ORAL MUCOSAL LESIONS IN PATIENTS FROM CLINICS OF THE SCHOOL OF DENTISTRY, UNIVERSITY OF ANTIOQUIA, MEDELLÍN, COLOMBIA
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Álvarez Gómez, G;Rodríguez Montoya, G;López, A;Saldarriaga, A;Alzate, M;Muñoz, L;
| DOI: 10.1016/j.oooo.2021.03.039
Background To our knowledge, there are no studies in Colombia that describe the frequency of oral mucosal lesions. Only the ENSAB IV evaluated potentially malignant lesions and lesions associated with a removable prosthesis. Objective The aim of this study was to determine the frequency of oral mucosal lesions and their risk indicators in patients attending clinics of the School of Dentistry, University of Antioquia. Methods Structured interviews, clinical examination, and a biopsy, if deemed necessary, were conducted in a nonprobabilistic sample of 539 patients. Results Eight hundred forty mucosal lesions were found in 409 patients (75.9%). The average age was 35.26 years (SD = 23.4); 69.7% of patients were female. The most frequent lesions were exfoliative cheilitis (17.4%), frictional keratosis (15.4%), and vascular lesions (11.5%). In exploring the relationship between the number of lesions and sociodemographic characteristics and habits, a correlation was found with age (P = .001), use of removable appliances (P = .042), type of appliance (P = .001), and the variable “you have seen or felt something in your mouth” (P = .004). Conclusions The most frequent lesions in this study were exfoliative cheilitis. There was a low percentage of potentially malignant disorders, and no malignant lesions were found. In the teaching programs of dentistry and even to establish the diagnosis of presumption, it is necessary to know the frequency of lesions of the oral mucosa in the region.
SALIVARY MICRORNA 155, 146a/b, AND 203: POTENTIAL NONINVASIVE DIAGNOSTIC BIOMARKERS OF PERIODONTITIS AND DIABETES
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Al-Rawi, N;Al–Marzooq, F;Hamoudi, R;
| DOI: 10.1016/j.oooo.2021.03.038
Background Dysregulated expression of microRNAs (miRNAs) plays important role in the initiation and progression of both diabetes and periodontitis. Objective The aim of the study is to identify miRNAs in saliva as potential predictive biomarkers of periodontal disease among patients with diabetes mellitus. Methods MiRNAs were extracted from the saliva of 24 adult subjects with diabetes mellitus and 27 age- and sex-matched healthy controls. Each group was subdivided into periodontally healthy or having periodontitis. In silico analysis identified 4 miRNAs (miRNA 155, 146 a/b and 203) as immune modulators. The expression of miRNAs 146a/b, 155, and 203 was tested using quantitative polymerase chain reaction. The expression levels in the study groups were compared to explore the effect of diabetes and/or periodontitis. Results In our cohort, the 4 miRNAs expressed were higher in patients with periodontitis and/or diabetes. miRNA 155 and miRNA 146 a/b were the most reliable predictors of periodontitis among subjects without diabetes with an optimum cutoff value of
METASTATIC MEDULLOBLASTOMA TO THE MANDIBLE: A CASE REPORT
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Alotaiby, F;Bhattacharyya, I;Fatani, H;
| DOI: 10.1016/j.oooo.2021.03.037
Introduction Medulloblastoma is the most common tumor of the brain of neuroendocrine origin in children and typically demonstrates an aggressive, relentless clinical behavior and high recurrence rate. Extraneuraxial metastasis of medulloblastoma to the jaw is extremely rare, with fewer than 10 cases reported in the literature. Case Report A 10-year-old male patient presented with a swelling in the right side of the face for 15 days. The patient had a past history of medulloblastoma diagnosed a few years earlier. Clinical examination revealed a diffuse painless mass in the right mandible. Multiplanar reconstruction demonstrated a 1.5 × 1.5 cm well-defined round lesion with extensive necrosis involving mostly the ramus of right mandible with resultant bone erosion on the lingual aspect. The lesion involved the regional structures including maxillary sinus, pterygoid process, and carotid sheath. Microscopic examination of the biopsy specimen exhibited sheets of poorly differentiated malignant small round blue cells with extensive necrosis. The tumor cells revealed molding of nuclei with speckled chromatin and inconspicuous cytoplasm. Evidence of vascular and perineural invasion was noted. Immunohistochemical studies demonstrated weak granular positivity for synaptophysin, but staining for AE1/3, desmin, CD99, and LCA was negative in the lesion tissue. A diagnosis of round blue cell malignancy of neuroendocrine origin compatible with medulloblastoma metastatic to the jaw was rendered. Our case represents only the 10th such as case in the English-language literature. Owing to the rarity of this entity, a more accurate understanding of the prognosis and treatment of metastatic medulloblastoma is not well known.
IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice
Luo, X;Chen, O;Wang, Z;Bang, S;Ji, J;Lee, S;Huh, Y;Furutani, K;He, Q;Tao, X;Ko, M;Bortsov, A;Donnelly, C;Chen, Y;Nackley, A;Berta, T;Ji, R;
| DOI: 10.1016/j.neuron.2021.06.015
Although sex dimorphism is increasingly recognized as an important factor in pain, female-specific pain signaling is not well studied. Here we report that administration of IL-23 produces mechanical pain (mechanical allodynia) in female but not male mice, and chemotherapy-induced mechanical pain is selectively impaired in female mice lacking Il23 or Il23r. IL-23-induced pain is promoted by estrogen but suppressed by androgen, suggesting an involvement of sex hormones. IL-23 requires C-fiber nociceptors and TRPV1 to produce pain but does not directly activate nociceptor neurons. Notably, IL-23 requires IL-17A release from macrophages to evoke mechanical pain in females. Low-dose IL-17A directly activates nociceptors and induces mechanical pain only in females. Finally, deletion of estrogen receptor subunit α (ERα) in TRPV1+ nociceptors abolishes IL-23- and IL-17-induced pain in females. These findings demonstrate that the IL-23/IL-17A/TRPV1 axis regulates female-specific mechanical pain via neuro-immune interactions. Our study also reveals sex dimorphism at both immune and neuronal levels.
Long noncoding RNA BS-DRL1 modulates the DNA damage response and genome stability by interacting with HMGB1 in neurons
Lou, MM;Tang, XQ;Wang, GM;He, J;Luo, F;Guan, MF;Wang, F;Zou, H;Wang, JY;Zhang, Q;Xu, MJ;Shi, QL;Shen, LB;Ma, GM;Wu, Y;Zhang, YY;Liang, AB;Wang, TH;Xiong, LL;Wang, J;Xu, J;Wang, WY;
PMID: 34210972 | DOI: 10.1038/s41467-021-24236-z
Long noncoding RNAs (lncRNAs) are known to regulate DNA damage response (DDR) and genome stability in proliferative cells. However, it remains unknown whether lncRNAs are involved in these vital biological processes in post-mitotic neurons. Here, we report and characterize a lncRNA, termed Brain Specific DNA-damage Related lncRNA1 (BS-DRL1), in the central nervous system. BS-DRL1 is a brain-specific lncRNA and depletion of BS-DRL1 in neurons leads to impaired DDR upon etoposide treatment in vitro. Mechanistically, BS-DRL1 interacts with HMGB1, a chromatin protein that is important for genome stability, and is essential for the assembly of HMGB1 on chromatin. BS-DRL1 mediated DDR exhibits cell-type specificity in the cortex and cerebellum in gamma-irradiated mice and BS-DRL1 knockout mice show impaired motor function and concomitant purkinje cell degeneration. Our study extends the understanding of lncRNAs in DDR and genome stability and implies a protective role of lncRNA against neurodegeneration.
A live single-cell reporter assay links intratumor heterogeneity to metastatic proclivity in Ewing sarcoma
Keskin, T;Rucci, B;Cornaz-Buros, S;Martin, P;Fusco, C;Broye, L;Cisarova, K;Perez, EM;Letovanec, I;La Rosa, S;Cherix, S;Diezi, M;Renella, R;Provero, P;Suvà, ML;Stamenkovic, I;Riggi, N;
PMID: 34215585 | DOI: 10.1126/sciadv.abf9394
Targeting of the most aggressive tumor cell subpopulations is key for effective management of most solid malignancies. However, the metastable nature of tumor heterogeneity, which allows cells to transition between strong and weak tumorigenic phenotypes, and the lack of reliable markers of tumor-promoting properties hamper identification of the most relevant cells. To overcome these obstacles, we designed a functional microRNA (miR)-based live-cell reporter assay to identify highly tumorigenic cells in xenotransplants of primary Ewing sarcoma (EwS) 3D cultures. Leveraging the inverse relationship between cell pluripotency and miR-145 expression, we successfully separated highly tumorigenic, metastasis-prone (miR-145low) cells from poorly tumorigenic, nonmetastatic (miR-145high) counterparts. Gene expression and functional studies of the two cell populations identified the EPHB2 receptor as a prognostic biomarker in patients with EwS and a major promoter of metastasis. Our study provides a simple and powerful means to identify and isolate tumor cells that display aggressive behavior.
First-in-human DR5 PET reveals insufficient DR5 expression in patients with gastrointestinal cancer
Journal for immunotherapy of cancer
Wang, S;Zhu, H;Li, Y;Ding, J;Wang, F;Ding, L;Wang, X;Zhao, J;Zhang, Y;Yao, Y;Zhou, T;Li, N;Wu, A;Yang, Z;
PMID: 34301815 | DOI: 10.1136/jitc-2021-002926
Death receptor 5 (DR5) is a promising therapeutic target for cancer therapy. However, many clinical trials of DR5 agonists failed to show significant therapeutic efficacy in patients with cancer. The study aimed to investigate the feasibility of using 89Zr-CTB006 positron emission tomography (PET) for noninvasive imaging of DR5 expression in preclinical models and patients with gastrointestinal (GI) cancers.Balb/c, Sp2/0 xenograft and patient-derived tumor xenograft were employed for micro-PET/CT imaging in vivo. In the clinical study, patients with GI cancers planning to undergo surgical operation were enrolled and underwent 18F-FDG and 89Zr-CTB006 PET/CT. The tumor tissues were obtained through surgical operation and DR5 expression levels were confirmed by RNAscope.Preclinical studies showed that 89Zr-CTB006 PET could specifically detect DR5 expression levels in vivo. Twenty-one patients, including nine gastric cancers and 12 colorectal cancers, were enrolled. The biodistribution showed high uptake in the liver and spleen and low uptake in the brain, lung and muscle with an acceptable whole-body dosimetry of 0.349 mSv/MBq. Strikingly, the adrenal glands maintained stable high uptake over the entire examination in all patients. The tumor lesions showed different levels of uptake of 89Zr-CTB006 with a mean maximum standardized uptake value (SUVmax) of 6.63±3.29 (range 1.8-13.8). Tumor tissue was obtained from 18 patients, and 89Zr-CTB006 uptake in patients with RNAscope scores of 3-4 was significantly higher than that in patients with scores of 0-2. An SUVmax of 9.3 at 48 hours and 6.3 at 72 hours could be used to discriminate the DR5 expression status of tumors both with a sensitivity and specificity of 100% and 92.9%, respectively.89Zr-CTB006 PET/CT is capable of detecting DR5 expression in cancer patients and is a promising approach to screen patients with DR5 overexpression.
Intestinal MYC modulates obesity-related metabolic dysfunction
Luo, Y;Yang, S;Wu, X;Takahashi, S;Sun, L;Cai, J;Krausz, KW;Guo, X;Dias, HB;Gavrilova, O;Xie, C;Jiang, C;Liu, W;Gonzalez, FJ;
PMID: 34211180 | DOI: 10.1038/s42255-021-00421-8
MYC is a transcription factor with broad biological functions, notably in the control of cell proliferation. Here, we show that intestinal MYC regulates systemic metabolism. We find that MYC expression is increased in ileum biopsies from individuals with obesity and positively correlates with body mass index. Intestine-specific reduction of MYC in mice improves high-fat-diet-induced obesity, insulin resistance, hepatic steatosis and steatohepatitis. Mechanistically, reduced expression of MYC in the intestine promotes glucagon-like peptide-1 (GLP-1) production and secretion. Moreover, we identify Cers4, encoding ceramide synthase 4, catalysing de novo ceramide synthesis, as a MYC target gene. Finally, we show that administration of the MYC inhibitor 10058-F4 has beneficial effects on high-fat-diet-induced metabolic disorders, and is accompanied by increased GLP-1 and reduced ceramide levels in serum. This study positions intestinal MYC as a putative drug target against metabolic diseases, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
CB1 R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky-Pudlak syndrome
Clinical and translational medicine
Cinar, R;Park, JK;Zawatsky, CN;Coffey, NJ;Bodine, SP;Abdalla, J;Yokoyama, T;Jourdan, T;Jay, L;Zuo, MXG;O'Brien, KJ;Huang, J;Mackie, K;Alimardanov, A;Iyer, MR;Gahl, WA;Kunos, G;Gochuico, BR;Malicdan, MCV;
PMID: 34323400 | DOI: 10.1002/ctm2.471
Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1 R system and inducible nitric oxide synthase (iNOS) for dual-target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS-PF patient-derived lung fibroblasts, and bleomycin-induced PF in pale ear mice (HPS1ep/ep ). We found overexpression of CB1 R and iNOS in fibrotic lungs of HPSPF patients and bleomycin-infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin-induced PF. Simultaneous targeting of CB1 R and iNOS by MRI-1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI-1867 treatment abrogated bleomycin-induced increases in lung levels of the profibrotic interleukin-11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1 R inhibition. Dual inhibition of CB1 R and iNOS is an effective antifibrotic strategy for HPSPF.
Next-generation imaging: New insights from multicolor microscopy in liver biology and disease
Heymann, F;Guillot, A;Peiseler, M;Tacke, F;
| DOI: 10.1016/j.eng.2021.06.015
Abstract Unavailable
Structural and Functional Characterization of a Testicular Long Non-coding RNA (4930463O16Rik) Identified in the Meiotic Arrest of the Mouse Topaz1-/- Testes
Frontiers in cell and developmental biology
Chadourne, M;Poumerol, E;Jouneau, L;Passet, B;Castille, J;Sellem, E;Pailhoux, E;Mandon-Pépin, B;
PMID: 34277642 | DOI: 10.3389/fcell.2021.700290
Spermatogenesis involves coordinated processes, including meiosis, to produce functional gametes. We previously reported Topaz1 as a germ cell-specific gene highly conserved in vertebrates. Topaz1 knockout males are sterile with testes that lack haploid germ cells because of meiotic arrest after prophase I. To better characterize Topaz1 -/- testes, we used RNA-sequencing analyses at two different developmental stages (P16 and P18). The absence of TOPAZ1 disturbed the expression of genes involved in microtubule and/or cilium mobility, biological processes required for spermatogenesis. Moreover, a quarter of P18 dysregulated genes are long non-coding RNAs (lncRNAs), and three of them are testis-specific and located in spermatocytes, their expression starting between P11 and P15. The suppression of one of them, 4939463O16Rik, did not alter fertility although sperm parameters were disturbed and sperm concentration fell. The transcriptome of P18-4939463O16Rik -/- testes was altered and the molecular pathways affected included microtubule-based processes, the regulation of cilium movement and spermatogenesis. The absence of TOPAZ1 protein or 4930463O16Rik produced the same enrichment clusters in mutant testes despite a contrasted phenotype on male fertility. In conclusion, although Topaz1 is essential for the meiosis in male germ cells and regulate the expression of numerous lncRNAs, these studies have identified a Topaz1 regulated lncRNA (4930463O16Rik) that is key for both sperm production and motility.
Setting up a PDXO platform of pancreatic cancer with spatial-omics characterization
Michiels, E;Messaoudi, N;Heremans, Y;Giron, P;Janssens, T;Frederix, K;Aerts, S;Reynaert, H;Rooman, I;
| DOI: 10.1016/j.pan.2021.05.188
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is known for its aggressive biology and lethality. Due to a low success rate of current diagnostic and therapeutic approaches in clinic, there is an urgent need for preclinical research studies to investigate the underlying biology of this malignancy. This knowledge is indispensable to facilitate the development and validation of potential new therapeutic compounds. Superior to conventional biomedical research models, the focus of this study is on the development and use of a well-established patient-derived 3D model, mimicking the tumor as it is present in a human body. Aims: The development and characterization of patient-derived organoids (PDO) and patient-derived xenografts (PDX) of PDAC. Materials and Methods: The models are extensively analysed using advanced histological methods such as BaseScope®, 3D imaging and DNA hotspot sequencing. Results: 10 established PDAC-PDO and their corresponding parental tumors are already validated using immunostainings and DNA hotspot sequencing. The latter confirms presence of tumor cells in the organoids. In addition, this study is the first to show in situ detection of important driver mutations of pancreatic cancer, like KrasG12D, both in parental tumor and PDO. Thus far, 5 PDX have been generated that will undergo similar analysis. Conclusion: We have successfully started a pre-clinical screening platform for PDAC based on PDO and PDX. Altogether, spatial-omics analysis of both models can substantiate (1) resemblance to parental tissue and (2) spatial genomic characteristics associated with the type of model used. Ultimately, the screening platform can be used by pharmaceutical companies to facilitate oncological drug testing.