Lower Gene Expression Research Articles

Exploring the effects of dietary methionine supplementation on European seabass mucosal immune responses against Tenacibaculum maritimum

IntroductionDietary methionine supplementation has been shown to enhance immunity and disease resistance in fish. However, excessive intake may lead to adverse effects. The present study aimed to evaluate the immune status of European seabass (Dicentrarchus labrax) fed increasing levels of dietary methionine supplementation and to investigate the early immune response to Tenacibaculum maritimum.MethodsFor this purpose, juvenile European seabass were fed one of three experimental diets containing methionine at 8.6 mg/g (CTRL), 18.5 mg/g (MET2), and 29.2 mg/g (MET3) for four weeks, followed by a bath challenge with T. maritimum.ResultsWhile higher methionine intake reduced hemoglobin levels, no other significant changes in the immune status were observed. However, after infection, fish fed higher methionine levels exhibited a dose-dependent decrease in the mRNA expression of some proinflammatory genes. Similarly, RNA sequencing analysis of skin tissue revealed an attenuated immune response in the MET2 group at 24 hours post-infection, with few proinflammatory genes upregulated, which intensified at 48 h, potentially due to advanced tissue colonization by T. maritimum. The MET3 group displayed the least pronounced immune response, along with the enrichment of some immune-related pathways among the downregulated transcripts. These findings, together with the lower mRNA expression of proinflammatory genes in the head kidney and the higher mortality rates observed in this group, suggest a potential impairment of the immune response.`DiscussionOverall, these findings indicate that dietary methionine supplementation may significantly influence both systemic and local immune responses in European seabass, highlighting the need for careful consideration when supplementing diets with methionine.

Comprehensive analysis of H3K27me3 LOCKs under different DNA methylation contexts reveal epigenetic redistribution in tumorigenesis

BackgroundHistone modification H3K27me3 plays a critical role in normal development and is associated with various diseases, including cancer. This modification forms large chromatin domains, known as Large Organized Chromatin Lysine Domains (LOCKs), which span several hundred kilobases.ResultIn this study, we identify and categorize H3K27me3 LOCKs in 109 normal human samples, distinguishing between long and short LOCKs. Our findings reveal that long LOCKs are predominantly associated with developmental processes, while short LOCKs are enriched in poised promoters and are most associated with low gene expression. Further analysis of LOCKs in different DNA methylation contexts shows that long LOCKs are primarily located in partially methylated domains (PMDs), particularly in short-PMDs, where they are most likely responsible for the low expressions of oncogenes. We observe that in cancer cell lines, including those from esophageal and breast cancer, long LOCKs shift from short-PMDs to intermediate-PMDs and long-PMDs. Notably, a significant subset of tumor-associated long LOCKs in intermediate- and long-PMDs exhibit reduced H3K9me3 levels, suggesting that H3K27me3 compensates for the loss of H3K9me3 in tumors. Additionally, we find that genes upregulated in tumors following the loss of short LOCKs are typically poised promoter genes in normal cells, and their transcription is regulated by the ETS1 transcription factor.ConclusionThese results provide new insights into the role of H3K27me3 LOCKs in cancer and underscore their potential impact on epigenetic regulation and disease mechanisms.

Probiotic administration aggravates dextran sulfate sodium salt-induced inflammation and intestinal epithelium disruption in weaned pig

BackgroundA. muciniphila (AKK) has attracted extensive research interest as a potential next-generation probiotics, but its role in intestinal pathology is remains unclear. Herein, this study was conducted to investigate the effects of A. muciniphila DSM 22,959 on growth performance, intestinal barrier function, microecology and inflammatory response of weaned piglets stimulated by dextran sulfate sodium salt (DSS).MethodTwenty-four Duroc × Landrace × Yorkshire (DLY) weaned piglets used for a 2 × 2 factorial arrangement of treatments were divided into four groups with six piglets in each group. From 1 to 15 d, the CA and DA groups were orally fed with 1.0 × 1011 colony-forming units A. muciniphila per day, while the CON and DCON groups were received gastric infusion of anaerobic sterile saline per day. The pigs were orally challenged (DCON, DA) or not (CON, CA) with DSS from day 9 to the end of the experiment and slaughtered on day 16.ResultsPresence of A. muciniphila in DSS-challenged weaned pigs resulted in numerically increased diarrhea rate, blood neutrophilic granulocyte, serum C-reactive protein and immunoglobulin M levels, and numerically reduced final weight, average daily feed intake and average daily gain. The decrease in intestinal villus height, villous height: crypt depth ratio and digestibility was accompanied by lower expression of ZO1, ZO2, Claudin1, DMT1, CAT1, SGLT1 and PBD114 genes, as well as decreased enzyme activities of intestinal alkaline phosphatase, lactase, sucrase and maltase of piglets in DA group compared to piglets in DCON group. The abundance of Bifdobacterium, Lactobacillus, A. muciniphila, Ruminococcus gnavus was numerically higher in digesta of pigs in DA group than those in DCON group. The inflammatory responses of piglets were dramatically changed by the simultaneous presence of A. muciniphila and DSS: expression level of IL17A, IL17F, IL23, RORγt, Stat3 was elevated in DA pigs compared to the other pig groups.ConclusionsOur result showed that the oral A. muciniphila aggravates DSS-induced health damage of weaned piglet, which may attribute to the deteriorating intestinal morphology, dysbiosis of microbiota and inflammatory response disorders.

Sugarcane Pan-Transcriptome Identifying a Master Gene ScHCT Regulating Lignin and Sugar Traits.

Sugarcane has the most complex polyploid genome in the world, and sugar-related traits are one of the most important aims in sugarcane breeding. It is essential to construct a representative pan-transcriptome that contains all transcripts of a species for studies on genetic diversity, population expression, and omics analyses in sugarcane. In this study, we constructed the first comprehensive pan-transcriptome for sugarcane, and 8434 highly reliable open reading frames were found, which were not aligned with any published sugarcane genome. The core and dispensable gene clusters, as well as high- and low-expression gene clusters of the pan-transcriptome, were identified and analyzed. The integration of two sugar content differential transcriptome data revealed nine key candidate genes, including the ScHCT gene, encoding a crucial enzyme for lignin synthesis. Furthermore, the function of the ScHCT gene was validated inArabidopsis, which was negatively correlated with sugar content and positively correlated with lignin content. The interaction protein of ScHCT, ScABH, was screened via a yeast two-hybrid assay and further validated by point-to-point Y2H and bimolecular fluorescence complementation assays. The phenotype of the Arabidopsis abh mutant line revealed that loss of function of ABH resulted in a decrease of sucrose content in stem tissue. This study provides important reference information and genetic resources for sugarcane research and varietal improvement.

Hormone Receptor-Positive HER2-Negative/MammaPrint High-2 Breast Cancers Closely Resemble Triple-Negative Breast Cancers.

The MammaPrint (MP) prognostic assay categorizes breast cancers into high- and low-risk subgroups, and the high-risk group can be further subdivided into high-1 (MP-H1), and very high-risk high-2 (MP-H2). The aim of this analysis was to assess clinical and molecular differences between the hormone receptor-positive (HR+)/HER2-negative MP-H1, -H2, and triple-negative (TN) MP-H1 and -H2 cancers. Pretreatment gene expression data from 742 HER2-negative breast cancers enrolled in the I-SPY2 neoadjuvant trial were used. Prognostic risk categories were assigned using the MP assay. Transcriptional similarities across the four receptor and prognostic groups were assessed using principal component analyses and by identifying differentially expressed genes. We also examined pathologic complete response rates and event-free survivals by risk group. Principal component analysis showed that HR+/MP-H2 tumors clustered with TN/MP-H2 cancers. Only 125 genes showed differential expression between the HR+/MP-H2 and TN/MP-H2 cancers, whereas 1,465 genes were differentially expressed between HR+/MP-H2 and -H1. Gene set analysis revealed similarly high expression of cell cycle, DNA repair, and immune infiltration-related pathways in HR+/MP-H2 and TN/MP-H2 cancers. HR+/MP-H2 cancers also showed low estrogen receptor-related gene expression. Pathologic complete response rates were similarly high in TN/MP-H2 and HR+/MP-H2 cancers (42% vs. 30.5%; P = 0.11), and MP-H2 cancers with residual cancer had similarly poor event-free survival regardless of estrogen receptor status. In conclusion, HR+/MP-H2 cancers closely resemble TN breast cancers in transcriptional and clinical features and benefit from similar treatment strategies.

Effects of quantum dot zinc oxide, nano zinc oxide and zinc oxide on genes expression and aflatoxine production due to Aspergillus flavus ATCC50041

Aflatoxin, which is mainly produced by Aspergillus flavus and Aspergillus parasiticus, is a severe problem and threat in the fields of medicine and agriculture and is classified as the first class human carcinogen due to its carcinogenic, mutagenic, teratogenic, hepatotoxicity, and immune system defects. This toxin contaminates many agricultural products around the world. Considering the high toxicity of aflatoxin and the destructive effects of this metabolite, achieving low-risk and cost-effective methods to control toxin production is of great importance. In this study, the effects of different concentrations of quantum dot zinc oxide, nano zinc oxide, and zinc oxide on the expression of important key genes (aflR, aflP, aflM, aflD) in the gene cluster of aflatoxin production and also the amount of aflatoxin production (B1, B2) in Aspergillus flavus was studied. The fungus was cultured in different concentrations of quantum dot zinc oxide, nano zinc oxide, and zinc oxide (2000, 4000, 6000 ppm) for 3 days at 30 ◦C. The results showed that quantum dot zinc oxide significantly reduced toxin production and gene expression compared to other groups, in which the concentration of aflatoxin was decreased by increasing quantum dot zinc oxide. Regarding the obtained results, nano zinc oxide was effective just at 6000 ppm, and zinc oxide is suggested because nano zinc oxide and zinc oxide cannot completely dissolve in water. Hence, nano zinc oxide and zinc oxide showed weak activity in reducing aflatoxin concentration. All three agents under study significantly caused low gene expression, but quantum-dot zinc oxide showed more activity than the others. The formulation of highly active quantum dot zinc oxide to reduce aflatoxin may be a potential feed additive for the future management of mycotoxins.

Clinical Implications of Breast Cancer Intrinsic Subtypes.

Estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers have different genomic architecture and show large-scale gene expression differences consistent with different cellular origins, which is reflected in the luminal (i.e., ER+) versus basal-like (i.e., ER-) molecular class nomenclature. These two major molecular subtypes have distinct epidemiological risk factors and different clinical behaviors. Luminal cancers can be subdivided further based on proliferative activity and ER signaling. Those with a high expression of proliferation-related genes and a low expression of ER-associated genes, called luminal B, have a high risk of early recurrence (i.e., within 5years), derive significant benefit from adjuvant chemotherapy, and may benefit from adding immunotherapy to chemotherapy. This subset of luminal cancers is identified as the genomic high-risk ER+ cancers by the MammaPrint, Oncotype DX Recurrence Score, EndoPredict, Prosigna, and several other molecular prognostic assays. Luminal A cancers are characterized by low proliferation and high ER-related gene expression. They tend to have excellent prognosis with adjuvant endocrine therapy. Adjuvant chemotherapy may not improve their outcome further. These cancers correspond to the genomic low-risk categories. However, these cancers remain at risk for distant recurrence for extended periods of time, and over 50% of distant recurrences occur after 5years. Basal-like cancers are uniformly highly proliferative and tend to recur within 3-5years of diagnosis. In the absence of therapy, basal-like breast cancers have the worst survival, but these also include many highly chemotherapy-sensitive cancers. Basal-like cancers are often treated with preoperative chemotherapy combined with an immune checkpoint inhibitor which results in 60-65% pathologic complete response rates that herald excellent long-term survival. Patients with residual cancer after neoadjuvant therapy can receive additional postoperative chemotherapy that improves their survival. Currently, there is no clinically actionable molecular subclassification for basal-like cancers, although cancers with high androgen receptor (AR)-related gene expression and those with high levels of immune infiltration have better prognosis, but currently their treatment is not different from basal-like cancers in general. A clinically important, minor subset of breast cancers are characterized by frequent HER2 gene amplification and high expression of a few dozen genes, many residing on the HER2 amplicon. This is an important subset because of the highly effective HER2 targeted therapies which are synergistic with endocrine therapy and chemotherapy. The clinical behavior of HER2-enriched cancers is dominated by the underlying ER subtype. ER+/HER2-enriched cancers tend to have more indolent course and lesser chemotherapy sensitivity than their ER counterparts.

Liver lipid metabolism, oxidative stress, and inflammation in glutamine-supplemented ob/ob mice.

Glutamine availability may be reduced in chronic diseases, such as type 2 diabetes mellitus (T2DM)-induced by obesity. Herein, the antioxidant, anti-inflammatory and lipid metabolism effects of chronic oral glutamine supplementation in its free and dipeptide form were assessed in ob/ob mice. Adult male C57BL/6J ob/ob mice were supplemented with L-alanyl-L-glutamine (DIP) or free L-glutamine (GLN) in the drinking water for 40 days, whilst C57BL/6J Wild-type lean (WT) and control ob/ob mice (CTRL) received fresh water only. Plasma and tissue (skeletal muscle and liver) glutamine levels, and insulin resistance parameters (e.g., GTT, ITT, insulin) were determined. Oxidative stress (e.g., GSH system, Nrf2 translocation), inflammatory (e.g., NFkB translocation, TNF-α gene expression) and lipid metabolism parameters (e.g., plasma and liver triglyceride levels, SRBP-1, FAS, ACC, and ChRBP gene expression) were also analyzed. CTRL ob/ob mice showed lower glutamine levels in plasma and tissue, as well as increased insulin resistance and fat in the liver. Conversely, chronic DIP supplementation restored glutamine levels in plasma and tissues, improved glucose homeostasis and reduced plasma and liver lipid levels. Also, Nrf2 restoration, reduced NFkB translocation, and lower TNF-α gene expression was observed in the DIP group. Interestingly, chronic free GLN only increased muscle glutamine stores but reduced overall insulin resistance, and attenuated plasma and liver lipid metabolic biomarkers. The results presented herein indicate that restoration of body glutamine levels reduces oxidative stress and inflammation in obese and T2DM ob/ob mice. This effect attenuated hepatic lipid metabolic changes observed in obesity.

The crosstalk between efflux pump and resistance gene mutation in Helicobacter pylori

ABSTRACT Efflux pumps play a crucial role in the development of antibiotic resistance. The aim of this study was to investigate the relationship between efflux pump gene expression and resistance gene mutations in Helicobacter pylori. Twenty-six clinical strains with varying resistance characteristics were selected for further experiment. Seven susceptible strains were induced to become resistant, and the expression of efflux pump genes and point mutations were recorded. Four susceptible strains were selected to undergo candidate mutation construction, and changes in efflux pump gene expression were detected. Efflux pump knockout strains were constructed, and their effects on preventing and reversing antibiotic resistance gene mutations were assessed. Results showed that the expression of efflux pump genes hefA and hefD was significantly higher in the multidrug-resistant group compared to other groups. During the process of antibiotic-induced resistance, efflux pump gene expression did not exhibit a steady increase or decrease. Strains with the A2143G or A2142G point mutations in 23S rRNA exhibited lower hefA gene expression. Strains with mutations at 87K/91N, 87N/91 G, 87K/91D, or 87N/91Y in gyrA and the 194insertA mutation in rdxA showed higher hefA gene expression compared to the wild-type strain. During the process of antibiotic-induced resistance, the strain with the knockout of the efflux pump gene hefA developed mutations in the 23S rRNA, gyrA, or rdxA genes later compared to the wild-type strain. Knockout of the efflux pump gene could reverse the phenotypic resistance to clarithromycin or metronidazole in some strains but had no effect on reverse resistance gene mutation. This study suggested that different resistance gene point mutations may have varying effects on efflux pump gene expression. Knockout of the efflux pump gene can delay or prevent antibiotic resistance gene mutations to some extent and can reverse phenotypic resistance to clarithromycin and metronidazole in certain strains.

The RNA-binding protein HuR impairs adipose tissue anabolism in pancreatic cancer cachexia.

Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC), and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice. Human antigen R (HuR) is an RNA-binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC-bearing mice. Adult C57BL/6J mice received orthotopic PDAC cell (Kras G12D ; p53 R172H/+ ; Pdx1-cre) (OT-PDAC) or PBS (sham) injections. Mice exhibiting moderate cachexia (9 days after injection) were fasted for 24h, or fasted 24h and refed 24h before euthanasia. A separate cohort of PDAC mice were treated with an established HuR inhibitor (KH-3, 100 mg/kg) and subjected to the fast/refeed paradigm. We analyzed body mass, gross fat pad mass, and adipose tissue mRNA expression. We quantified lipolytic rate as the normalized quantity of glycerol released from 3T3-L1 adipocytes in vitro, and gonadal fat pads (gWAT) ex vivo. 3T3-L1 adipocytes treated with PDAC cell conditioned media (CM) liberated less triglyceride into the culture media than control-treated adipocytes (-28.1%) and had lower expression of lipolysis and lipogenesis genes than control cells. PDAC gWAT cultured ex vivo displayed decreased lipolysis compared to sham gWAT (-54.7%). PDAC and sham mice lost equivalent fat mass after a 24h fast, however, PDAC mice could not restore inguinal fat pads (iWAT) (-40.5%) or gWAT (-31.8%) mass after refeeding. RNAseq revealed 572 differentially expressed genes in gWAT from PDAC compared to sham mice. Downregulated genes (n=126) were associated with adipogenesis (adj p=0.05), and expression of adipogenesis master regulators Pparg and Cebpa were reduced in gWAT from PDAC mice. Immunohistochemistry revealed increased HuR staining in gWAT (+74.9%) and iWAT (+41.2%) from PDAC mice. Inhibiting HuR binding restored lipogenesis in refed animals with a concomitant increase in iWAT mass (+131.7%) and genes regulating adipogenesis (Pparγ, Cebpa, Retn, Adipoq, Fasn). Our work highlights deficient adipose anabolism as a driver of wasting in 3T3-L1 adipocytes treated with PDAC conditioned media and OT-PDAC mice. The small molecule KH3, which disrupts HuR binding, was sufficient to restore adipogenic and lipogenic gene expression and prevent adipose wasting. This highlights HuR as a potentially targetable regulatory node for adipose anabolism in cancer cachexia.

Cytological, Physiological, and Transcriptome Analysis of Leaf-Yellowing Mutant in Camellia chekiangoleosa.

Color variation in plant leaves has a significant impact on their photosynthesis and plant growth. Camellia chekiangoleosa yellow-leaf mutants are ideal materials for studying the mechanisms of pigment synthesis and photosynthesis, but their mechanism of leaf variation is not clear. We systematically elucidated the intrinsic causes of leaf yellowing in the new Camellia chekiangoleosa variety 'Diecui Liuji' in terms of changes in its cell structure, pigment content, and transcript levels. This study indicates that the incomplete structure of chloroplast-like vesicles, the decrease in blue-green chlorophyll a, and the increase in yellow-green chlorophyll b in yellowing leaves are the direct causes of yellowing-leaf formation. The high expression of genes that catalyze the degradation of chlorophyll a (PAO and RCCR) and its conversion to chlorophyll b (CAO) in yellowing leaves leads to a decrease in the chlorophyll a content, while the low expression of CLH genes is the main reason for the increase in the chlorophyll b content. We also found transcription factors such as ERF, E2F, WRKY, MYB, TPC, TGA, and NFYC may regulate their expression. RT-qPCR assays of 12 DEGs confirm the RNA-seq results. This study will provide a foundation for investigating the transcriptional and regulatory mechanisms of leaf color changes.

Correlations of mucin 5B gene polymorphisms and expression levels with the risk of onset of coal workers’ pneumoconiosis

This study investigates the correlations of mucin 5B (MUC5B) rs2672794, rs2075854, and rs868903 polymorphisms and MUC5B expression level with the risk of the onset of coal workers’ pneumoconiosis (CWP). Overall, 506 Han Chinese men were included in this study. Among them, 143 were healthy individuals, 132 were dust-exposed workers who underwent health monitoring periodically, and 231 were patients with CWP. The participants were categorized into the following groups based on health status: healthy, exposure, CWP stage I, and CWP stage II groups. Genotyping was performed using the MassARRAY platform, and gene expression levels were measured via real-time fluorescence quantitative polymerase chain reaction. Subsequently, the correlations of 3 single-nucleotide polymorphisms (rs2672794, rs2075854, and rs868903) and MUC5B gene expression with the risk of CWP onset were analyzed. Distributions of the rs2672794 (P = .82) and rs2075854 (P = .72) genotypes were not significantly different among the various groups. Frequencies of the CC and CT genotypes of single-nucleotide polymorphism rs868903 and the C allele of MUC5B were higher in patients with CWP than in the healthy group (P = .04). The MUC5B expression level of patients with CWP was significantly lower than those of the exposure and healthy groups (P < .001). Receiver operating characteristic curve analysis revealed that MUC5B in blood cells was a sensitive biomarker for CWP diagnosis. Significant differences were observed in MUC5B gene expression levels among different genotypes of rs868903 (P < .001), with individuals carrying the CC and CT genotypes exhibiting lower MUC5B gene expression levels than those with the TT genotype. The rs868903 polymorphism in the MUC5B gene could be associated with the susceptibility to CWP, and early monitoring would aid in identifying individuals at high risk. MUC5B might serve as a valuable early screening biomarker for CWP.

Iron Deficiency in Tomatoes Reversed by Pseudomonas Strains: A Synergistic Role of Siderophores and Plant Gene Activation.

An alkaline pH in soils reduces Fe availability, limiting Fe uptake, compromising plant growth, and showing chlorosis due to a decrease in chlorophyll content. To achieve proper Fe homeostasis, dicotyledonous plants activate a battery of strategies involving not only Fe absorption mechanisms, but also releasing phyto-siderophores and recruiting siderophore-producing bacterial strains. A screening for siderophore-producing bacterial isolates from the rhizosphere of Pinus pinea was carried out, resulting in two Pseudomonas strains, Z8.8 and Z10.4, with an outstanding in vitro potential to solubilize Fe, Mn, and Co. The delivery of each strain to 4-week-old iron-starved tomatoes reverted chlorosis, consistent with enhanced Fe contents up to 40%. Photosynthesis performance was improved, revealing different strategies. While Z8.8 increased energy absorption together with enhanced chlorophyll "a" content, followed by enhanced energy dissipation, Z10.4 lowered pigment contents, indicating a better use of absorbed energy, leading to a better survival rate. The systemic reprogramming induced by both strains reveals a lower expression of Fe uptake-related genes, suggesting that both strains have activated plant metabolism to accelerate Fe absorption faster than controls, consistent with increased Fe content in leaves (47% by Z8.8 and 42% by Z10.4), with the difference probably due to the ability of Z8.8 to produce auxins affecting root structure. In view of these results, both strains are effective candidates to develop biofertilizers.

Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined With Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies.

To evaluate linrodostat mesylate, a selective, oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, combined with nivolumab ± ipilimumab in advanced solid tumors and hematologic malignancies. In this phase 1/2 study, patients received once-daily (QD) linrodostat (part 1 [escalation], 25-400 mg; part 2 [expansion], 100 or 200 mg) plus nivolumab (480 mg every [Q] 4 weeks [W] or 240 mg Q2W) or triplet therapy (part 3, linrodostat 20-100 mg QD; nivolumab 360 mg Q3W or 480 mg Q4W; ipilimumab 1 mg/kg Q6W or Q8W). Endpoints included safety and efficacy (co-primary; parts 2, 3), pharmacokinetics, pharmacodynamics, biomarkers, and efficacy (part 1). Fifty-five, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1%-63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naive patients. Kynurenine decreased with linrodostat + nivolumab, regardless of response. In contrast, interferon gamma (IFN-γ) gene expression signature was associated with response; in nonmelanoma patients, a composite of low tryptophan 2,3-dioxygenase (TDO2) gene expression plus high IFN-γ signature was associated with response. Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported IDO1 pathway inhibition but did not correlate with response. A composite biomarker of low TDO2 expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.

TCF12 and LncRNA MALAT1 Cooperatively Harness High Cyclin D1 but Low β-Catenin Gene Expression to Exacerbate Colorectal Cancer Prognosis Independently of Metastasis.

Metastasis is a well-known factor worsening colorectal cancer (CRC) prognosis, but mortality mechanisms in non-metastatic patients with poor outcomes are less understood. TCF12 is a transcription factor that can be physically associated with the long non-coding RNA MALAT1, creating an alliance with correlated expression levels in CRC patients. This TCF12-MALAT1 alliance is linked to poorer prognosis independently of age and metastasis. To identify the downstream effects responsible for this outcome, we analyzed 2312 common target genes of TCF12 and MALAT1, finding involvement in pathways like Aurora B, ATM, PLK1, and non-canonical WNT. We investigated the impact of WNT downstream genes CTNNB1 and CCND1, encoding β-catenin and cyclin D1, respectively, on survival in CRC patients with this alliance. Tumors with higher TCF12 and MALAT1 gene expressions alongside increased β-catenin gene expressions were classified as having a "Pan-CMS-2 pattern", showing relatively better prognoses. Conversely, tumors with high TCF12, MALAT1, and cyclin D1 gene expressions but low β-catenin expression were categorized as "TMBC pattern", associated with poor survival, with survival rates dropping sharply from 60% at one year to 30% at three years. This suggests that targeting cyclin D1-associated CDK4/6 could potentially reduce early mortality risks in TMBC patients, supporting personalized medicine approaches.

Low prostaglandin-endoperoxide synthase-2 gene expression in colorectal carcinomas may predict poorer survival

Low prostaglandin-endoperoxide synthase-2 gene expression in colorectal carcinomas may predict poorer survival

Lower expression of MMP2, FLNA, and CFL1 is correlated with favorable prognosis in invasive micropapillary breast cancer.

Despite its recognized aggressive clinical manifestations, invasive micropapillary carcinoma has a controversial prognosis in comparison to invasive ductal carcinoma of the breast. This retrospective study aimed to explore the prognosis and underlying molecular mechanisms of invasive micropapillary carcinoma. Through the SEER database, we compared patients survival outcomes with invasive micropapillary carcinoma versus invasive ductal carcinoma, and developed a nomogram to predict the overall survival of the former group. We explored gene profiles in the GEO database. Hub genes were identified as the top ten genes in the PPI network with the highest degrees of connectivity, and three of them were selected for validation by immunohistochemistry. Invasive micropapillary carcinoma patients had better overall survival and breast cancer-specific survival than invasive ductal carcinoma patients did. Multivariate analysis revealed age, marital status, TN stage, ER status, and chemotherapy as independent prognostic factors for invasive micropapillary carcinoma patients, which were used to construct a nomogram with good performance. A total of 294 DEGs were identified, with ten hub genes, including MMP2, FLNA and CFL1, which were expressed at lower levels in invasive micropapillary carcinoma patients than in invasive ductal carcinoma patients, indicating favorable outcomes. Patients with invasive micropapillary carcinoma generally have a better prognosis than those with invasive ductal carcinoma does, which could be attributed to the lower expression of pro-oncogenic genes in the former group; however, the underlying mechanism needs further investigation.

Auxin Triggers AHR Pathway Activation in the Auxin-Inducible Degron System in Mammalian Cells.

The auxin-inducible degron (AID) system is widely used to study function of various proteins. Theplant hormone auxin is used as an inducer in this system, which easily penetrates into the cells and causes proteasomal degradation of the protein of interest fused to a small degron tag. It is often assumed that as a plant hormone, auxin does not significantly affect physiology of animal cells. In order to test how auxin affects gene expression in human and mouse cells, we collected a set of published data on the levels of gene expression in various experiments with the auxin degradation system of various proteins. The analysis showed that in human HCT116, DLD1, and HAP1 cell lines, as well as in mouse embryonic stem cell lines, auxin treatment leads to activation of aryl hydrocarbon receptor (AHR)-related genes. However, activation of AHR pathway genes does not occur upon auxin treatment in the human IMR32 cells and mouse G1E-ER4 cells, which are characterized by low AHR gene expression. To verify this observation, we conducted an experiment treating human U87, A549, and HCT116 cells with auxin and demonstrated activation of one of the main AHR pathway responders, the CYP1B1 gene. We believe that activation of the AHR pathway should be taken into account by those using the auxin degradation system in their studies.

Machine Learning Enabled Prediction of Biologically Relevant Gene Expression Using CT‐Based Radiomic Features in Non‐Small Cell Lung Cancer

ABSTRACTBackgroundNon‐small‐cell lung cancer (NSCLC) remains a global health challenge, driving morbidity and mortality. The emerging field of radiogenomics utilizes statistical methods to correlate radiographic tumor features with genomic characteristics from biopsy samples. Radiomic techniques automate the precise extraction of imaging features from tumor regions in radiographic scans, which are subjected to machine learning (ML) to predict genomic attributes.MethodsIn a retrospective study of two NSCLC patient cohorts separated by 5 years, we performed a radiogenomic analysis of previously disseminated data from 2018 (n = 116) and newly acquired data from 2023 (n = 44) using RNA sequencing and lung CT images. Combining the data from two cohorts post binarization (of gene expression) or batch normalization (of radiomic features) in each cohort proved to be a better approach as compared to training the model on one cohort and validating on the other.ResultsOur ML‐based radiogenomic modeling identified specific imaging features—wavelet, three‐dimensional local binary patterns, and logarithmic sigma of gray‐level variance—as predictive indicators for high (1) vs. low (0) gene expression of pivotal NSCLC‐related genes: SLC35C1, BCL2L1, and MAPK1. These genes have recognized implications in a variety of biological pathways and mechanisms of drug resistance pertinent to NSCLC.ConclusionThe successful integration of heterogeneous radiogenomic datasets underscores the potential of imaging biomarkers in uncovering NSCLC biological processes through gene expression profiles.

The NLRP3-inflammasome inhibitor MCC950 improves cardiac function in a HFpEF mouse model

Heart failure with preserved ejection fraction (HFpEF) is posing a significant medical challenge due to its growing prevalence, high hospitalization rates and limited response to current treatment options. Accumulating evidence suggests that a comorbidity-driven systemic pro-inflammatory state, including activation of the NLRP3 inflammasome, contributes to the pathogenesis of HFpEF. This study aimed to investigate the potential cardiac protective effects of the selective NLRP3 inhibitor MCC950, in a mouse model of HFpEF. HFpEF was obtained in 18–22 months old female mice using high-fat diet (HFD) and angiotensin II (AngII) infusion. Mice developed HFpEF and comorbidities such as obesity, type 2 diabetes, and hypertension. MCC950 was added to HFD and groups were treated for four weeks until the study endpoint. MCC950 treatment resulted in lower plasma IL-18 levels (-47.3 %), illustrating target engagement. First, we observed that MCC950 treatment improved left ventricular function, demonstrated by enhanced global longitudinal strain (GLS, 3.9 %, P<0.01) and reverse peak longitudinal strain (RPLSR, +46.8 %, P<0.05). Second, MCC950 reduced cardiac hypertrophy (cardiomyocyte size -19.5 %, P<0.001) and fibrosis (-32.5 %, P<0.05), accompanied by lower expression of pro-fibrotic genes. Finally, MCC950 treatment reduced macrophage infiltration in left ventricular tissue and attenuated macrophage accumulation in visceral adipose tissue, even more as compared to caloric restriction. Overall, this suggests that NLRP3 inhibition could be a promising treatment for HFpEF patients with a pro-inflammatory profile, potentially improving heart function, systemic inflammation, and metabolic parameters.