Microarray Studies Research Articles

TTF-1 is a highly sensitive but not fully specific marker for pulmonary and thyroidal cancer: a tissue microarray study evaluating more than 17,000 tumors from 152 different tumor entities.

Thyroid transcription factor 1 (TTF-1) immunohistochemistry (IHC) is routinely used for the distinction of primary pulmonary adenocarcinomas. However, TTF-1 can also occur in other malignancies. A tissue microarray containing 17,772 samples from 152 different tumor types was analyzed. Napsin-A, CK20, SATB2, FABP1, and Villin-1 IHC data were available from previous studies. TTF-1 staining was seen in 82 of 152 tumor categories including thyroidal cancers (19-100%), adenocarcinomas (94%), neuroendocrine tumors (67%) of the lung, small cell neuroendocrine carcinomas (71-80%), mesenchymal tumors (up to 42%), and thymomas (39%). Comparative analysis of TTF-1 and Napsin-A revealed a sensitivity/specificity of 94%/86% (TTF-1), 87%/98% (Napsin-A), and 85%/99.1% (TTF-1 and Napsin-A) for the distinction of pulmonary adenocarcinomas. Combined analysis of TTF-1 and enteric markers revealed a positivity for TTF-1 and at least one enteric marker in 22% of pulmonary adenocarcinomas but also a TTF-1 positivity in 6% of colorectal, 2% of pancreatic, and 3% of gastric adenocarcinomas. TTF-1 is a marker of high sensitivity but insufficient specificity for pulmonary adenocarcinomas. A small fraction of TTF-1-positive gastrointestinal adenocarcinomas represents a pitfall mimicking enteric-type pulmonary adenocarcinoma. Combined analysis of TTF-1 and Napsin-A improves the specificity of pulmonary adenocarcinoma diagnosis.

Expression of Trefoil Factor 1 (TFF1) in Cancer: A Tissue Microarray Study Involving 18,878 Tumors.

Background/Objectives: Trefoil factor 1 (TFF1) plays a role in the mucus barrier. Methods: To evaluate the prevalence of TFF1 expression in cancer, a tissue microarray containing 18,878 samples from 149 tumor types and 608 samples of 76 normal tissue types was analyzed through immunohistochemistry (IHC). Results: TFF1 staining was detectable in 65 of 149 tumor categories. The highest rates of TFF1 positivity were found in mucinous ovarian carcinomas (76.2%), colorectal adenomas and adenocarcinomas (47.1-75%), breast neoplasms (up to 72.9%), bilio-pancreatic adenocarcinomas (42.1-62.5%), gastro-esophageal adenocarcinomas (40.4-50.0%), neuroendocrine neoplasms (up to 45.5%), cervical adenocarcinomas (39.1%), and urothelial neoplasms (up to 24.3%). High TFF1 expression was related to a low grade of malignancy in non-invasive urothelial carcinomas of the bladder (p = 0.0225), low grade of malignancy (p = 0.0003), estrogen and progesterone receptor expression (p < 0.0001), non-triple negativity (p = 0.0005) in invasive breast cancer of no special type, and right-sided tumor location (p = 0.0021) in colorectal adenocarcinomas. Conclusions: TFF1 IHC has only limited utility for the discrimination of different tumor entities given its expression in many tumor entities. The link between TFF1 expression and parameters of malignancy argues for a relevant biological role of TFF1 in cancer. TFF1 may represent a suitable therapeutic target due to its expression in only a few normal cell types.

Effects of Short-Term Treatment of Rabbit Extraocular Muscle With Ciliary Neurotrophic Factor.

Little is known about the effect of ciliary neurotrophic factor (CNTF) on extraocular muscles, but microarray studies suggested CNTF might play a role in the development and/or maintenance of strabismus. The effect of short-term treatment of adult rabbit extraocular muscle with injected CNTF was examined for its ability to alter muscle characteristics. Eight adult New Zealand white rabbits received an injection into one superior rectus muscle of 2 µg/100 µL CNTF on 3 consecutive days. One week after the first injection, the rabbits were euthanized, and the treated and contralateral superior rectus muscles were assessed for force generation capacity and contraction characteristics using an in vitro stimulation protocol and compared to naïve control superior rectus muscles. All muscles were analyzed to determine mean cross-sectional areas and expression of slow twitch myosin heavy chain isoform. Short-term treatment of rabbit superior rectus muscles with CNTF resulted in a significant decrease in muscle force generation, but only at the higher stimulation frequencies. Significantly decreased myofiber cross-sectional areas of the treated muscles correlated with the decreased generated force. In addition, there were significant changes to contractile properties of the treated muscles, as well as a decrease in the number of myofibers expressing slow twitch myosin heavy chain. We show that short-term treatment of a single rabbit superior rectus muscle results in decreased myofiber size, decreased force, and altered contractile characteristics. Further studies are needed to determine if it can play a role in improving alignment in animal models of strabismus.

Broad-Spectrum Legionaminic Acid-Specific Antibodies in Pooled Human IgGs Revealed by Glycan Microarrays with Chemoenzymatically Synthesized Nonulosonosides.

The presence and the level of antibodies in human sera against bacterial glycans are indications of prior encounters with similar antigens and/or the bacteria that express them by the immune system. An increasing number of pathogenic bacteria that cause human diseases have been shown to express polysaccharides containing a bacterial nonulosonic acid called 5,7-di-N-acetyllegionaminic acid (Leg5,7Ac2). To investigate the immune recognition of Leg5,7Ac2, which is critical for the fight against bacterial infections, a highly effective chemoenzymatic synthon strategy was applied to construct a library of α2-3/6-linked Leg5,7Ac2-glycans via their diazido-derivatives (Leg5,7diN3-glycans) formed by efficient one-pot three-enzyme (OP3E) synthetic systems from a diazido-derivative of a six-carbon monosaccharide precursor. Glycan microarray studies using this synthetic library of a Leg5,7Ac2-capped collection of diverse underlying glycan carriers and their matched sialoside counterparts revealed specific recognition of Leg5,7Ac2 by human IgG antibodies pooled from thousands of healthy donors (IVIG), suggesting prior human encounters with Leg5,7Ac2-expressing pathogenic bacteria at the population level. These biologically relevant Leg5,7Ac2-glycans and their immune recognition assays are important tools to begin elucidating their biological roles, particularly in the context of infection and host-pathogen interactions.

Prevalence of S-methyl-5'-thioadenosine Phosphorylase (MTAP) Deficiency in Human Cancer: A Tissue Microarray Study on 13,067 Tumors From 149 Different Tumor Types.

Loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression is a common event in cancer leading to a critical vulnerability of cancer cells towards anti-cancer drugs. Homozygous MTAP deletions result in a complete expression loss that can be detected by immunohistochemistry (IHC). In this study, a tissue microarray containing 17,078 samples from 149 different tumor entities was analyzed by IHC, and complete MTAP loss was validated by fluorescence in situ hybridization. MTAP loss was observed in 83 of 149 tumor categories, including neuroendocrine neoplasms (up to 80%), Hodgkin lymphoma (50.0%), mesothelioma (32.0% to 36.8%), gastro-intestinal adenocarcinoma (4.0% to 40.5%), urothelial neoplasms (10.5% to 36.7%), squamous cell carcinomas (up to 38%), and various types of sarcomas (up to 20%) and non-Hodgkin lymphomas (up to 14%). Homozygous MTAP deletion was found in 90% to 100% of cases with MTAP expression loss in most tumor categories. However, neuroendocrine tumors, Hodgkin lymphomas, and other lymphomas lacked MTAP deletions. MTAP deficiency was significantly linked to unfavorable tumor phenotype in selected tumor entities and the presence of PD-L1 expression on tumor cells, absence of PD-L1 expression on immune cells, and a low density of CD8 + lymphocytes. In summary, MTAP deficiency can occur in various tumor entities and is linked to unfavorable tumor phenotype and noninflamed tumor microenvironment, but is not always related to deletions. MTAP IHC is of considerable diagnostic value for the detection of neoplastic transformation in multiple different applications.

PAX8 expression in cancerous and non-neoplastic tissue: a tissue microarray study on more than 17,000 tumors from 149 different tumor entities

PAX8 plays a role in development of the thyroid, kidney, and the Wolffian and Mullerian tract. In surgical pathology, PAX8 immunohistochemistry is used to determine tumors of renal and ovarian origin, but data on its expression in other tumors are conflicting. To evaluate PAX8 expression in normal and tumor tissues, a tissue microarray containing 17,386 samples from 149 different tumor types and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. PAX8 results were compared with previously collected data on cadherin 16 (CDH16). PAX8 positivity was found in 40 different tumor types. The highest rate of PAX8 positivity was found in thyroidal neoplasms of follicular origin (98.6–100%), gynecological carcinomas (up to 100%), renal tumors (82.6–97.8%), and urothelial neoplasms (2.3–23.7%). Important tumors with near complete absence of PAX8 staining (< 1%) included all subtypes of breast cancers, hepatocellular carcinomas, gastric, prostatic, pancreatic, and pulmonary adenocarcinomas, neuroendocrine neoplasms, small cell carcinomas of various sites, and lymphomas. High PAX8 expression was associated with low tumor grade in 365 non-invasive papillary urothelial carcinomas (p < 0.0001) but unrelated to patient outcome and/or tumor phenotype in clear cell renal cell carcinoma, high-grade serous ovarian cancer, and endometrioid endometrial carcinoma. For determining a renal tumor origin, sensitivity was 88.1% and specificity 87.2% for PAX8, while sensitivity was 85.3% and specificity 95.7% for CDH16. The combination of PAX8 and CDH16 increased specificity to 96.8%. In conclusion, PAX8 immunohistochemistry is a suitable diagnostic tool. The combination of PAX8 and CDH16 positivity has high specificity for renal cell carcinoma.

Diseases Caused by Faulty Gene Expression. There are Several Hereditary Diseases that may be Entirely Cured if Detected and Treated Early Enough

Many genes and environmental factors often work together to cause a disease. The identification of significant genetic factors is useful for both medical (by aiding drug development and personalised therapy) and scientific (by shedding light on mechanistic and evolutionary aspects of illness) purposes. Linkage analysis (which joins loci that have a propensity to be inherited together) and association studies are two of the many genetic methods that have shown correlations between illnesses and particular sections of the genome (mapping correlation between alleles at different loci). Several hundreds of genes are examined in these types of studies, much too numerous to be tested experimentally as potential disease genes. The use of computer methods to assess the possibility of individual genes within a certain chromosomal area being disease genes is thus quite useful. Many diseases' susceptibilities have been demonstrated to a fair degree. changes in the rate at which genes are expressed in various cell types. In instance, if a gene or gene cluster is more common in sick individuals than in healthy people, it's likely that the gene plays a role in illness. Microarray studies were the major method for detecting the differences in expression levels.

Potentially actionable targets in synovial sarcoma: A tissue microarray study

BackgroundSynovial sarcoma (SynSa) is one of the most common translocation-related soft tissue sarcomas. Patients with metastatic SynSa have limited treatment options and a very poor prognosis. Several novel experimental therapies are currently being explored in clinical trials, including T cell-based therapies targeting cancer testis antigens such as New York esophageal squamous cell carcinoma 1 (NY-ESO-1) or melanoma-associated antigen A4 (MAGE-A4), and degraders targeting bromodomain-containing protein 9 (BRD9). Preclinical studies investigate inhibitors of Yes associated protein 1 (YAP1), transcriptional co-activator with PDZ-binding motif (TAZ) and inhibitors of chemokine receptor 4 (CXCR4). MethodsWe explored the immunohistochemical expression of these targets using a tissue microarray (TMA) constructed from 91 clinical SynSa samples and correlated these findings with corresponding clinicopathological data. ResultsExpression of MAGE-A4 and NY-ESO-1 was found in 69 % and 56 % of the samples, respectively. NY-ESO-1 was statistically higher expressed in samples from metastatic lesions as compared to samples from primary tumors. Nuclear expression of YAP1 and TAZ was observed in 92 % and 51 % of the samples, respectively. CXCR4 was expressed in the majority of the samples (82 %). BRD9 was highly expressed in all specimens. No prognostic role could be identified for any of the investigated proteins. ConclusionThis study is a comprehensive study providing real-world data on the expression of several actionable proteins in a large proportion of SynSa samples. All evaluated markers were expressed in a clinically meaningful proportion of cases represented in our TMA, supporting the relevance of ongoing preclinical and clinical research with novel agents directed against these targets.

KLK7 expression in human tumors: a tissue microarray study on 13,447 tumors

BackgroundKallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine protease which is essential for the desquamation of corneocytes and thus plays a pivotal role in maintaining skin homeostasis. In cancer, KLK7 overexpression was suggested to represent a route for metastasis through cleavage of cell junction and extracellular matrix proteins of cancer cells.MethodsTo comprehensively determine KLK7 protein expression in normal and neoplastic tissues, a tissue microarray containing 13,447 samples from 147 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry.ResultsKLK7 positivity was found in 64 of 147 tumor categories, including 17 tumor categories with at least one strongly positive case. The highest rate of KLK7 positivity was found in squamous cell carcinomas from various sites of origin (positive in 18.1%-63.8%), ovarian and endometrium cancers (4.8%-56.2%), salivary gland tumors (4.8%-13.7%), bilio-pancreatic adenocarcinomas (20.0%-40.4%), and adenocarcinomas of the upper gastrointestinal tract (3.3%-12.5%). KLK7 positivity was linked to nodal metastasis (p = 0.0005), blood vessel infiltration (p = 0.0037), and lymph vessel infiltration (p < 0.0001) in colorectal adenocarcinoma, nodal metastasis in hepatocellular carcinoma (p = 0.0382), advanced pathological tumor stage in papillary thyroid cancer (p = 0.0132), and low grade of malignancy in a cohort of 719 squamous cell carcinomas from 11 different sites of origin (p < 0.0001).ConclusionsThese data provide a comprehensive overview on KLK7 expression in normal and neoplastic human tissues. The prognostic relevance of KLK7 expression and the possible role of KLK7 as a drug target need to be further investigated.

Poorly cohesive gastric cancer with increased epithelial‑mesenchymal transition is associated with a poor prognosis.

The present study examined the surgical outcome and prognosis of patients with poorly cohesive carcinoma (PCC), and characterized the molecular pathological factors, epithelial-mesenchymal transition (EMT) and interstitial signals of the disease. A total of 281 patients who underwent gastric cancer (GC) surgery between April 2015 and August 2020 were included. Furthermore, tissue samples from another 197 patients with GC who underwent surgery between 1999 and 2003 were assessed using a tissue microarray. Preoperatively treated cases and endoscopic submucosal dissection cases were excluded, and multiple blocks containing the invasion region were collected for tissue microarray. For tissue microarray analysis, the clinicopathological factors of protein wnt3a (wnt3a), leucine-rich repeat-containing G-protein coupled receptor 5, transforming growth factor-β-induced, phosphorylated serine/threonine-protein kinase mTOR and E-cadherin expression were collected as EMT markers. The results of the surgical case evaluation and tissue microarray indicated that PCC was more common in younger patients and women, as the ratio of women to men was higher in the PCC group compared with that in the non-PCC group. However, none of the results revealed that the prognosis was worse in all patients with PCC compared with the non-PCC group. Furthermore, in the tissue microarray study, PCC samples exhibited significantly decreased expression of the cell adhesion molecule E-cadherin, suggesting enhanced EMT, which activates wnt3a signaling. PCC with increased EMT was significantly associated with a poor prognosis.

Microarray Analysis of Tumor Suppressor Proteins p53 and p63: Their Role in Tumor Cell Dynamics

Background: Microarray technology has become essential in cancer research, providing insights into gene expression patterns and regulatory networks governed by key transcription factors. This review focuses on using microarray technology to elucidate genes regulated by tumor suppressor proteins p53 and p63. These proteins maintain genomic stability, regulate the cell cycle, and induce programmed cell death. Dysregulation of p53 and p63 is common in various cancers, highlighting their significance in cancer biology. Methods: Microarray technology enables high-throughput analysis of thousands of genes simultaneously. Researchers compare gene expression profiles in cancer cells and tissues with functional p53 and p63 against those with impaired function. This comparative analysis identifies numerous downstream target genes and pathways influenced by these transcription factors. Results: Microarray studies have revealed a wide array of genes regulated by p53 and p63, involved in DNA repair, apoptosis, cell cycle control, and epithelial differentiation. These findings enhance our understanding of molecular mechanisms driving cancer initiation, progression, and therapeutic resistance. Additionally, microarray technology enables the stratification of cancer subtypes based on distinct gene expression signatures associated with p53 and p63 status, offering insights into patient prognosis, treatment responses, and personalized therapeutic strategies. Conclusion: Microarray technology has significantly advanced our knowledge of gene regulatory networks orchestrated by p53 and p63 in cancer. Despite limitations like data interpretation and cross-hybridization, advancements in bioinformatics and complementary technologies are improving study accuracy and reliability, promising better cancer diagnostics, prognostics, and targeted therapies.

Stimulator of Interferon Genes Protein (STING) Expression in Cancer Cells: A Tissue Microarray Study Evaluating More than 18,000 Tumors from 139 Different Tumor Entities.

Stimulator of interferon genes protein (STING) activates the immune response in inflammatory cells. STING expression in cancer cells is less well characterized, but STING agonists are currently being evaluated as anticancer drugs. A tissue microarray containing 18,001 samples from 139 different tumor types was analyzed for STING by immunohistochemistry. STING-positive tumor cells were found in 130 (93.5%) of 139 tumor entities. The highest STING positivity rates occurred in squamous cell carcinomas (up to 96%); malignant mesothelioma (88.5%-95.7%); adenocarcinoma of the pancreas (94.9%), lung (90.3%), cervix (90.0%), colorectum (75.2%), and gallbladder (68.8%); and serous high-grade ovarian cancer (86.0%). High STING expression was linked to adverse phenotypes in breast cancer, clear cell renal cell carcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, and papillary carcinoma of the thyroid (p < 0.05). In pTa urothelial carcinomas, STING expression was associated with low-grade carcinoma (p = 0.0002). Across all tumors, STING expression paralleled PD-L1 positivity of tumor and inflammatory cells (p < 0.0001 each) but was unrelated to the density of CD8+ lymphocytes. STING expression is variable across tumor types and may be related to aggressive tumor phenotype and PD-L1 positivity. The lack of relationship with tumor-infiltrating CD8+ lymphocytes argues against a significant IFN production by STING positive tumor cells.

Beadex, the Drosophila LIM only protein, is required for the growth of the larval neuromuscular junction.

The appropriate growth of the neurons, accurate organization of their synapses, and successful neurotransmission are indispensable for sensorimotor activities. These processes are highly dynamic and tightly regulated. Extensive genetic, molecular, physiological, and behavioral studies have identified many molecular candidates and investigated their roles in various neuromuscular processes. In this article, we show that Beadex (Bx), the Drosophila LIM only (LMO) protein, is required for motor activities and neuromuscular growth of Drosophila. The larvae bearing Bx7, a null allele of Bx, and the RNAi-mediated neuronal-specific knockdown of Bx show drastically reduced crawling behavior, a diminished synaptic span of the neuromuscular junctions (NMJs) and an increased spontaneous neuronal firing with altered motor patterns in the central pattern generators (CPGs). Microarray studies identified multiple targets of Beadex that are involved in different cellular and molecular pathways, including those associated with the cytoskeleton and mitochondria that could be responsible for the observed neuromuscular defects. With genetic interaction studies, we further show that Highwire (Hiw), a negative regulator of synaptic growth at the NMJs, negatively regulates Bx, as the latter's deficiency was able to rescue the phenotype of the Hiw null mutant, HiwDN. Thus, our data indicate that Beadex functions downstream of Hiw to regulate the larval synaptic growth and physiology.NEW & NOTEWORTHY A novel role for Beadex (Bx) regulates the larval neuromuscular junction (NMJ) structure and function in a tissue-specific manner. Bx is expressed in a subset of Toll-6-expressing neurons and is involved in regulating synaptic span and physiology, possibly through its negative interaction with Highwire (Hiw). The findings of this study provide insights into the molecular mechanisms underlying NMJ development and function and warrant further investigation to understand the role of Bx in these processes fully.

MiR-450b-5p enhances the radiosensitivity of HR+ and HER2− breast cancer by targeting CDK6

Abstract Background The sensitivity of breast cancer cells to radiation is a key cause of locoregional recurrence after postoperative radiotherapy. Several studies have reported that microRNAs (miRNAs) are involved in the radiosensitivity of human breast cancer cells. One miRNA microarray study showed that miR-450b-5p was overexpressed 13.3-fold in patients with estrogen receptor–positive (ER+) and human epidermal growth factor receptor 2–negative (HER2−) breast cancer and no local relapse compared with local relapse patients. However, its underlying mechanism of action remains unknown. Methods The predicted target mRNAs of miR-450b-5p were screened using the TargetScan, miRDB, and miRWalk databases. Western blotting, quantitative polymerase chain reaction, and dual-luciferase reporter assays explored the association between cyclin-dependent kinase 6 (CDK6) and miR-450b-5p. The cell counting kit-8 assay and flow cytometry detected the proliferation of transfected MCF7 cells. Colony formation and xenograft tumors detected the radiosensitivity of the transfected MCF7 cells. Results Bioinformatics analysis, Western blotting, quantitative polymerase chain reaction, and dual-luciferase reporter assays demonstrated that CDK6 was the target gene of miR-450b-5p. Furthermore, in vitro and in vivo experiments showed that miR-450b-5p inhibited MCF7 cell proliferation and cell cycle progression, increased the sensitizer enhancement ratio, and decreased the volume of xenograft tumors after irradiation by regulating CDK6. Conclusions This study demonstrates that miR-450b-5p enhances the radiosensitivity of hormone receptor–positive (HR+) and HER2− breast cancer cells and elucidates its mechanism. miR-450b-5p may be considered a therapeutic target in HR+ and HER2− breast cancer treated with radiotherapy.

Inhibition of P21-activated kinases 1 and 4 synergistically suppresses the growth of pancreatic cancer by stimulating anti-tumour immunity

BackgroundPancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer, and KRAS oncogene occurs in over 90% of cases. P21-activated kinases (PAK), containing six members (PAK1 to 6), function downstream of KRAS. PAK1 and PAK4 play important roles in carcinogenesis, but their combinational effect remains unknown. In this study, we have determined the effect of dual inhibition of PAK1 and PAK4 in PDA progression using knockout (KO) cancer cell lines.MethodsMurine wild-type (WT) and PAK1KO pancreatic cancer cell lines were isolated from PAK1+/+ and PAK1−/− KPC (LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx-1-Cre) mice. KPC PAK4KO and KPC PAK1&4 KO cell lines were generated from KPC WT and KPC PAK1KO cell lines respectively using the CRISPR-CAS9 gene knockout technique. PAK WT and KO cell lines were used in mouse models of pancreatic tumours. Cells and tumour tissue were also used in flow cytometry and proteomic studies. A human PDA tissue microarray was stained by immunohistochemistry.ResultsDouble knock out of PAK1 and PAK4 caused complete regression of tumour in a syngeneic mouse model. PAK4KO inhibited tumour growth by stimulating a rapid increase of cytotoxic CD8+ T cell infiltration. PAK1KO synergistically with PAK4KO increased cytotoxic CD8+ T cell infiltration and stimulated a sustained infiltration of CD8+ T cells at a later phase to overcome the immune evasion in the PAK4KO tumour. The human PDA tissue microarray study showed the important role of PAK1 and PAK4 in intra-tumoral T-cell function.ConclusionOur results demonstrated that dual inhibition of PAK1 and PAK4 synergistically suppressed PDA progression by stimulating cytotoxic CD8 + T cell response.

METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs

Bisphosphonate-related osteonecrosis of jaw (BRONJ) is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells (BMSCs). Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders. However, the role of corin in BRONJ-related BMSCs dysfunction remains unclarified. A m6A epitranscriptomic microarray study from our group shows that the CORIN gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation. Corin knockdown inhibits BMSCs osteogenic differentiation, whereas corin overexpression or soluble corin (sCorin) exerts a promotion effect. Furthermore, corin expression is negatively regulated by bisphosphonates (BPs). Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability. Mechanistically, we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation. PD98059 (a selective ERK inhibitor) blocks the corin-mediated promotion effect. With regard to the high methylation level of corin during osteogenic differentiation, we apply a non-selective m6A methylase inhibitor, Cycloleucine, which also blocks the corin-mediated promotion effect. Furthermore, we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function, indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability. To conclude, our study reveals that corin reverses BPs-induced BMSCs dysfunction, and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway. We hope this brings new insights into future clinical treatments for BRONJ.

Blocking H1R signal aggravates atherosclerosis by promoting inflammation and foam cell formation.

Atherosclerosis (AS) is a chronic inflammatory arterialdisease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1receptor (H1R)antagonist is a commonly encountered anti-allergic agent in theclinic. However, the role and mechanism of H1R in atherosclerosis have not been fully elucidated. Here, we explored the effect of H1R on atherosclerosis using ApolipoproteinE-knockout (ApoE-/-)mice with astemizole (AST, a long-acting H1R antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endotheliallipase (LIPG) in CD11b+ myeloid cells derived from HDC-knockout (HDC-/-) mice compared to WT mice. Blocking H1R promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38mitogen-activatedproteinkinase (p38 MAPK) and LIPG signalingpathway. Taken together, these findings demonstrate that blocking H1R signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signalingpathway. KEY MESSAGES: Blocking H1R signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fatdiet (HFD)-fed ApoE-/- mice. Blocking H1R signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signalingpathway.

The long non-coding RPPH1 is decreased in leukocytes and increased in plasma from women developing pre-eclampsia†.

Previous studies show differentially expressed long non-coding RNA present in the placenta from women with pre-eclampsia, potentially playing a vital role in the pathogenesis of the complication. In a published microarray study, Ribonuclease P RNA component H1 was decreased in leukocytes from women that later developed pre-eclampsia. We hypothesized that Ribonuclease P RNA component H1 decreased during pregnancy in women developing pre-eclampsia and important for the development of the complication. We isolated RNA from extracellular vesicles, leukocytes and plasma using blood samples taken at weeks 22-24 and 36-38 in women who subsequently developed pre-eclampsia and from healthy pregnancy. The expression of Ribonuclease P RNA component H1 was quantified using qPCR. Expression of Ribonuclease P RNA component H1 at 22-24weeks was further examined to investigate its discriminatory potential of subsequent pre-eclampsia and association with clinical markers. We found lower expression of Ribonuclease P RNA component H1 in leukocytes at 22-24 and 36-38weeks amongst women who subsequent developed pre-eclampsia compared with those who did not, while increased Ribonuclease P RNA component H1 expression was found in plasma at 36-38weeks. Pre-eclampsia risk factors could not account for this difference in the Ribonuclease P RNA component H1 expression. Prediction of pre-eclampsia at 22-24weeks using Ribonuclease P RNA component H1 expression in leukocytes in addition to the screening algorithm used today had a significantly better performance. In conclusion, Ribonuclease P RNA component H1 expression in leukocytes was significantly decreased in women with pre-eclampsia, and the expression at 22-24weeks associated with the subsequent development of pre-eclampsia. Ribonuclease P RNA component H1 in leukocytes may be a useful biomarker for prediction and/or early detection of pre-eclampsia and an unknown regulator of the signaling affecting immune cells.

Clinical, pathologic, and genomic characteristics of two pediatric glioneuronal tumors with a CLIP2::MET fusion

Integration of molecular data with histologic, radiologic, and clinical features is imperative for accurate diagnosis of pediatric central nervous system (CNS) tumors. Whole transcriptome RNA sequencing (RNAseq), a genome-wide and non-targeted approach, allows for the detection of novel or rare oncogenic fusion events that contribute to the tumorigenesis of a substantial portion of pediatric low- and high-grade glial and glioneuronal tumors. We present two cases of pediatric glioneuronal tumors occurring in the occipital region with a CLIP2::MET fusion detected by RNAseq. Chromosomal microarray studies revealed copy number alterations involving chromosomes 1, 7, and 22 in both tumors, with Case 2 having an interstitial deletion breakpoint in the CLIP2 gene. By methylation profiling, neither tumor had a match result, but both clustered with the low-grade glial/glioneuronal tumors in the UMAP. Histologically, in both instances, our cases displayed characteristics of a low-grade tumor, notably the absence of mitotic activity, low Ki-67 labeling index and the lack of necrosis and microvascular proliferation. Glial and neuronal markers were positive for both tumors. Clinically, both patients achieved clinical stability post-tumor resection and remain under regular surveillance imaging without adjuvant therapy at the last follow-up, 6 months and 3 years, respectively. This is the first case report demonstrating the presence of a CLIP2::MET fusion in two pediatric low-grade glioneuronal tumors (GNT). Conservative clinical management may be considered for patients with GNT and CLIP2:MET fusion in the context of histologically low-grade features.

TRPS1 is a Highly Sensitive Marker for Breast Cancer: A Tissue Microarray Study Evaluating More Than 19,000 Tumors From 152 Different Tumor Entities.

Trichorhinophalangeal syndrome 1 (TRPS1) is a nuclear protein highly expressed in breast epithelial cells. TRPS1 immunohistochemistry (IHC) has been suggested as a breast cancer marker. To determine the diagnostic and prognostic utility of TRPS1 IHC, tissue microarrays containing 19,201 samples from 152 different tumor types and subtypes were analyzed. GATA3 IHC was performed in a previous study. TRPS1 staining was seen in 86 of 152 tumor categories with 36 containing at least one strongly positive case. TRPS1 staining predominated in various types of breast carcinomas (51%-100%), soft tissue tumors (up to 100%), salivary gland tumors (up to 46%), squamous cell carcinomas (up to 35%), and gynecological cancers (up to 40%). TRPS1 positivity occurred in 1.8% of 1083 urothelial neoplasms. In invasive breast carcinoma of no special type, low TRPS1 expression was linked to high grade ( P = 0.0547), high pT ( P < 0.0001), nodal metastasis ( P = 0.0571), loss of estrogen receptor and progesterone receptor expression ( P < 0.0001 each), and triple-negative status ( P < 0.0001) but was unrelated to patient survival ( P = 0.8016). In squamous cell carcinomas from 11 different sites, low TRPS1 expression was unrelated to tumor phenotype. Positivity for both TRPS1 and GATA3 occurred in 47.4% to 100% of breast cancers, up to 30% of salivary gland tumors, and 29 (0.3%) of 9835 tumors from 134 other cancer entities. TRPS1 IHC has high utility for the identification of cancers of breast (or salivary gland) origin, especially in combination with GATA3. The virtual absence of TRPS1 positivity in urothelial neoplasms is useful for the distinction of GATA3-positive urothelial carcinoma from breast cancer.