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Gliomas are the most common primary malignant tumors of the brain, accounting for about 80% of all central nervous system malignancies. With the development of molecular biology, the molecular phenotypes of gliomas have been shown to be closely related to the process of diagnosis and treatment. The molecular phenotype of glioma also plays an important role in guiding treatment plans and evaluating treatment effects and prognosis. However, due to the heterogeneity of the tumors and the trauma associated with the surgical removal of tumor tissue, the application of molecular phenotyping in glioma is limited. With the development of imaging technology, functional magnetic resonance imaging (MRI) can provide structural and function information about tumors in a noninvasive and radiation-free manner. MRI is very important for the diagnosis of intracranial lesions. In recent years, with the development of the technology for tumor molecular diagnosis and imaging, the use of molecular phenotype information and imaging procedures to evaluate the treatment outcome of tumors has become a hot topic. By reviewing the related literature on glioma treatment and molecular typing that has been published in the past 20 years, and referring to the latest 2020 NCCN treatment guidelines, summarizing the imaging characteristic and sensitivity of radiotherapy and chemotherapy of different molecular phenotypes of glioma. In this article, we briefly review the imaging characteristics of different molecular phenotypes in gliomas and their relationship with radiosensitivity and chemosensitivity of gliomas. [ABSTRACT FROM AUTHOR]

Among central nervous system-associated malignancies, glioblastoma (GBM) is the most common and has the highest mortality rate. The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide. In precision medicine, research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity, as well as the refractory nature of GBM toward therapy. Deep understanding of the different molecular expression patterns of GBM subtypes is critical. Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes. The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors. These subtypes also exhibit high plasticity in their regulatory pathways, oncogene expression, tumor microenvironment alterations, and differential responses to standard therapy. Herein, we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype. Furthermore, we review the mesenchymal transition mechanisms of GBM under various regulators.

The intensification of warming-induced mass-mortalities in invertebrate populations including in temperate regions is a critical global issue. Mesophotic zones (30–150 m depth) have been suggested as potential refuges from climate change for gorgonian populations, offering hope for reseeding damaged shallow populations. Using a proteomic approach, we investigated the responses and acclimatization ability of the yellow gorgonian Eunicella cavolini along an environmental gradient following reciprocal transplantations between shallow (20 m) and mesophotic (70 m) zones. Our findings indicate that yellow gorgonians from mesophotic waters exhibit a greater plasticity when transplanted to shallow waters, compared to shallow gorgonians transplanted to the mesophotic zone at 70 m. Transplanted colonies from mesophotic to shallow waters showed an increasing level of proteins involved in immune response but displayed no signs of necrosis or apoptosis, highlighting the acclimation potential of mesophotic populations. These results suggest that Eunicella cavolini populations may exhibit physiological plasticity in response to future climate change, allowing natural colonization from mesophotic populations. This analysis offers valuable insights into gorgonians' cellular and molecular responses to environmental changes. [ABSTRACT FROM AUTHOR]

Acylcarnitines are metabolic intermediates of fatty acids and branched-chain amino acids having vital biofunctions and pathophysiological significances. Here, we developed a high-throughput method for quantifying hundreds of acylcarnitines in one run using ultrahigh performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). This enabled simultaneous quantification of 1136 acylcarnitines (C0–C26) within 10-min with good sensitivity (limit of detection 0.992), accuracy (relative error < 20%), precision (coefficient of variation (CV), CV 0.998) for predicting retention time (tR) of acylcarnitines with no standards and built a database of their multiple reaction monitoring parameters (tR, ion-pairs, and collision energy). Furthermore, we quantified 514 acylcarnitines in human plasma and urine, mouse kidney, liver, heart, lung, and muscle. This provides a rapid method for quantifying acylcarnitines in multiple biological matrices.

Acylcarnitines are metabolic intermediates of fatty acids and branched-chain amino acids having vital biofunctions and pathophysiological significances. Here, we developed a high-throughput method for quantifying hundreds of acylcarnitines in one run using ultrahigh performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). This enabled simultaneous quantification of 1136 acylcarnitines (C0–C26) within 10-min with good sensitivity (limit of detection < 0.7 fmol), linearity (correlation coefficient > 0.992), accuracy (relative error < 20%), precision (coefficient of variation (CV), CV < 15%), stability (CV < 15%), and inter-technician consistency (CV < 20%, n = 6). We also established a quantitative structure-retention relationship (goodness of fit > 0.998) for predicting retention time (t R) of acylcarnitines with no standards and built a database of their multiple reaction monitoring parameters (t R , ion-pairs, and collision energy). Furthermore, we quantified 514 acylcarnitines in human plasma and urine, mouse kidney, liver, heart, lung, and muscle. This provides a rapid method for quantifying acylcarnitines in multiple biological matrices. [Display omitted] • A sensitive 10-min method for simultaneous quantification of multiple acylcarnitines. • Quantification of 514 acylcarnitines in multiple biofluids and tissues for molecular phenotyping. • Quantitative structure-retention relationship and database of MRM parameters (t R , ion-pairs, and CE) for 1136 acylcarnitines. [ABSTRACT FROM AUTHOR]

Aging is a major risk factor for heart failure (HF) and is the leading cause of death worldwide. Currently, the nature of the relationship between aging and HF is not entirely clear. Herein, this study aimed to explore new diagnostic biomarkers, molecular typing and therapeutic strategies for HF by investigating the biological significance of aging‐related genes in HF. A total of 157 differentially expressed genes (DEGs) were screened totally between HF and normal samples, and functional enrichment analysis of DEGs revealed the strong association of HF progression with aging, immune processes and metabolism. Six HF‐specific aging‐related genes were further identified, and a diagnostic model was developed and validated for good diagnostic efficacy. In addition, we collected blood samples from 10 normal controls and 10 HF patients for RT‐qPCR analysis to verify the bioinformation. We also identified two aging‐associated subtypes with distinctly different immune infiltration and metabolic microenvironment. Further single‐cell sequencing analysis conducted in the study identified SERPINE1 as a key gene in HF. The distinctive role of SERPINE1 fibroblasts was revealed, including three main findings: (I) fibroblasts had a higher proportion and expression of SERPINE1 levels in HF; (II) the ligand–receptor pair MDK‐LRP1 made the most contributions in high interactions with other cell types in SERPINE1 fibroblasts; and (III) SERPINE1 fibroblasts were associated with the interaction of extracellular matrix and receptor and may be regulated by the transcription factor EGR1. In conclusion, this study highlights the importance of aging‐related genes in diagnosing HF and regulating immune infiltration. We also identified different HF subtypes and a potentially crucial gene, which may provide a better understanding of the molecular‐level mechanisms of aging‐related HF and aid in developing effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the endometrial characteristics (pathomorphological and immunological) of women with infertility. Methods and Results: Data from an immunohistochemical study of endometrial biopsies (TNF-α, IL-10, GM-CSF, CXCL16, BCA1, TGF-β1) collected during the “implantation window” and microbiota studied by real-time polymerase chain reaction in 171 patients (21 women with unexplained infertility, 36 - chronic endometritis, 74 - tubal-peritoneal infertility, 22 - external genital endometriosis, 8 - "thin" endometrium, and 10 healthy fertile women from the comparison group) were analyzed to identify molecular signatures. Chronic endometritis was verified morphologically and immunohistochemically. Each group revealed different immune endometrial phenotypes. The basis of the "normal" phenotype was a controlled immune inflammation and a Lactobacillus-dominant microbiota (LDM) type. In contrast to the comparison group, in the group with the phenotype of chronic inflammation, an excessive immune response (overexpression of TNF-α, GM-CSF, CXCL16, BCA1, and a decrease in IL-10 and TGF-β1 in glandular epithelium and stroma) was determined on the background of non-Lactobacillus-dominated microbiota (NLDM) type (63.3%) (P

BackgroundThe stability of molecular T2/non-T2 phenotypes remains uncertain. The objectives of this study were to assess the stability of these phenotypes and the correlation between serum periostin and asthma T2 phenotypes and endotypes.MethodsDemographics, clinical data, and blood samples were collected. Patients diagnosed with moderate-to-severe asthma were classified into T2 or non-T2 according to previously defined thresholds of blood eosinophilia and serum total IgE levels. Asthma endotype was also determined. After at least 1 year of follow-up, the stability of T2 phenotypes and endotypes was assessed.ResultsA total of 53 patients (72% women), mean age 47 years (range 16–77), were included. In the initial and second evaluations, the T2 phenotype was found in 41.5% and 43.4% of patients and the non-T2 phenotype was found in 58.4% and 56.7%, respectively. The mean [standard deviation (SD), range] serum periostin level was 52.7 (26.2, 22.6–129.7) ng/mL in patients with T2 phenotype, and 39.3 (25.6, 7.7–104.) ng/mL in non-T2 patients (P = 0.063). Periostin levels correlated to endotypes (P = 0.001): 45.7 (27.9) ng/mL in allergic asthma (n = 16 patients), 64.7 (24.9) in aspirin-exacerbated respiratory disease (n = 14), 59.0 (27.6) ng/mL in late-onset eosinophilic asthma (n = 4), and 28.3 (13.3) ng/mL in non-eosinophilic asthma (n = 18).ConclusionsT2 and non-T2 asthma phenotypes assessed by accessible methods in daily practice are stable over time yet widely heterogeneous. Serum periostin does not discriminate between T2 and non-T2 phenotypes. Nevertheless, its correlation to asthma endotypes may contribute to guide therapies targeting T2 cytokines in a more personalized approach.

The interactions of evolutionary forces are difficult to analyse in free‐living populations. However, when properly understood, they provide valuable insights into evolutionary biology and conservation genetics. This is particularly important for the interplay of genetic drift and natural selection in immune genes that confer resistance to disease. The Galápagos Islands are inhabited by four closely related species of mockingbirds (Mimus spp.). We used 12 different‐sized populations of Galápagos mockingbirds and one population of their continental relative northern mockingbird (Mimus polyglottos) to study the effects of genetic drift on the molecular evolution of immune genes, the Toll‐like receptors (TLRs: TLR1B, TLR4 and TLR15). We found that neutral genetic diversity was positively correlated with island size, indicating an important effect of genetic drift. However, for TLR1B and TLR4, there was little correlation between functional (e.g., protein) diversity and island size, and protein structural properties were largely conserved, indicating only a limited effect of genetic drift on molecular phenotype. By contrast, TLR15 was less conserved and even its putative functional polymorphism correlated with island size. The patterns observed for the three genes suggest that genetic drift does not necessarily dominate selection even in relatively small populations, but that the final outcome depends on the degree of selection constraint that is specific for each TLR locus. [ABSTRACT FROM AUTHOR]

Abstract Background Preliminary clinical observations show that contemporaneous hereditary breast cancer (CHBC) patients suffered breast cancer at an early age, which requires further analysis. Methods 38 familial hereditary breast cancer patients (18 CHBC patients and 20 non-CHBC patients) were screened out and 152 non-hereditary breast cancer patients were used as control subjects. Clinical pathologic subtypes, age, tumor location, histological grade, lymph node metastasis, and molecular phenotype expression (ER, PR, HER-2, Ki-67, CK5/6, E-cad, P63, and P120) were compared across all subgroups. Results The incidence of CHBC was 9.47% (18/190) in breast cancer patients. The average ages of onset of CHBC patients, non-CHBC patients, and non-hereditary breast cancer patients were 49.06 ± 6.42, 60.75 ± 9.95 and 61.69 ± 14.34 respectively; whereas there were no significant differences with respect to pathological type or tumor location. There were significant differences in some histological grading (grade II/III), lymph node metastasis and PR expression between hereditary and non-hereditary breast cancers (P

Abstract Background Promoters are sites of transcription initiation that harbour a high concentration of phenotype-associated genetic variation. The evolutionary gain and loss of promoters between species (collectively, termed turnover) is pervasive across mammalian genomes and may play a prominent role in driving human phenotypic diversity. Results We classified human promoters by their evolutionary history during the divergence of mouse and human lineages from a common ancestor. This defined conserved, human-inserted and mouse-deleted promoters, and a class of functional-turnover promoters that align between species but are only active in humans. We show that promoters of all evolutionary categories are hotspots for substitution and often, insertion mutations. Loci with a history of insertion and deletion continue that mode of evolution within contemporary humans. The presence of an evolutionary volatile promoter within a gene is associated with increased expression variance between individuals, but only in the case of human-inserted and mouse-deleted promoters does that correspond to an enrichment of promoter-proximal genetic effects. Despite the enrichment of these molecular quantitative trait loci (QTL) at evolutionarily volatile promoters, this does not translate into a corresponding enrichment of phenotypic traits mapping to these loci. Conclusions Promoter turnover is pervasive in the human genome, and these promoters are rich in molecularly quantifiable but phenotypically inconsequential variation in gene expression. However, since evolutionarily volatile promoters show evidence of selection, coupled with high mutation rates and enrichment of QTLs, this implicates them as a source of evolutionary innovation and phenotypic variation, albeit with a high background of selectively neutral expression variation.

Vascular stem cells exist in the three-layer structure of blood vessel walls and play an indispensable role in angiogenesis under physiological conditions and vascular remodeling under pathological conditions. Vascular stem cells are mostly quiescent, but can be activated in response to injury and participate in endothelial repair and neointima formation. Extensive studies have demonstrated the differentiation potential of stem/progenitor cells to repair endothelium and participate in neointima formation during vascular remodeling. The stem cell population has markers on the surface of the cells that can be used to identify this cell population. The main positive markers include Stem cell antigen-1 (Sca1), Sry-box transcription factor 10 (SOX10). Stromal cell antigen 1 (Stro-1) and Stem cell growth factor receptor kit (c-kit) are still controversial. Different parts of the vessel have different stem cell populations and multiple markers. In this review, we trace the role of vascular stem/progenitor cells in the progression of atherosclerosis and neointima formation, focusing on the expression of stem cell molecular markers that occur during neointima formation and vascular repair, as well as the molecular phenotypic changes that occur during differentiation of different stem cell types. To explore the correlation between stem cell molecular markers and atherosclerotic diseases and neointima formation, summarize the differential changes of molecular phenotype during the differentiation of stem cells into smooth muscle cells and endothelial cells, and further analyze the signaling pathways and molecular mechanisms of stem cells expressing different positive markers participating in intima formation and vascular repair. Summarizing the limitations of stem cells in the prevention and treatment of atherosclerotic diseases and the pressing issues that need to be addressed, we provide a feasible scheme for studying the signaling pathways of vascular stem cells involved in vascular diseases.

Current human Single Amino acid Variants (SAVs) databases provide a link between a SAVs and their effect on the carrier individual phenotype, often dividing them into Deleterious/Neutral variants. This is a very coarse-grained description of the genotype-to-phenotype relationship because it relies on un-realistic assumptions such as the perfect Mendelian behavior of each SAV and considers only dichotomic phenotypes. Moreover, the link between the effect of a SAV on a protein (its molecular phenotype) and the individual phenotype is often very complex, because multiple level of biological abstraction connect the protein and individual level phenotypes. Here we present HPMPdb, a manually curated database containing human SAVs associated with the detailed description of the molecular phenotype they cause on the affected proteins. With particular regards to machine learning (ML), this database can be used to let researchers go beyond the existing Deleterious/Neutral prediction paradigm, allowing them to build molecular phenotype predictors instead. Our class labels describe in a succinct way the effects that each SAV has on 15 protein molecular phenotypes, such as protein-protein interaction, small molecules binding, function, post-translational modifications (PTMs), sub-cellular localization, mimetic PTM, folding and protein expression. Moreover, we provide researchers with all necessary means to re-producibly train and test their models on our database. The webserver and the data described in this paper are available at hpmp.esat.kuleuven.be.

Abstract Purpose We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression. Methods Five patients in a phase II clinical trial of CS1001 (PD-L1 inhibitor) for relapsed or refractory (R/R) cHL were retrospectively reviewed. Formalin-fixed, paraffin-embedded whole tissues from the five patients were evaluated for 9p24.1 genetic alterations based on FISH and the expression of PD-L1, PD-L2, PD-1, major histocompatibility complex (MHC) class I–II, and the tumor microenvironment factorsCD163 and FOXP3 in the microenvironmental niche, as revealed by multiplex immunofluorescence. Results All five patients showed primary refractory disease during first-line treatment. Four patients received PD-1 inhibitor after dropping out of the clinical trial, and all demonstrated at least a partial response. The progression-free survival ranged from 7 to 28 months (median = 18 months), and 9p24.1 amplification was observed in all five patients at the PD-L1/PD-L2 locus. PD-L1 and PD-L2 were colocalized on Hodgkin Reed-Sternberg (HRS) cells in four of the five (80%) patients. There was differential expression of PD-L1 and PD-L2 in cells in the tumor microenvironment in cHL, especially in HRS cells, background cells and tumor-associated macrophages. Conclusions PD-L1 monotherapy may not be sufficient to block the PD-1 pathway; PD-L2 was expressed in HRS and background cells in cHL. The immunologic function of the PD-L2 pathway in anti-tumor activity may be underestimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment.

Simple Summary: The Cancer Genome Atlas (TCGA) and more recent genome profiling recently revealed major intrinsic molecular subtypes in urothelial carcinoma (UC). Here we propose a fast and standardized immunophenotypical classification score (Piescore) that may discriminate between luminal, basal, or neu-like UC as a surrogate of molecular profile, and we describe, for the first time, an intratumoral phenotypical switch in tissue protein expression, from non-muscle to muscle-invasive progression. Our data show that a change from a luminal to a neu-like phenotype could worsen overall survival compared with a transition to a basal phenotype. In recent years, immunohistochemical protein expression was studied as a surrogate to the molecular classification of bladder cancer, although no tissue biomarkers are available for clinical use to predict survival or the response to neoadjuvant chemotherapy (CT) in UC, as the literature produced conflicting results. This retrospective study included TURB specimens harboring foci of HG pT2 muscle-invasive bladder carcinoma (MIBC) from 251 patients who subsequently underwent radical cystectomy. We performed immunohistochemical analysis on tumor samples, for relevant gene-expression-based markers for basal type (CD44, CK5/6) and luminal type (CK20 and pPARγ). Piescore, investigated in both non-muscle-invasive (NMI) and muscle-invasive (MI) components of the tumor, divided basal and luminal UC-types when at least three of the four markers were consistent with a specific phenotype, mixed types if one/two luminal and basal markers were present simultaneously, and neu-like types when all four markers investigated were negative. Eighteen selected cases were also investigated with RT-PCR to validate, and to increase the specificity of, the immunohistochemical results. We observe an immunophenotypical difference in the NMI and MI components in 96/251 UC patients (38.25%): half of tumors (44/96 cases) have a transition to basal, 36.46% (35/96 cases) to neu-like, 12.5% (12/96 cases) to mixed, and 5.2% (5/96 cases) to luminal phenotypes. Mixed tumors in the NMI component are more likely to change phenotype than other groups, particularly compared with basal tumors, which demonstrate greater stability (only 8/96 cases, p < 0.00001). The transition of luminal tumors to basal display a better OS compared with the transition toward neu-like tumors (p = 0.027). Overall, the phenotypical switch does not affect lymphovascular invasion, pT, DFS, or OS compared with non-switched cases. In the MI component, the presence of CD44 expression, irrespective of score-related phenotype, shows a protective effect in papillary-type UC (OS p = 0.008, HR 0.453, PFS p = 0.07, HR 0.599), and in UC naïve for CT (p = 0.0479). Piescore immunophenotyping reveals an intratumoral phenotypical transition between the NMI and MI components of the same tumor. The molecular change is a common event in the mixed and luminal categories, but not in basal tumors, which show better phenotypical stability. This phenomenon could partially explain the sensitivity of a subset of luminal UC to chemotherapy: good responders could be "non-real" luminal UC, which acquire nasal markers, such as CD44. [ABSTRACT FROM AUTHOR]

Purpose: The early detection of breast cancer in women under the age of 40 has posed significant challenges. This can be attributed in part to the limited research conducted on the breast cancer in this age group, particularly with regards to large sample sizes. We aimed to address this gap by analyzing and comparing the ultrasound imaging and pathological characteristics of breast cancer in women aged under 40 and those aged 40 and above. Methods: A retrospective assessment was conducted to examine the ultrasound imaging and clinicopathologic characteristics of 555 women with surgically confirmed breast cancers. The patient cohort consisted of 160 individuals below the age of 40 and 395 individuals aged 40 years and above. Results: Our study identified the breast cancer in patients under 40 years was more likely to show regular shape ( p = 0.043) compared with tumors in patients who were 40 years and over. Furthermore, in young female patients (<40 years), irregular shape was correlated with the HER2-enriched type ( p = 0.02), circumscribed margin ( p = 0.001), and a lack of calcifications ( p = 0.02) were associated with the triple-negative type. In another group (≥40 years), only a lack of calcifications ( p = 0.003) were associated with the triple-negative type. Conclusion: Breast cancer in women under the age of 40 exhibits distinct ultrasonographic characteristics patterns that vary across different immunophenotypes, which may provide certain predictive information for physicians.

Proteomic analysis was carried out on the Crab (upper-shore) and Wave (lower-shore) ecotypes of Littorina saxatilis from a hybrid zone at Silleiro Cape, Spain. Proteome profiles of individual snails were obtained. Protein expression in F1 hybrid snails bred in the laboratory and snails with intermediate shell phenotypes collected from the mid-shore were compared with Crab and Wave ecotypes using analytical approaches used to study dominance. Multivariate analysis over many protein spots showed that the F1 snails are distinct from both ecotypes but closer to the Wave ecotype. The intermediate snails are highly variable, some closer to the Crab and others to the Wave ecotype. Considered on a protein by protein basis, some proteins are significantly closer in expression to the Crab and others to the Wave ecotype for both F1 and intermediate snails. Furthermore, a significant majority of proteins were closer in expression to the Wave ecotype for the F1, consistent with the multivariate analysis. No such significant majority toward either the Crab or Wave ecotype was observed for the intermediate snails. The closer similarity of F1 and Wave ecotype expression patterns could be the result of similar selective pressures in the similar mid-shore and low-shore environments. For a significantly larger number of proteins, intermediate snails were closer in expression to the ecotype having the lower expression, for both Crab and Wave ecotypes. This is somewhat unexpected as lower expression might be expected to be an indication of impairment of function and lower fitness. Proteomic analysis could be important for the identification of candidate proteins useful for gaining improved understanding of adaptation and barriers to gene flow in hybrid zones. [ABSTRACT FROM AUTHOR]

Background: Preliminary clinical observations show that contemporaneous hereditary breast cancer (CHBC) patients suffered breast cancer at an early age, which requires further analysis.Methods: 38 familial hereditary breast cancer patients (18 CHBC patients and 20 non-CHBC patients) were screened out and 152 non-hereditary breast cancer patients were used as control subjects. Clinical pathologic subtypes, age, tumor location, histological grade, lymph node metastasis, and molecular phenotype expression (ER, PR, HER-2, Ki-67, CK5/6, E-cad, P63, and P120) were compared across all subgroups.Results: The incidence of CHBC was 9.47% (18/190) in breast cancer patients. The average ages of onset of CHBC patients, non-CHBC patients, and non-hereditary breast cancer patients were 49.06 ± 6.42, 60.75 ± 9.95 and 61.69 ± 14.34 respectively; whereas there were no significant differences with respect to pathological type or tumor location. There were significant differences in some histological grading (grade II/III), lymph node metastasis and PR expression between hereditary and non-hereditary breast cancers (P < 0.05; P < 0.05 and P < 0.005, respectively). Significantly different HER-2 expression was observed when comparing all hereditary or CHBC patients with non-hereditary breast cancers (P < 0.05 and P < 0.005, respectively). There were significant differences in E-cad and P63 between contemporaneous hereditary and non-hereditary breast cancers (P < 0.005 and P < 0.05, respectively).Conclusions: CHBC patients accounted for 9.47% (18/190) of breast cancer patients, had earlier disease onset, and showed differences compared to non-hereditary breast cancer patients with respect to molecular phenotype and clinical characteristics. [ABSTRACT FROM AUTHOR]

The data presented in this article are related to the research article entitled "The autoimmune risk gene ZMIZ1 is a vitamin D responsived marker of a molecular phenotype of multiple sclerosis" Fewings et al. (2017) [1]. Here we identify the set of genes correlated with ZMIZ1 in multiple cohorts, provide phenotypic details on those cohorts, and identify the genes negatively correlated with ZMIZ1 and the cells predominantly expressing those genes. We identify the metabolic pathways in which the molecular phenotype genes are over-represented. Finally, we present the flow cytometry gating strategy we have used to identify the immune cells from blood which are producing ZMIZ1 and RPS6.

Background: Cancer of the breast is the most common organ-specific cancer, affecting women worldwide with disproportionately higher mortality seen among women of Africa ancestry. Molecular phenotyping is crucial for tailored treatment of such patients. Aim: The aim of the study is to describe the molecular phenotypes of carcinomas of the breast based on their oestrogen, progesterone, and HER-2/Neu receptors status in our centre. Design: This was a retrospective analysis of 136 histologically diagnosed breast carcinomas, for which oestrogen, progesterone, and HER2 receptors status data were available at the Pathology Unit in a Nigerian District Hospital. Materials and Methods: Relevant biodata and pathology and molecular information of all patients with histologically diagnosed breast cancer (BC) were extracted from patients' forms and reports archived in the department. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue blocks of 136 (54.4%) cases of the BCs utilizing the avidin-biotin complex technique. Results: The ages of the patients ranged from 17 to 74 years, and the mean age was 47.3 ± 11.7 at diagnosis. All affected patients were females except for a male teenager. oestrogen, progesterone, and HER-2/Neu receptor-positive breast carcinomas were 43.4% (59), 39% (53), and 27.2% (37), respectively. Triple-negative breast carcinoma (39%, 53/136) was the most prevalent phenotype, followed by Luminal A (33.8%, 46/136) and Luminal B (14.7%, 20/136), while HER2-enriched (12.5%, 17/136) was the least common molecular subtype in our series. Conclusion: Breast carcinomas are predominantly of the triple-negative molecular phenotype in our setting and commonly affected young women.

Breast cancer is a common cause of mortality among women worldwide. The incidence of this disease is higher in developing countries than in Western countries. Variations are noted in the distribution of breast cancer subtypes between Eastern and Western populations. Breast cancer is a heterogeneous lesion at the molecular level, and its prognosis is dependent on multiple factors. The present study aimed to determine the distribution of various molecular phenotypes of breast cancer and its association with tumor volume in patients presenting to a tertiary care hospital. The present observational cross-sectional study was conducted at a tertiary care medical college hospital. Following analysis using immunohistochemistry for estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and Ki67, all patients with breast cancer were classified into the luminal A, luminal B, HER2-enriched and triple-negative breast cancer (TNBC) groups. In addition, the age and tumor volume of the patients were compared among the different subtypes of breast cancer. Of the 165 patients with infiltrating ductal carcinoma (type not otherwise specified), the most common molecular phenotype was TNBC (39.4%), followed by luminal B (24.2%). The HER2-enriched and luminal A subtypes constituted 20.6 and 15.8%, respectively. There was no significant difference in the average age of the patients among the different molecular phenotypes. The smallest median tumor volume was observed in the luminal A (4.5 cm3) group, followed by the HER2-enriched (8.0 cm3), TNBC (24.0 cm3) and luminal B (29.94 cm3) groups. TNBC was the most common molecular phenotype. The tumor volume was the smallest in the patients with the luminal A subtype. As tumor volume has prognostic value, the poor prognosis of patients with TNBC and HER2-enriched breast cancer may be improved via targeted therapy. It is hoped that the findings of the present study may prove useful in the management of patients with breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression.Methods: Five patients in a phase II clinical trial of CS1001 (PD-L1 inhibitor) for relapsed or refractory (R/R) cHL were retrospectively reviewed. Formalin-fixed, paraffin-embedded whole tissues from the five patients were evaluated for 9p24.1 genetic alterations based on FISH and the expression of PD-L1, PD-L2, PD-1, major histocompatibility complex (MHC) class I-II, and the tumor microenvironment factorsCD163 and FOXP3 in the microenvironmental niche, as revealed by multiplex immunofluorescence.Results: All five patients showed primary refractory disease during first-line treatment. Four patients received PD-1 inhibitor after dropping out of the clinical trial, and all demonstrated at least a partial response. The progression-free survival ranged from 7 to 28 months (median = 18 months), and 9p24.1 amplification was observed in all five patients at the PD-L1/PD-L2 locus. PD-L1 and PD-L2 were colocalized on Hodgkin Reed-Sternberg (HRS) cells in four of the five (80%) patients. There was differential expression of PD-L1 and PD-L2 in cells in the tumor microenvironment in cHL, especially in HRS cells, background cells and tumor-associated macrophages.Conclusions: PD-L1 monotherapy may not be sufficient to block the PD-1 pathway; PD-L2 was expressed in HRS and background cells in cHL. The immunologic function of the PD-L2 pathway in anti-tumor activity may be underestimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment. [ABSTRACT FROM AUTHOR]

ObjectiveAging acts as a dominating risk factor for human cancers. Herein, we systematically dissected the features of transcriptional aging-relevant genes in gastric cancer from multiple perspectives.MethodsBased on the transcriptome profiling of prognostic aging-relevant genes, patients with gastric cancer in The Cancer Genome Atlas (TCGA) stomach adenocarcinoma (TCGA-STAD) cohort were clustered with a consensus clustering algorithm. Mutational landscape and chemotherapeutic responses were analyzed and immunological features (immunomodulators, immune checkpoint molecules, cancer immunity cycle, and tumor-infiltrating immune cells) were systematically evaluated across gastric cancer. Weighted gene co-expression network (WGCNA) was conducted for screening aging molecular phenotype-relevant genes, and key genes were identified with Molecular Complex Detection (MCODE) analyses. Expressions of key genes were examined in 20 paired tumors and controls with RT-qPCR and Western blotting. Proliferation and apoptosis were investigated in two gastric cancer cells under MYL9 deficiency.ResultsThree aging-based molecular phenotypes (namely, C1, C2, and C3) were conducted in gastric cancer. Phenotype C1 presented the most prominent survival advantage and highest mutational frequencies. Phenotype C2 indicated low responses to sorafenib and gefitinib, while C3 indicated low responses to vinorelbine and gemcitabine. Additionally, phenotype C2 was characterized by enhanced immune and stromal activation and an inflamed tumor microenvironment. Seven aging molecular phenotype-relevant key genes (ACTA2, CALD1, LMOD1, MYH11, MYL9, MYLK, and TAGLN) were identified, which were specifically upregulated in tumors and in relation to dismal prognosis. Among them, MYL9 deficiency reduced proliferation and enhanced apoptosis in gastric cancer cells.ConclusionCollectively, aging-based molecular subtypes may offer more individualized therapy recommendations and prognosis assessment for patients in distinct subtypes.

Problematic severe asthma remains a significant challenge to manage, accounting for the majority of healthcare utilization among children with asthma. The heterogeneity is recognized and the clinical phenotypes of "difficult‐to‐treat" asthma (DA) and "severe therapy‐resistant asthma" (STRA) help to guide management. Recent evidence supports molecular distinctions between these phenotypes and shows poor correlations between peripheral and airway markers of inflammation, especially in STRA. Airway neutrophils in the context of childhood severe asthma have been explored, but their role in disease causation, protection, or as bystanders remain unknown, and thus, treatment implications are unclear. Several novel management strategies, including once‐daily maintenance therapy, single‐device maintenance and reliever therapy, and novel biological treatments are being increasingly used for DA and STRA. However, pediatric data for efficacy of novel treatments is scarce, and when available, is restricted to adolescents. The aim of this review is to highlight recent advances in objective biomarkers that aid stratification and management of childhood severe asthma and to highlight gaps in pediatric evidence. Specifically, the urgent need for efficacy studies to improve the management of problematic severe asthma in children younger than 12 years. [ABSTRACT FROM AUTHOR]

Molecular phenotypic variations in metabolites offer the promise of rapid profiling of physiological and pathological states for diagnosis, monitoring, and prognosis. Since present methods are expensive, time-consuming, and still not sensitive enough, there is an urgent need for approaches that can interrogate complex biological fluids at a system-wide level. Here, we introduce hyperspectral surface-enhanced Raman spectroscopy (SERS) to profile microliters of biofluidic metabolite extraction in 15 min with a spectral set, SERSome, that can be used to describe the structures and functions of various molecules produced in the biofluid at a specific time via SERS characteristics. The metabolite differences of various biofluids, including cell culture medium and human serum, are successfully profiled, showing a diagnosis accuracy of 80.8% on the internal test set and 73% on the external validation set for prostate cancer, discovering potential biomarkers, and predicting the tissue-level pathological aggressiveness. SERSomes offer a promising methodology for metabolic phenotyping., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Among central nervous system-associated malignancies, glioblastoma (GBM) is the most common and has the highest mortality rate. The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide. In precision medicine, research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity, as well as the refractory nature of GBM toward therapy. Deep understanding of the different molecular expression patterns of GBM subtypes is critical. Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes. The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors. These subtypes also exhibit high plasticity in their regulatory pathways, oncogene expression, tumor microenvironment alterations, and differential responses to standard therapy. Herein, we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype. Furthermore, we review the mesenchymal transition mechanisms of GBM under various regulators., Competing Interests: No potential conflicts of interest are disclosed., (Copyright: © 2024, The Authors.)

In recent years, immunohistochemical protein expression was studied as a surrogate to the molecular classification of bladder cancer, although no tissue biomarkers are available for clinical use to predict survival or the response to neoadjuvant chemotherapy (CT) in UC, as the literature produced conflicting results. This retrospective study included TURB specimens harboring foci of HG pT2 muscle-invasive bladder carcinoma (MIBC) from 251 patients who subsequently underwent radical cystectomy. We performed immunohistochemical analysis on tumor samples, for relevant gene-expression-based markers for basal type (CD44, CK5/6) and luminal type (CK20 and pPARγ). Piescore, investigated in both non-muscle-invasive (NMI) and muscle-invasive (MI) components of the tumor, divided basal and luminal UC-types when at least three of the four markers were consistent with a specific phenotype, mixed types if one/two luminal and basal markers were present simultaneously, and neu-like types when all four markers investigated were negative. Eighteen selected cases were also investigated with RT-PCR to validate, and to increase the specificity of, the immunohistochemical results. We observe an immunophenotypical difference in the NMI and MI components in 96/251 UC patients (38.25%): half of tumors (44/96 cases) have a transition to basal, 36.46% (35/96 cases) to neu-like, 12.5% (12/96 cases) to mixed, and 5.2% (5/96 cases) to luminal phenotypes. Mixed tumors in the NMI component are more likely to change phenotype than other groups, particularly compared with basal tumors, which demonstrate greater stability (only 8/96 cases, p < 0.00001). The transition of luminal tumors to basal display a better OS compared with the transition toward neu-like tumors (p = 0.027). Overall, the phenotypical switch does not affect lymphovascular invasion, pT, DFS, or OS compared with non-switched cases. In the MI component, the presence of CD44 expression, irrespective of score-related phenotype, shows a protective effect in papillary-type UC (OS p = 0.008, HR 0.453, PFS p = 0.07, HR 0.599), and in UC naïve for CT (p = 0.0479). Piescore immunophenotyping reveals an intratumoral phenotypical transition between the NMI and MI components of the same tumor. The molecular change is a common event in the mixed and luminal categories, but not in basal tumors, which show better phenotypical stability. This phenomenon could partially explain the sensitivity of a subset of luminal UC to chemotherapy: good responders could be “non-real” luminal UC, which acquire nasal markers, such as CD44.

Abstract Background Modern molecular profiling techniques are yielding vast amounts of data from patient samples that could be utilized with machine learning methods to provide important biological insights and improvements in patient outcomes. Unsupervised methods have been successfully used to identify molecularly-defined disease subtypes. However, these approaches do not take advantage of potential additional clinical outcome information. Supervised methods can be implemented when training classes are apparent (e.g., responders or non-responders to treatment). However, training classes can be difficult to define when assessing relative benefit of one therapy over another using gold standard clinical endpoints, since it is often not clear how much benefit each individual patient receives. Results We introduce an iterative approach to binary classification tasks based on the simultaneous refinement of training class labels and classifiers towards self-consistency. As training labels are refined during the process, the method is well suited to cases where training class definitions are not obvious or noisy. Clinical data, including time-to-event endpoints, can be incorporated into the approach to enable the iterative refinement to identify molecular phenotypes associated with a particular clinical variable. Using synthetic data, we show how this approach can be used to increase the accuracy of identification of outcome-related phenotypes and their associated molecular attributes. Further, we demonstrate that the advantages of the method persist in real world genomic datasets, allowing the reliable identification of molecular phenotypes and estimation of their association with outcome that generalizes to validation datasets. We show that at convergence of the iterative refinement, there is a consistent incorporation of the molecular data into the classifier yielding the molecular phenotype and that this allows a robust identification of associated attributes and the underlying biological processes. Conclusions The consistent incorporation of the structure of the molecular data into the classifier helps to minimize overfitting and facilitates not only good generalization of classification and molecular phenotypes, but also reliable identification of biologically relevant features and elucidation of underlying biological processes.

The White Striping (WS) and Wooden Breast (WB) defects are two myopathic syndromes whose occurrence has recently increased in modern fast-growing broilers. The impact of these defects on the quality of breast meat is very important, as they greatly affect its visual aspect, nutritional value, and processing yields. The research conducted to date has improved our knowledge of the biological processes involved in their occurrence, but no solution has been identified so far to significantly reduce their incidence without affecting growing performance of broilers. This study aims to follow the evolution of molecular phenotypes in relation to both fast-growing rate and the occurrence of defects in order to identify potential biomarkers for diagnostic purposes, but also to improve our understanding of physiological dysregulation involved in the occurrence of WS and WB. This has been achieved through enzymatic, histological, and transcriptional approaches by considering breast muscles from a slow- and a fast-growing line, affected or not by WS and WB. Fast-growing muscles produced more reactive oxygen species (ROS) than slow-growing ones, independently of WS and WB occurrence. Within fast-growing muscles, despite higher mitochondria density, muscles affected by WS or WB defects did not show higher cytochrome oxidase activity (COX) activity, suggesting altered mitochondrial function. Among the markers related to muscle remodeling and regeneration, immunohistochemical staining of FN1, NCAM, and MYH15 was higher in fast- compared to slow-growing muscles, and their amount also increased linearly with the presence and severity of WS and WB defects, making them potential biomarkers to assess accurately their presence and severity. Thanks to an innovative histological technique based on fluorescence intensity measurement, they can be rapidly quantified to estimate the injuries induced in case of WS and WB. The muscular expression of several other genes correlates also positively to the presence and severity of the defects like TGFB1 and CTGF, both involved in the development of connective tissue, or Twist1, known as an inhibitor of myogenesis. Finally, our results suggested that a balance between TGFB1 and PPARG would be essential for fibrosis or adiposis induction and therefore for determining WS and WB phenotypes.

The White Striping (WS) and Wooden Breast (WB) defects are two myopathic syndromes whose occurrence has recently increased in modern fast-growing broilers. The impact of these defects on the quality of breast meat is very important, as they greatly affect its visual aspect, nutritional value, and processing yields. The research conducted to date has improved our knowledge of the biological processes involved in their occurrence, but no solution has been identified so far to significantly reduce their incidence without affecting growing performance of broilers. This study aims to follow the evolution of molecular phenotypes in relation to both fast-growing rate and the occurrence of defects in order to identify potential biomarkers for diagnostic purposes, but also to improve our understanding of physiological dysregulation involved in the occurrence of WS and WB. This has been achieved through enzymatic, histological, and transcriptional approaches by considering breast muscles from a slow- and a fast-growing line, affected or not by WS and WB. Fast-growing muscles produced more reactive oxygen species (ROS) than slow-growing ones, independently of WS and WB occurrence. Within fast-growing muscles, despite higher mitochondria density, muscles affected by WS or WB defects did not show higher cytochrome oxidase activity (COX) activity, suggesting altered mitochondrial function. Among the markers related to muscle remodeling and regeneration, immunohistochemical staining of FN1, NCAM, and MYH15 was higher in fast- compared to slow-growing muscles, and their amount also increased linearly with the presence and severity of WS and WB defects, making them potential biomarkers to assess accurately their presence and severity. Thanks to an innovative histological technique based on fluorescence intensity measurement, they can be rapidly quantified to estimate the injuries induced in case of WS and WB. The muscular expression of several other genes correlates also positively to the presence and severity of the defects like TGFB1 and CTGF , both involved in the development of connective tissue, or Twist1 , known as an inhibitor of myogenesis. Finally, our results suggested that a balance between TGFB1 and PPARG would be essential for fibrosis or adiposis induction and therefore for determining WS and WB phenotypes. [ABSTRACT FROM AUTHOR]

Triple-negative tumors are characterized immunohistochemically by the absence of positivity to sex hormone receptors and to human epidermal growth factor receptor 2. Additionally, they are differentiated into basal-like and non-basal (or null) subtypes, based on the presence of basal cytokeratin expression (CK5/6, 14, and17). Triple-negative subtypes are yet to be characterized in male dogs, to our knowledge. We report herein the clinical and pathologic findings and molecular characterization of carcinoma in the mammary glands of 2 male dogs. Case 1 was diagnosed as a grade II tubulopapillary carcinoma; case 2 was diagnosed as a grade II carcinoma in a mixed tumor. The tumors were characterized phenotypically as triple-negative basal and triple-negative non-basal, respectively. [ABSTRACT FROM AUTHOR]

Genetic alterations in oncogenic pathways are critical for cancer initiation, development, and treatment resistance. However, studies are limited regarding pathways correlated with prognosis, sorafenib, and transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). In this study, 1928 patients from 11 independent datasets and a clinical in-house cohort were screened to explore the relationships among canonical pathway alterations in HCC patients. The molecular mechanisms, biological functions, immune landscape, and clinical outcomes among three heterogeneous phenotypes were further explored. We charted the detailed landscape of pathway alterations in the TCGA-LIHC cohort, screened three pivotal pathways (p53, PI3K, and WNT), identified co-occurrence patterns and mutual exclusively, and stratified patients into three altered-pathway dominant phenotypes (ADPs). P53|PI3K ADP characterized by genomic instability (e.g., highest TMB, FGA, FGG, and FGL) indicated an unfavorable prognosis. While, patients in WNT ADP suggested a median prognosis, enhanced immune activation, and sensitivity to PD-L1 therapy. Remarkably, sorafenib and TACE exhibited efficacy for patients in WNT ADP and low frequent alteration phenotype (LFP). Additionally, ADP could work independently of common clinical traits (e.g., AJCC stage) and previous molecular classifications (e.g., iCluster, serum biomarkers). ADP provides a new perspective for identifying patients at high risk of recurrence and could optimize precision treatment to improve the clinical outcomes in HCC. The work flow in current study. [Display omitted] • We creatively developed three altered-pathway dominant phenotypes (ADPs) of HCC based on co-occurrence and mutual exclusively. • P53|KI3K ADP possessed genomic instability and an unfavorable mortality rate and recurrence. • WNT ADP and low frequent alteration phenotype (LFP) benefited from sorafenib and TACE. • WNT ADP suggested the sensitivity to PD-L1 therapy and displayed enhanced immune activation. [ABSTRACT FROM AUTHOR]

Because immune checkpoint inhibitors have been approved for treating advanced urothelial carcinoma (UC), programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been widely used as companion or complementary diagnostic tests for predicting treatment outcomes. Because different clones, scoring algorithms, and cutoffs have been used for interpretation, this study investigated the variation, correlation, and concordance of four validated PD-L1 clones (SP142, SP263, 22C3, and 28-8) and proposed a practical solution for the harmonization of PD-L1 IHC. A tissue microarray, including 46 muscle-invasive UCs, was constructed for PD-L1 testing with the four clones. Tumor cell (TC) and immune cell (IC) expression was analyzed. SP142 had significantly low TC expression, whereas SP263, 22C3, and 28-8 exhibited a moderate correlation (rho ≥ 0.6), with almost perfect concordance (intraclass correlation coefficient > 0.8) in TC expression. Fair to moderate correlation and concordance were observed in IC expression in most pairwise comparisons of clones. Substantial concordance (kappa > 0.6) was noted when high PD-L1 expression was defined by applying clone-specific cutoffs to each clone. Our findings imply that a universal cutoff value is not feasible for UC; we propose that PD-L1 IHC assays for UC should be interpreted according to a clone-specific scoring algorithm and cutoff value.

Background: Modern molecular profiling techniques are yielding vast amounts of data from patient samples that could be utilized with machine learning methods to provide important biological insights and improvements in patient outcomes. Unsupervised methods have been successfully used to identify molecularly-defined disease subtypes. However, these approaches do not take advantage of potential additional clinical outcome information. Supervised methods can be implemented when training classes are apparent (e.g., responders or non-responders to treatment). However, training classes can be difficult to define when assessing relative benefit of one therapy over another using gold standard clinical endpoints, since it is often not clear how much benefit each individual patient receives. Results: We introduce an iterative approach to binary classification tasks based on the simultaneous refinement of training class labels and classifiers towards self-consistency. As training labels are refined during the process, the method is well suited to cases where training class definitions are not obvious or noisy. Clinical data, including time-to-event endpoints, can be incorporated into the approach to enable the iterative refinement to identify molecular phenotypes associated with a particular clinical variable. Using synthetic data, we show how this approach can be used to increase the accuracy of identification of outcome-related phenotypes and their associated molecular attributes. Further, we demonstrate that the advantages of the method persist in real world genomic datasets, allowing the reliable identification of molecular phenotypes and estimation of their association with outcome that generalizes to validation datasets. We show that at convergence of the iterative refinement, there is a consistent incorporation of the molecular data into the classifier yielding the molecular phenotype and that this allows a robust identification of associated attributes and the underlying biological processes. Conclusions: The consistent incorporation of the structure of the molecular data into the classifier helps to minimize overfitting and facilitates not only good generalization of classification and molecular phenotypes, but also reliable identification of biologically relevant features and elucidation of underlying biological processes. [ABSTRACT FROM AUTHOR]

Understanding the genetic basis of local adaptation has long been a focus of evolutionary biology. Recently, there has been increased interest in deciphering the evolutionary role of Daphnia's plasticity and the molecular mechanisms of local adaptation. Using transcriptome data, we assessed the differences in gene expression profiles and sequences in four European Daphnia galeata populations. In total, ~33% of 32,903 transcripts were differentially expressed between populations. Among 10,280 differentially expressed transcripts, 5,209 transcripts deviated from neutral expectations and their population‐specific expression pattern is likely the result of local adaptation processes. Furthermore, a SNP analysis allowed inferring population structure and distribution of genetic variation. The population divergence at the sequence level was comparatively higher than the gene expression level by several orders of magnitude consistent with strong founder effects and lack of gene flow between populations. Using sequence homology, the candidate transcripts were annotated using a comparative genomics approach. Additionally, we also performed a weighted gene co‐expression analysis to identify population‐specific regulatory patterns of transcripts in D. galeata. Thus, we identified candidate transcriptomic regions for local adaptation in this key species of aquatic ecosystems in the absence of any laboratory‐induced stressor. Understanding the patterns of variation at the regulatory and sequence level provide insights into the genetic basis of local adaptation. Using transcriptome data, we observed contrasting patterns of divergence at the gene expression and sequence level. Our combination of approaches helped to identify candidate transcripts for local adaptation in European Daphnia galeata populations. [ABSTRACT FROM AUTHOR]

Guanine quadruplex (G4) structures are among the most stable secondary DNA structures that can form in vitro, and evidence for their existence in vivo has been steadily accumulating. Originally described mainly for their deleterious effects on genome stability, more recent research has focused on (potential) functions of G4 structures in telomere maintenance, gene expression, and other cellular processes. The combined research on G4 structures has revealed that properly regulating G4 DNA structures in cells is important to prevent genome instability and disruption of normal cell function. In this short review we provide some background and historical context of our work resulting in the identification of FANCJ, RTEL1 and BLM as helicases that act on G4 structures in vivo. Taken together these studies highlight important roles of different G4 DNA structures and specific G4 helicases at selected genomic locations and telomeres in regulating gene expression and maintaining genome stability.

Background: The stability of molecular T2/non-T2 phenotypes remains uncertain. The objectives of this study were to assess the stability of these phenotypes and the correlation between serum periostin and asthma T2 phenotypes and endotypes., Methods: Demographics, clinical data, and blood samples were collected. Patients diagnosed with moderate-to-severe asthma were classified into T2 or non-T2 according to previously defined thresholds of blood eosinophilia and serum total IgE levels. Asthma endotype was also determined. After at least 1 year of follow-up, the stability of T2 phenotypes and endotypes was assessed., Results: A total of 53 patients (72% women), mean age 47 years (range 16-77), were included. In the initial and second evaluations, the T2 phenotype was found in 41.5% and 43.4% of patients and the non-T2 phenotype was found in 58.4% and 56.7%, respectively. The mean [standard deviation (SD), range] serum periostin level was 52.7 (26.2, 22.6-129.7) ng/mL in patients with T2 phenotype, and 39.3 (25.6, 7.7-104.) ng/mL in non-T2 patients ( P  = 0.063). Periostin levels correlated to endotypes ( P  = 0.001): 45.7 (27.9) ng/mL in allergic asthma ( n  = 16 patients), 64.7 (24.9) in aspirin-exacerbated respiratory disease ( n  = 14), 59.0 (27.6) ng/mL in late-onset eosinophilic asthma ( n  = 4), and 28.3 (13.3) ng/mL in non-eosinophilic asthma ( n  = 18)., Conclusions: T2 and non-T2 asthma phenotypes assessed by accessible methods in daily practice are stable over time yet widely heterogeneous. Serum periostin does not discriminate between T2 and non-T2 phenotypes. Nevertheless, its correlation to asthma endotypes may contribute to guide therapies targeting T2 cytokines in a more personalized approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Bobolea, Guillén-Vera, De las Cuevas-Moreno, García-Granero, Loli-Ausejo and Melero-Moreno.)

ABSTRACT: Long‐term in vitro expansion of bone marrow stromal (skeletal) stem cells (also known as human mesenchymal stem cells [hMSC]) is associated with replicative senescence and impaired functions. We have previously reported that telomerization of hMSC through hTERT overexpression led to bypassing a replicative senescence phenotype and improved in vitro and in vivo functions. However, the molecular consequence of telomerization is poorly characterized. Thus, we compared the molecular phenotype of a well‐studied telomerized hMSC (hMSC‐TERT) cell line with primary hMSC. At a cellular level, both cell populations exhibited strong concordance for the known hMSC CD markers, similar responses to osteoblast (OB) differentiation induction, and formed heterotopic bone in vivo. Overall gene expression was highly correlated between both cell types with an average Pearson's correlation coefficient (R2) between the gene expression of all primary hMSC and all hMSC‐TERT samples of 0.95 (range 0.93–0.96). Quantitative analysis of gene expression of CD markers, OB cell markers, and transcription factors (TF) showed a high degree of similarity between the two cell populations (72%, 77%, and 81%, respectively). The hMSC‐TERT population was enriched mainly for genes associated with cell cycle and cell cycle signaling when compared with primary hMSC. Other enrichment was observed for genes involved in cell adhesion and skeletal system development and immune response pathways. Interestingly, hMSC‐TERT shared a telomerization signature with upregulation of cancer/testis antigens, MAGE, and PAGE genes. Our data demonstrate that the enhanced biological characteristics of hMSC after telomerization are mainly due to enhanced expression of cell proliferation genes, whereas gene expression responses to differentiation are maintained. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research [ABSTRACT FROM AUTHOR]

Present guidelines for classification of constitutional variants do not incorporate inferences from mutations seen in tumors, even when these are associated with a specific molecular phenotype. When somatic mutations and constitutional mutations lead to the same molecular phenotype, as for the mismatch repair genes, information from somatic mutations may enable interpretation of previously unclassified variants. To test this idea, we first estimated likelihoods that somatic variants in MLH1 , MSH2 , MSH6 , and PMS2 drive microsatellite instability and characteristic IHC staining patterns by calculating likelihoods of high versus low normalized variant read fractions of 153 mutations known to be pathogenic versus those of 760 intronic passenger mutations from 174 paired tumor-normal samples. Mutations that explained the tumor mismatch repair phenotype had likelihood ratio for high variant read fraction of 1.56 (95% CI 1.42–1.71) at sites with no loss of heterozygosity and of 26.5 (95% CI 13.2–53.0) at sites with loss of heterozygosity. Next, we applied these ratios to 165 missense, synonymous, and splice variants observed in tumors, combining in a Bayesian analysis the likelihood ratio corresponding with the adjusted variant read fraction with pretest probabilities derived from published analyses and public databases. We suggest classifications for 86 of 165 variants: 7 benign, 31 likely benign, 22 likely pathogenic, and 26 pathogenic. These results illustrate that for mismatch repair genes, characterization of tumor mutations permits tumor mutation data to inform constitutional variant classification. We suggest modifications to incorporate molecular phenotype in future variant classification guidelines. [ABSTRACT FROM AUTHOR]