Altered Gene Research Articles

P3.06D.12 Racial Differences in ALK Gene Alterations Detected by Tissue and Liquid Biopsy Across Patients with Lung Cancer

P3.06D.12 Racial Differences in ALK Gene Alterations Detected by Tissue and Liquid Biopsy Across Patients with Lung Cancer

Gene expression profiles in placenta and their association with anesthesia, delivery mode and maternal diabetes

IntroductionFetal development is dependent on placenta and affected by multiple factors including maternal diabetes. Here we aimed to identify maternal diabetes-associated changes in placentas and analyzed placental gene expression to understand its modulation by maternal diabetes and birth mode. MethodsPlacental RNAseq transcriptome analyses were performed on maternally-derived decidua and fetal-derived villous tissue from pregnancies of mothers with type 1 diabetes (n = 14), gestational diabetes (n = 6) and without diabetes (n = 14). Information on delivery mode and anesthesia were included as covariables. Analyses were performed separately for decidua and fetal tissues and adjusted for sex. ResultsSubstantial placenta gene expression variation was associated with factors other than maternal diabetes, including site, sex, anesthesia type and delivery mode. Two dominant gene expression clusters aligned to anesthesia and delivery mode were observed for decidua and villous tissue. Upregulation of genes within pathways related to organ morphogenesis and downregulation of immune response to steroid- and hypoxia pathway genes was characteristic of placentas from primary cesarean section deliveries with spinal anesthesia. Opposite profiles were observed for placentas from secondary cesarean and epidural anesthesia deliveries. Placentas from vaginal delivery had intermediate gene expression profiles. More subtle changes were associated with maternal diabetes: upregulation of ribosome activity, down-regulation of maternally-derived decidua chemokine signaling pathways and for gestational diabetes, alteration in hypoxia response genes. DiscussionThe findings reveal suppression of immune pathways and upregulation of ribosome activity in the placenta by maternal diabetes highlighting the importance of confounding factors when examining cell and tissue expression profiles. Further studies should determine whether the observed gene expression differences are related to underlying causes for cesarean section deliveries.

Nanopolystyrene and phoxim pollution: A threat to hepatopancreas toxicity in Chinese mitten crab (Eriocheir sinensis)

Significant concerns have been raised by the widespread pollutants phoxim (PHO) and nanopolystyrene (NP) in the natural environment. This study evaluated the toxicity effects on the hepatopancreas of Eriocheir sinensis caused by NP and/or PHO at concentrations found in the environment. Subchronic exposure to NP and/or PHO triggered hepatopancreas histological damage within a 21-day exposure period. The NP, PHO, and co-exposure (NPO) groups exhibited fewer blister-like (B) cells, along with the appearance of vacuolation. Furthermore, these exposures induced impairment in the hepatic tubule mucus barrier and mechanical barrier, as evidenced by altered expression of oxidative stress-related genes, mucin-related genes, and TJ-related genes. Additionally, alterations in immunity-related genes and inflammatory cytokine genes expression were observed. The findings showed that hepatopancreas inflammation was caused by both individual and combined exposure to NP and PHO and that the inflammatory response was exacerbated by the co-exposure. The possible pathways of hepatopancreas toxicity were further investigated by transcriptomic analysis. Hepatopancreas inflammation was brought on by subchronic exposure to PHO and co-exposure; this inflammation was exacerbated by co-exposure and was backed by the activation of NF-κB signaling pathway via targeting-related genes. In summary, this research represents the initial documentation, to the best of our understanding of the detrimental effects of exposured to NP and/or PHO at levels found in the environment disrupt the hepatopancreas mucus and mechanical barrier in crustaceans, triggering inflammatory responses. These findings highlight the significance of NP and/or PHO pollution for hepatopancreas health.

A Rare Case with KMT2D: BCOR Fusion Alteration Sarcoma in A 14-Year-Old-Female

Abstract Introduction/Objective Tumors with BCL6-correpresor gene (BCOR) alteration are a heterogeneous group of undifferentiated sarcomas, occurring in various age groups and anatomic sites, characterized by spindle and round cell phenotype and diffuse immunoreactivity for BCOR. With widespread genomic testing, these alterations are now associated with different histologies. These sarcomas show a striking male predominance and occur in children/ adolescents. Methods/Case Report The Patient was a 14 years-old female presented after an accident with RLQ abdominal pain. Her pan-CT showed a 9.0 x 5.5 x 4.0 cm omental mass with free pelvic fluid in the anterior and upper pelvis. Results (if a Case Study enter NA) Microscopic examination showed lobulated spindle cell tumor with myxoid areas, extensive necrosis, focal calcifications, and perivascular lymphocytic infiltrates The tumor composed of bundles of monotonous cells with bizarre nuclei. Mitoses were brisk (44 mitoses per 10HPF). The tumor appeared to infiltrate adipose tissue and it had peritheliomatous pattern of proliferation. Beta-catenin, inhibin, BCL2, and Pan-TRK were positive in the spindle cells. PAX8 showed patchy positivity. EMA, CAM5.2, DOG-1, CD117, ALK1, CD34, HMB45, STAT6, SMA, CD31, S100, CD99, p63, SALL-4, CD10 were negative. Trichrome highlighted the intervening fibrous septae. Molecular Next Generation Sequencing studies showed a structural genomic alteration between the KMT2D and BCOR genes [t(12;X)(12q13.11;Xp11.4)]. Conclusion Tumors harboring rare fusion variants of BCOR, such as BCOR- KMT2D, were also positive for pan-TRK staining and NTRK3 overexpression. These rearrangements are so rare. And therefore, efficient diagnosis of BCOR rearranged sarcomas can be achieved by using a combination of FISH and RT-PCR assays. The therapeutic implication of this finding awaits further investigation.

Rapidly Progressive Primary Cutaneous Gamma Delta T-Cell Lymphoma With FYN Gene Alteration.

Primary cutaneous gamma delta T-cell lymphoma (PCGDTCL) is a rare type of non-Hodgkin lymphoma accounting for <1% of primary cutaneous T-cell lymphomas. The exact cause of PCGDTCL is not known, however, it is thought that chronic antigen exposure in the skin may lead to immune dysregulation at the site, resulting in abnormal proliferation of mature, post-thymic cytotoxic gamma delta T cells. Mutations are the most common genetic alteration seen in PCGDTCL, while structural abnormalities such as gene fusions are not common. We report a case of PCGDTCL with atypical immunophenotypic features, including expression of CD5 with lack of cytotoxic marker expression, and a structural alteration leading to FYN deletion at exon 8. Recently, it was described that a deletion of the area between FYN exon 8 and TRAF3IP2 intron 2 results in a novel FYN::TRAF3IP2 fusion in peripheral T-cell lymphoma, not otherwise specified. We describe our patient's clinical course, differential diagnosis, and potential implications of FYN deletion on disease pathogenesis. To our knowledge, this is the first report of an FYN structural alteration to be described in PCGDTCL.

Bladder cancer`s genetic Tapestry: Insights from two Cases with Ataxia Telangiectasia Mutated Gene Alterations

Abstract Introduction/Objective Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and is common in several tumor types including bladder cancer. The specific impact of ATM alterations on prognosis and therapy response in bladder cancer is uncertain. However, some data suggests shorter overall survival and benefit in patients treated with immune checkpoint inhibitors. This abstract explores the clinicopathologic features of two young patients of bladder cancer, harboring the ATM gene mutation. Methods/Case Report The institutional database was searched for diagnosis of urothelial carcinoma from January 2020 to December 2023. Only patients under the age of 30 years were included. Two cases were identified. Data such as patient age, gender, clinical history and presentation, histologic features, and gene mutations were collected. Results (if a Case Study enter NA) One patient was a 21-year-old male who presented with hematuria and the other was 17-year-old female who presented for work up vaginal bleeding. Both were non-smokers and had no family history of bladder cancer. Cystoscopy showed papillary tumors in both patients and TURBT specimens showing low grade non-invasive urothelial carcinoma in both patients. Genetic testing revealed ATM mutation in both patients. The male patient had recurrent disease twice and received intravesical BCG therapy, the female patient remains without recurrence 12 months later. Both patients remain under surveillance cystoscopy every three months. Conclusion These cases contribute to the growing body of evidence emphasizing the need for personalized therapeutic approaches and further research to unravel the complexities of bladder cancer in the context of ATM gene mutation among young patients.

Whole Exome Sequencing of Intracranial Epidermoid Cysts Reveals Immune-Associated Mechanistic and Potential Targets.

Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor genetic profiling has revealed potential targets for drug development, including FDA-approved options and reshaping treatment. The genetic landscape of IECs has not been explored. We applied Whole Exome Sequencing (WES) to IECs to gain insights into the mechanisms of oncogenesis and identify potential therapeutic targets. Methods: We performed WES on tumor tissue and matched blood samples, when available. Following GATK best practices, we conducted read processing, quality control, somatic variant calling, and copy-number inference. Data analyses and visualization were conducted in R. Results: Top altered genes are associated with the immune system and tumor microenvironment, suggesting a mechanism of immune evasion. Gene and pathway enrichment revealed a high mutation burden in genes associated with Extracellular Matrix (ECM) and PI3K-AKT-mTOR cascades. Recurrent and deleterious alterations in NOTCH2 and USP8 were identified in 50% and 30% of the cohort, respectively. Frequent amplifications in deubiquitinases and beta-defensins strengthened the involvement of immune mechanisms for oncogenic transformation. Conclusions: Top altered genes and recurrent mutations may play a role in shaping the microenvironment and modulating immune evasion in IECs. USP8 and NOTCH2 may serve as clinically relevant target for IECs. Finally, we present evidence that the crosstalk between the PI3K-Akt-mTOR and ECM signaling pathways may play a role in modulating the immune escape mechanism in IECs.

High soybean dietary supplementation with quercetin improves antioxidant capacity of spotted sea bass Lateolabrax maculatus

This study aimed to examine the effect of quercetin (QUE) on the antioxidant capacity of spotted sea bass that were fed a high soybean meal diet. 44 % fish meal was used as a healthy control, and soybean meal instead of 50 % fish meal induced a negative reaction. On this basis, 0.25, 0.50, 0.75, and 1.00 g/kg QUE were added, respectively. A total of 540 spotted sea bass were randomly allocated into 6 groups and provided with diets that corresponded to their respective groups for a duration of 56 days. The results showed a significant decrease in the antioxidant capacity of spotted sea bass fed a high soybean meal diet. The inclusion of QUE considerably improved the antioxidant capacity of spotted sea bass. This was evidenced by the notable rise in glutathione (GSH) levels in the intestine and liver, as well as the elevated levels of catalase (CAT) and total antioxidant capacity (T-AOC) in the liver. Furthermore, transcriptome results showed that the S-transferase (GST) gene in the glutathione metabolism pathway was significantly down-regulated by high soybean meal, while with the addition of QUE, noteworthy alterations in genes associated with the PI3K-Akt signaling pathway, Foxo signaling pathway, and AMPK signaling pathway. These signaling pathways are involved in signal transduction, apoptosis, and oxidative stress. On the other hand, genes related to energy metabolism, such as phosphoenolpyruvate carboxykinase (PEPCK), were observed to be upregulated. These pathways could potentially contribute to the antioxidant properties of QUE.

Genetic Variation and Metabolic Basis of Kidney Cancer: New Opportunities for Targeted Therapy

Renal cell carcinoma (RCC) has previously been considered as a single disease. However, it is currently characterized as a heterogeneous group of tumors that differ in histological features, genetic abnormalities, and variable clinical course. In normal cells, energy is produced by the cleavage of chemical bonds in nutrients through the oxidation of fats, proteins, or carbohydrates. Mutational alterations in genes associated with RCC, including VHL, FLCN, PTEN and SDH, lead to abnormal cellular adaptation to changes in oxygen status, iron metabolism and nutrients. The present paper reviews the known genetic abnormalities observed in RCC and their impact on metabolic alterations. Understanding the genetic and metabolic mechanisms underlying RCC is crucial for the development of effective therapies. Targeting specific genetic abnormalities or metabolic pathways represents a promising approach to the RCC treatment. In addition, studies into the metabolic basis of RCC contribute to the development of new biomarkers for early diagnosis and monitoring of the disease. Moreover, investigating the role of VHL, FLCN, PTEN, and SDH genes in the development of RCC provides valuable information on the molecular mechanisms behind the disease. As a result, it may lead to the development of new treatment strategies aimed at restoring the normal function of these genes or compensating for their abnormalities. Overall, an integrated approach to the study of RCC that considers genetic, metabolic, and clinical aspects will ensure that more effective treatments are developed and prognosis for patients with this disease are improved.

Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma.

Dramatic advances in biological discoveries, since the 1990s, have continued to reshape the treatment paradigm of metastatic renal cell carcinoma (RCC). Von Hippel Lindau (VHL) gene alterations are associated with pro-angiogenic activity and are central to the pathogenesis of clear cell RCC (ccRCC), the most predominant histologic subtype of RCC. Antiangiogenic strategies revolving around this VHL/HIF/VEGF axis have been shown to improve survival in metastatic ccRCC. The discovery of immune checkpoints and agents that target their inhibition introduced a new treatment paradigm for patients with RCC. While initially approved as monotherapy, studies investigating immune checkpoint inhibitor combinations have led to their approval as the new standard of care, providing durable responses and unprecedented improvements in clinical outcome. Despite these advances, the projected 14390 deaths in 2024 from RCC underscore the need to continue efforts in expanding and optimizing treatment options for patients with metastatic RCC. This article reviews key findings that have transformed the way we understand and treat metastatic RCC, in addition to highlighting novel treatment strategies that are currently under development.

Unraveling the socio-cognitive consequences of KCC2 disruption in zebrafish: implications for neurodevelopmental disorders and therapeutic interventions.

During postnatal brain development, maintaining a delicate balance between excitation and inhibition (E/I) is essential for the precise formation of neuronal circuits. The K+/cl- cotransporter 2 (KCC2) is instrumental in this process, and its dysregulation is implicated in various neurological disorders. This study utilized zebrafish (Danio rerio) to investigate the socio-cognitive consequences of KCC2 disruption. Through CRISPR-Cas9 technology, biallelic kcc2a knockout zebrafish larvae were generated, revealing behavioral abnormalities, including impaired social interactions and memory deficits. Molecular analyses unveiled alterations in key genes associated with the GABAergic and glutamatergic systems, potentially contributing to E/I imbalance. Additionally, KCC2 disruption influenced the expression of oxytocin and BDNF, crucial regulators of social behaviors, synaptic plasticity, and memory formation. The study also explored the therapeutic potential of KCC2 modulation using pharmaceuticals, showing the rescuing effects of CLP-290 and LIT-001 on social abnormalities. However, the selective impact of LIT-001 on social behaviors, not memory, highlights the complexity of neurobehavioral modulation. In summary, this study sheds light on the pivotal role of KCC2 in shaping socio-cognitive functions and suggests potential therapeutic avenues for KCC2-related neurological disorders.

Structural alterations of the EGFR gene in glioblastoma samples as a prognostic factor and molecular target for therapy

Introduction. Epidermal growth factor receptor (EGFR) is a transmembrane protein of the receptor tyrosine kinase family that is activated in various cancers (non-small cell lung cancer, colorectal cancer, head and neck tumors). In glial brain tumors, increased EGFR expression levels are characteristic of the most aggressive subtype, glioblastoma. Frequent structural changes of EGFR in glioblastoma are amplification of the chromosome region where the EGFR gene is located, point mutations, as well as deletion of exons 2–7 of the EGFR gene leading to the formation of EGFRvIII transcript.Aim. To determine structural changes of the EGFR gene (point mutations and amplification of the EGFR gene, EGFRvIII transcript) in tumor samples using different methods and to evaluate their potential clinical significance.Materials and methods. The study included 75 patients with brain gliomas (70 of them glioblastoma) aged 34 to 78 years (mean age 56 years). DNA and RNA isolation was performed from fresh frozen tumor tissue, as well as from peripheral blood leukocytes. EGFR gene mutations were determined by next-generation sequencing (NGS), and β allele frequency (BAF) comparative analysis (normal-tumor) was performed to determine the copy number of chromosome 7 regions. Quantitative polymerase chain reaction was used to confirm the EGFR gene amplification in tumor samples, and reverse transcription-PCR was used to detect EGFRvIII variant.Results. The NGS method revealed 11/70 (16 %) mutations in coding regions of EGFR gene in glioblastoma samples, the EGFR gene amplification was detected in 26/70 (37 %) cases; no structural changes of the EGFR gene were detected in 5 glioma samples (astrocytoma, oligodendroglioma). All cases of EGFR gene amplification detected by NGS were confirmed by quantitative polymerase chain reaction. To search for EGFRvIII transcript, 31 tumor RNA samples were examined, of which EGFR amplification was present in 12 samples. EGFRvIII transcript was detected only in samples with EGFR gene amplification – 4/12 (33 %). To assess the clinical significance of structural gene alterations, the frequency of occurrence in primary and recurrent glioblastoma samples was compared.Conclusion. The NGS method allows to detect both point mutations and amplification of the EGFR gene. The EGFR gene amplification was associated with EGFRvIII mutation in 33 % of cases. No statistically significant differences in the frequency of structural changes in the EGFR gene between primary and relapsed glioblastomas were found.

Xylooligosaccharide interferes with the cell cycle and reduces the antibiotic tolerance of avian pathogenic Escherichia coli by associating with its potential antimetabolic actions

This study aimed to probe if xylooligosaccharide (XOS) could act as an antimetabolite to impact the cell cycle and antibiotic tolerance of avian pathogenic Escherichia coli (APEC). We firstly measured the bacteriostasis of XOS against APEC O78 and its effect on the growth of APEC O78 growing on different medium. Afterwards, the effects of XOS on xylose operon activation along with the cell cycle and antibiotic tolerance of APEC O78 were analyzed. The results showed that XOS caused no inhibitory circle against APEC O78 and did not affect (P > 0.05) the growth of APEC O78 growing on LB medium. Besides, APEC O78 was unable to grow on M9 medium (carbon-free) added with XOS. However, XOS exerted a similar role as xylose in increasing (P < 0.05) the expression of certain xylose operon genes including xylose isomerase (XylA)-encoding gene (xylA) and xylose-binding periplasmic protein (XylF)-encoding gene (xylF) in APEC O78. The molecular docking simulation revealed that the major monomer components (xylobiose, xylotriose and xylotetraose) of XOS had stable binding potentials to both XylA and XylF proteins of E. coli, as supported by the low binding free energy and the formation of considerable hydrogen bonds between them. The subsequent analysis showed that XOS altered certain cell cycle-related genes expression, especially elevated (P < 0.05) nrdB expression and decreased ihfB expression to a degree. Moreover, XOS played a similar role as 2-deoxy-glucose (a glucose analogue serving as a typical antimetabolite) in lowering (P < 0.05) the number of ampicillin-tolerant APEC O78. Collectively, XOS had no direct bacteriostasis against APEC and could not be metabolized/utilized by APEC O78. However, it might become an analogue of xylose and then activate xylose transport- and metabolism-related proteins in APEC O78, thus functioning as a potential antimetabolite and exerting anti-metabolic actions. This could at least partially interpret the observed roles of XOS in interfering with the cell cycle and diminishing the antibiotic tolerance of APEC O78. The above findings expand the knowledges about the functions of XOS and provide a basis for exploring novel strategies to reduce the antibiotic tolerance of APEC.

Transipedia.org: k-mer-based exploration of large RNA sequencing datasets and application to cancer data

Indexing techniques relying on k-mers have proven effective in searching for RNA sequences across thousands of RNA-seq libraries, but without enabling direct RNA quantification. We show here that arbitrary RNA sequences can be quantified in seconds through their decomposition into k-mers, with a precision akin to that of conventional RNA quantification methods. Using an index of the Cancer Cell Line Encyclopedia (CCLE) collection consisting of 1019 RNA-seq samples, we show that k-mer indexing offers a powerful means to reveal non-reference sequences, and variant RNAs induced by specific gene alterations, for instance in splicing factors.

Mutational analysis differentiating sporadic carcinomas from colitis-associated colorectal carcinomas

BackgroundUlcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that is associated with increased risk of developing colitis-associated carcinoma (CAC). The genetic profile of CACs is fairly similar to the sporadic colorectal carcinomas (sCRCs), although showing certain differences in the timing and sequence of alterations that contribute to carcinogenesis. Also, both cancer types typically show a strong histological resemblance, which complicates the pathologists’ diagnosis. Due to the different clinical consequences, it is of utmost importance to categorize the corresponding cancer type correctly.MethodsIn this study, we determined the mutation profiles of 64 CACs and sCRCs in the hotspot regions of 50 cancer-associated genes and compared them to 29 controls to identify genetic gene variants that can facilitate the pathologists’ diagnosis. Pearson Chi-Square or Fisher’s exact tests were used for statistical analyses.ResultsWe found that sCRCs tend to mutate more frequently in APC and PIK3CA genes than CACs and that mainly males were affected. Our CAC cohort identified the KRAS G12D mutation as group-specific variant that was not detected in the sCRCs. When separating conventional from non-conventional CACs, it was discovered that the conventional type shows significantly more mutations for ATM.ConclusionsTaken together, our data highlights genetic differences between sCRC and CAC and enables the possibility to utilize specific gene alterations to support the pathologist’s diagnosis.

Single-cell analysis reveals alternations between the aged and young mice prostates

BackgroundAging of the male prostate is an inevitable process in which the prostate undergoes hyperplasia, and this growth may lead to compression of the urethra, resulting in voiding dysfunction and associated symptoms, and an increased risk of prostate cancer. Despite the significance of prostate aging, the molecular mechanisms involved are still not fully understood.MethodsProstate split by lobes from young (2 months) and aged (24 months) mice were collected for single-cell RNA sequencing (scRNA-seq) analysis. Tissues from both anterior prostate (AP) and ventral/dorsal/lateral prostate (VDLP) were included in the study. Data analysis included unsupervised clustering using the uniform manifold approximation and projection (UMAP) algorithm to identify distinct cell types based on marker gene expression. Differential gene expression analysis was performed to identify age-related changes in gene expression across different cell types. Functional enrichment analysis was conducted to elucidate biological pathways associated with differentially expressed genes. Additionally, cellular interactions and developmental trajectories were analyzed to characterize cellular dynamics during prostate aging.ResultsThe single-cell transcriptome analysis of the mouse prostate during aging revealed heterogeneity across various cell types and their changes during the aging process. We found a significant increase in the proportion of mesenchymal and immune cells in aged mice. Our study unveiled alterations in genes and pathways associated with cellular senescence, oxidative stress, and regeneration in epithelial cells. Furthermore, we observed that basal cells may undergo epithelial-mesenchymal transition (EMT) to become mesenchymal cells, particularly prominent in aged mice. Additionally, immune cells, notably macrophages and T cells, exhibited a heightened inflammatory response in aged mice.ConclusionIn summary, our study provides a comparative analysis of the single-cell transcriptome of the aged and young mice prostates, elucidating cellular and molecular changes between the aged and young mice prostates.

Exploring the role of ADAMTSL2 across multiple cancer types: A pan-cancer analysis and validated in colorectal cancer

BackgroundRecent studies have established a correlation between ADAMTSL2 (ADAMTS-like 2) and the development of various cancers. This study aims to conduct a comprehensive pan-cancer analysis in 37 cancer types and investigate its potential role in colon and rectal adenocarcinoma (COADREAD).MethodPan-cancer and mutation data were sourced from The Cancer Genome Atlas (TCGA) database and analyzed using Sangerbox analysis platform. We explored the expression patterns and prognostic implications of ADAMTSL2, and investigated its relationships with tumor heterogeneity, stemness, immune checkpoint genes, immune cell infiltration, RNA modifications, and mutational profiles across different cancers. Additionally, with Ethics Committee approval, we conducted immunohistochemical (IHC) analysis on 120 COADEAD samples to evaluate ADAMTSL2 expression and its association with clinicopathological parameters.ResultsADAMTSL2 expression was positively correlated with the hazard ratio of OS, DSS, DFI and PFI for ESCA and COADREAD. A negative correlation was observed between ADAMTSL2 expression and NEO levels in COAD. Gene alterations in ADAMTSL2 were observed, with a mutation frequency of 5.0% in COAD. There is a significant correlation between ADAMTSL2 expression and immune cell infiltration in a variety of cancers. The expression level of ADAMTSL2 protein was associated with T stage, N stage, M stage (p < 0.05). Kaplan‒Meier survival curves demonstrated that the high ADAMTSL2 group had a shorter OS time (p = 0.047) and progression free survival time (p = 0.026) than the low ADAMTSL2 group.ConclusionIn summary, we conducted a comprehensive pan-cancer analysis of ADAMTSL2 and we demonstrated that ADAMTSL2 may serve as a novel prognostic biomarker and immunotherapy target in COADREAD.

Decoupled fungal and bacterial functional responses to biochar amendment drive rhizosphere priming effect on soil organic carbon mineralization

The application of biochar to soil is widely recognized as a promising strategy for enhancing the accumulation and stability of soil organic carbon (SOC), which is crucial in mitigating climate change. However, the influence of interactions between plants and biochar on soil microbial communities and their involvement in SOC mineralization and stability remains unclear. This understanding is essential for optimizing carbon (C) sequestration in systems involving plants, soil, and biochar. In this study, employing a 13C natural abundance approach, we investigated the effect of biochar on the maize rhizosphere priming effect (RPE) in paddy soil. We also examined alterations in microbial communities and functional genes related to C degradation and fixation. Over the 99 days of maize growth, biochar application increased RPE and total SOC while decreasing dissolved organic C. It also elevated soil pH, resulting in shifts in fungal and bacterial community structure, favoring oligotrophic species. Fungal and bacterial assemblies were dominated by deterministic and stochastic processes, respectively. While the abundance of fungal guilds varied irregularly, bacterial guilds were uniformly enriched under biochar-plant interactions. Functional traits such as ecoenzymatic activities, bacterial guilds, and functional genes predominantly affected RPE under biochar application. Bacterial functional genes associated with C degradation and fixation were concurrently enhanced with biochar application. Our results indicate that interactions between plants and biochar can enhance native SOC mineralization and accumulation in a short timeframe by modulating functional traits of soil microorganisms, particularly the bacterial community involved in C degradation and fixation.Graphical

Proof of Concept for Genome Profiling of the Neurofibroma/Sarcoma Sequence in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness.

Targeting Protein Kinase, Membrane-Associated Tyrosine/Threonine 1 (PKMYT1) for Precision Cancer Therapy: From Discovery to Clinical Trial.

\Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1), an overlooked member of the WEE family responsible for regulating cell cycle transition, has recently emerged as a compelling therapeutic target for precision cancer therapy due to its established synthetic lethal relationship with CCNE1 (cyclin E1) amplification. Since the first-in-class selective PKMYT1 inhibitor, RP-6306, entered clinical trials in 2021, the field has experienced renewed interest underscored by the growing number of inhibitor patents and the exploration of additional gene alterations, such as KRAS/p53 mutations, FBXW7 mutation, and PPP2R1A mutation, as novel synthetic lethal partners. This perspective summarizes, for the first time, the PKMYT1 structure, function, and inhibitors in both the literature and patent applications reported to date. Compounds are described focusing on their design and optimization process, structural features, and biological activity with the aim to promoting further drug discovery efforts targeting PKMYT1 as a potential precision therapy.