyelinating leukodystrophy, and late onset of epileptic seizures, which had never previously been delineated in STXBP1-E. These findings strongly indicated that the haploinsufficiency of STXBP1 could also exhibit divergent clinical phenotypes because of the genetic heterogeneity in the subset of encephalopathies. Full article

The blood clam (Anadara granosa) is an economic bivalve that is relatively tolerant to hypoxia, but its molecular mechanism of hypoxia tolerance is unclear. We found that a significant decrease in extracellular Ca²⁺ concentration and a marked increase in intracellular Ca²⁺ concentration was observed in the blood clam through the fluorescence probe method, under hypoxic conditions at 0.5 mg/L. Concomitantly, there was a downward trend in the expression level of CaV2 mRNA, whereas NFAT (nuclear factor of activated T cells) expression increased by qRT-PCR. These findings suggest that the elevated intracellular Ca²⁺ concentration may activate negative transcription factors of NFAT, which subsequently suppresses the transcription of CaV2, leading to its decreased expression. Then, the NFAT RNA interference experiments supported this hypothesis. Sequence analysis and 3D structure prediction revealed conserved and mutated residue sites in blood clam compared to other bivalves. Hypoxia-induced changes in intracellular and extracellular Ca²⁺ concentrations, activating transcription factor NFAT and suppressing CaV2 expression. This study highlights the key roles of CaV2 and NFAT in hypoxia adaptation, paving the way for further exploration of hypoxia tolerance mechanisms in mollusca. Full article

Straw mulch quantity is an important indicator in the detection of straw returned to the field in conservation tillage, but there is a lack of large-scale automated measurement methods. In this study, we estimated global straw mulch quantity and completed the detection of straw returned to the field. We used an unmanned aerial vehicle (UAV) carrying a multispectral camera to acquire remote sensing images of straw in the field. First, the spectral index was selected using the Elastic-net (ENET) algorithm. Then, we used the Genetic Algorithm Hybrid Particle Swarm Optimization (GA-HPSO) algorithm, which embeds crossover and mutation operators from the Genetic Algorithm (GA) into the improved Particle Swarm Optimization (PSO) algorithm to solve the problem of machine learning model prediction performance being greatly affected by parameters. Finally, we used the Monte Carlo method to achieve a global estimation of straw mulch quantity and complete the rapid detection of field plots. The results indicate that the inversion model optimized using the GA-HPSO algorithm performed the best, with the coefficient of determination (R²) reaching 0.75 and the root mean square error (RMSE) only being 0.044. At the same time, the Monte Carlo estimation method achieved an average accuracy of 88.69% for the estimation of global straw mulch quantity, which was effective and applicable in the detection of global mulch quantity. This study provides a scientific reference for the detection of straw mulch quantity in conservation tillage and also provides a reliable model inversion estimation method for the estimation of straw mulch quantity in other crops. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with significant public health concerns. This review examines the landscape of KRAS inhibition in colorectal cancer (CRC), focusing on recent advances in therapeutic strategies targeting this oncogene. Historically deemed undruggable due to its complex structure and essential role in tumorigenesis, KRAS mutations are prevalent in CRC and are associated with poor prognosis. However, breakthroughs in drug development have led to the emergence of KRAS inhibitors as promising treatment options. This review discusses various classes of KRAS inhibitors, including covalent and non-covalent inhibitors, as well as combination therapies aimed at enhancing efficacy and overcoming resistance mechanisms. It highlights recent clinical trials evaluating the efficacy of KRAS inhibitors either as monotherapy or in combination with other agents, such as anti-EGFR antibodies. Despite challenges such as resistance mechanisms and tumor heterogeneity, the development of KRAS inhibitors represents a significant advance in CRC treatment and holds promise for improving patient outcomes in the future. Full article