Epithelial Proliferation Research Articles

Coral fossil: A potential adsorbent of natural source for cadmium removal in broilers

Cadmium (Cd) is a pollutant that poses a health risk for humans and animals. Coral fossil (CF) acts as an adsorbent, yet limited knowledge is available on impacts of CF on Cd toxicities. The work was performed to figure out the effects of CF on hematobiochemical details and specific organs in Cd exposed broilers. The experiment was carried out with 45 broilers and were divided into three groups (15 in each). Group A was served as control. The birds in group B received Cd (75 mg /kg b. w.) orally. Whereas group C was orally supplemented with Cd (75 mg /kg b. w.) and CF (1 gm/kg b. w.). The trial was lasted for 30 days. For hematobiochemical analysis, blood samples were drawn, and sera were separated. Liver, kidney and muscle were collected to assess accumulation concentration. Brain, liver and kidney samples were also collected for histopathological study. The results showed that hematological parameters (TEC, Hb, PCV, MCV, MCH, MCHC and DLC) were altered by Cd but restored with CF supplementation. Liver (AST, ALT and ALP) and kidney (total protein and creatinine) biomarkers were increased significantly in Cd treated broilers while decreased significantly after CF supplementation. CF reduced accumulation concentration of Cd in liver, kidney and muscle. Cd intoxicated broilers showed degenerative changes in brain, hyperplastic bile duct and proliferation of renal tubular epithelium with focal degeneration and necrosis; and these were improved after CF supplementation. Therefore, it can be concluded that CF is a potential adsorbent against Cd toxicities.

Bladder carcinosarcoma treated by cystectomy and adjuvant chemotherapy with good outcomes: a case report

BackgroundPrimary carcinosarcoma of the bladder is a rare and highly aggressive tumor, representing less than 1% of all bladder neoplasms. There is no specific treatment guideline has for carcinosarcoma of the bladder, and majority of published patients was treated exclusively by surgery.Case presentationWe report a case of 65-year-old Moroccan man, presented with macroscopic hematuria, pollakiuria and painful urination. Histological analysis showed a biphasic epithelial and mesenchymal proliferation, with invasion of lamina propria and muscularis, compatible with diagnosis of bladder carcinosarcoma. The patient was treated with cystectomy and adjuvant chemotherapy based on gemcitabin-cisplatin, 18 months after treatment, patient still free of recurrence.ConclusionCarcinosarcoma of the urinary bladder is a rare and aggressive tumor regardless treatment. A multidisciplinary management based on radical cystectomy and combined adjuvant treatments can improve prognosis. In this work, we suggest to propose adjuvant chemotherapy whenever possible.

TGF-β Isoforms Affect the Planar and Subepithelial Fibrogenesis of Human Conjunctival Fibroblasts in Different Manners.

Three highly homologous isoforms of TGF-β, TGF-β-1~3, are involved in the regulation of various pathophysiological conditions such as wound healing processes in different manners, despite the fact that they bind to the same receptors during their activation. The purpose of the current investigation was to elucidate the contributions of TGF-β-1 ~3 to the pathology associated with conjunctiva. For this purpose, the biological effects of these TGF-β isoforms on the structural and functional properties of two-dimensional (2D) and three-dimensional (3D) cultured human conjunctival fibroblasts (HconF) were subjected to the following analyses: 1) transendothelial electrical resistance (TEER), a Seahorse cellular metabolic measurement (2D), size and stiffness measurements of the 3D HTM spheroids, and the qPCR gene expression analyses of extracellular matrix (ECM) components (2D and 3D). The TGF-β isoforms caused different effects on the proliferation of the HconF cell monolayer evaluated by TEER measurements. The differences included a significant increase in the presence of 5 ng/mL TGF-β-1 and -2 and a substantial decrease in the presence of 5 ng/mL TGF-β-3, although there were no significant differences in the response to the TGF-β isoforms for cellular metabolism among the three groups. Similar to planar proliferation, the TGF-β isoforms also induced diverse effects toward the mechanical aspects of 3D HconF spheroids, where TGF-β-1 increased stiffness, TGF-β-2 caused no significant effects, and TGF-β-3 caused the downsizing of the spheroids and stiffness enhancement. The mRNA expression of the ECMs were also modulated in diverse manners by the TGF-β isoforms as well as the culture conditions for the 2D vs. 3D isoforms. Many of these TGF-β-3 inducible effects were markedly different from those caused by TGF-β1 and TGF-β-2. The findings presented herein suggest that the three TGF-β isoforms induce diverse and distinctly different effects on cellular properties and the expressions of ECM molecules in HconF and that these changes are independent of cellular metabolism, thereby inducing different effects on the epithelial and subepithelial proliferation of human conjunctiva.

Proliferating Pilar Tumors in the Scalp Over a Period of 23 Years in a General Hospital in Mexico City.

Proliferating pilar tumors are an unusual skin tumor, and they have a cystic component with trichilemmal keratinization and epithelial proliferation. These arise from the outer root sheath of hair follicles. It mainly affects women. The scalp is the most affected area. Diagnosis can be made by biopsy. Surgical excision is the best treatment option. Report the frequency of proliferating pilar tumors in the scalp in general hospital in Mexico over a period of 23 years. The authors reviewed the database of the dermatopathology service of the General Hospital "Dr Manuel Gea González" from 1999 to August 2022, selecting diagnosticated cases of proliferating pilar tumor, pilar cyst, trichilemmal cyst, or proliferating trichilemmal cyst in the scalp. The authors discovered 17 cases, 13 were women, the average age was 54.9 years, all the tumors affecting the scalp, and just 3 cases were reported as malignant. In comparison with the existing data, the authors can observe that most of their patients were women and the scalp is the most affected area. Most did not present associated symptoms. As the authors can see, most are benign and long-lasting: however, the authors cannot ignore that a small percentage can be malignant.

How to reduce conjunctival cyst formation after strabismus surgery?

ABSTRACT Purpose To determine our rate of conjunctival cyst developing after strabismus surgery and to minimize its formation Materials and Methods The data of 4026 eyes of 2662 patients were included in our retrospective analysis of, those that underwent strabismus surgery at the Beyoğlu Eye Training and Research Hospital Strabismus Unit between 2015 and 2021. Clinical characteristics and follow-up data of patients were recorded together with age, sex, and operation type. All patients were examined postoperatively on 1st day, 1st month and 6th month. Results The mean age of the patients was 15.66 ± 11.81 (1–59 years). While two eyes were operated on in 1494 patients, one eye was operated on in 1168 patients. The surgeries performed were recession and/or resection of the horizontal and vertical rectus muscles and inferior and superior oblique procedures. The conjunctival cyst was detected in 11 patients postoperatively between 20 days and 8 months. The cyst was detected on the nasal side in 7 cases and temporal in 4. Conclusion Conjunctival cyst is a rare complication after strabismus surgery and it is thought to be caused by a proliferation of the conjunctival epithelium. In addition to proper closure of the conjunctiva, attention to personal hygiene, avoidance of contacts that may increase suture contamination, and attention to the fact that the operation period is not long are actions that can help prevent conjunctival cyst formation.

Wnt/β-catenin signaling controls mouse eyelid growth by mediating epithelial-mesenchymal interactions

PurposeTo investigate the role of Wnt/β-catenin signaling in mouse eyelid development. MethodsWnt/β-catenin signaling was disrupted by deleting supraorbital mesenchymal β-catenin or epithelial Wls. p63 was removed to determine whether the expression of Wnts is affected. The eyelid morphology was examined at different stages. Proliferation, apoptosis, and expression of Wnt ligands and their target genes were analyzed via immunofluorescence staining, TUNEL assay, and in situ hybridization. ResultsDeletion of β-catenin in supraorbital mesenchyme abolishes eyelid growth by causing decreased proliferation in supraorbital epithelium and underlying mesenchyme. Inhibition of Wnt secretion by deleting Wls in supraorbital epithelium results in failure of eyelid development, similar to the effects of deleting mesenchymal β-catenin. Knockout of p63 results in formation of hypoplastic eyelids and reduced expression of several Wnt ligands in eyelid epithelium. ConclusionsEpithelial Wnt ligands activate mesenchymal Wnt/β-catenin signaling to control eyelid growth and their expression is partially regulated by p63.

Treatment of rheumatoid arthritis by injection of sinomenine solid lipid nanoparticles under a fluorescence endoscopic laser confocal microscope

A fluorescence endoscopic laser confocal microscope(FELCM) was used to direct the injection of sinomenine solid lipid nanoparticles(Sin-SLN) into the joint, and the in vitro effectiveness of Sin-SLN in the treatment of rheumatoid arthritis(RA) was evaluated. Sin-SLN was prepared with the emulsion evaporation-low temperature curing method. The Sin-SLN prepared under the optimal conditions showed the encapsulation efficiency of 64.79%±3.12%, the drug loading of 3.84%±0.28%, the average particle size of(215.27±4.21) nm, and the Zeta potential of(-32.67±0.84) mV. Moreover, the Sin-SLN demonstrated good stability after sto-rage for 30 days. The rabbit model of RA was established by the subcutaneous injection of ovalbumin and complete Freund's adjuvant. Five groups were designed, including a control group, a model group, a Sin(1.5 mg·kg~(-1)) group, a Sin-SLN(1.5 mg·kg~(-1)) group, and a dexamethasone(positive drug, 1.0 mg·kg~(-1), ig) group. The control group and the model group only received puncture treatment without drug injection. After drug administration, the local skin temperature and knee joint diameter were monitored every day. The knee joint diameter and the local skin temperature were lower in the drug administration groups than in the model group(P<0.05, P<0.01). FELCM recorded the morphological alterations of the cartilage of knee joint. The Sin-SLN group showed compact tissue structure and smooth surface of the cartilage. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the serum le-vels of interleukin-1(IL-1) and tumor necrosis factor-α(TNF-α). The findings revealed that the Sin-SLN group had lower IL-1 and TNF-α levels than the model group(P<0.05, P<0.01). Hematoxylin-eosin(HE) staining was employed to reveal the pathological changes of the synovial tissue, which were significantly mitigated in the Sin-SLN group. The prepared Sin-SLN had uniform particle size and high stability. Through joint injection administration, a drug reservoir was formed. Sin-SLN effectively alleviate joint swelling and cartilage damage of rabbit, down-regulated the expression of inflammatory cytokines, and inhibited the epithelial proliferation and inflammatory cell infiltration of the synovial tissue, demonstrating the efficacy in treating RA.

Missing link between tissue specific expressing pattern of ERβ and the clinical manifestations in LGBLEL.

Lacrimal gland benign lymphoepithelial lesion (LGBLEL) is an IgG4-related disease of unknown etiology with a risk for malignant transformation. Estrogen is considered to be related to LGBLEL onset. Seventy-eight LGBLEL and 13 control clinical samples were collected and studied to determine the relationship between estrogen and its receptors and LGBLEL development. The serological analysis revealed no significant differences in the levels of three estrogens be-tween the LGBLEL and control groups. However, immunohistochemical analyses indicated that the expression levels of ERβ and its downstream receptor RERG were relatively lower in LGBLEL samples than in control samples, with higher expression in the lacrimal gland and lower expression in the lymphocyte infiltration region. However, low expression of ERα was detected. The transcriptome sequence analysis revealed upregulated genes associated with LGBLEL enriched in lymphocyte proliferation and activation function; downregulated genes were enriched in epithelial and vascular proliferation functions. The key genes and gene networks were further analyzed. Interactions between B cells and epithelial cells were analyzed due to the identified involvement of leukocyte subsets and epithelial cells. B cell proliferation was found to potentially contribute to lacrimal gland apoptosis. Therefore, the tissue-heterogeneous expression pattern of ERβ is potentially related to the clinical manifestations and progression of LGBLEL, although further investigations are required to confirm this finding.

H04 The sign of Leser–Trélat: an eponymous misnomer?

Abstract The sign of Leser–Trélat is a paraneoplastic phenomenon consisting of a sudden eruption of seborrhoeic keratoses. It is credited to two surgeons, Edmund Leser (1853–1918) and Ulysse Trélat (1827–1890), who described cutaneous lesions associated with internal malignancies. Edmund Leser, the author of the Textbook of Special Surgery in 50 Lectures, initially studied law in Bonn before qualifying in medicine in Leipzig in 1880. He became Richard von Volkmann’s assistant at Martin Luther University. He was awarded his chair of surgery in 1894, 10 years after becoming a surgeon, and he practised in Goethe University, Frankfurt. Ulysse Trélat was born in Paris in 1827. His father was a republican political activist, Minister of Public Works and known as the founder of public hygiene in France. Ulysse Trélat was employed as an assistant anatomist in surgery at the ‘École Pratique’ 1 year before graduating high school in 1844. He finished his medical studies in 1854 and became a surgeon in 1857. In 1858, he was running the anatomy course in ‘École Pratique’. He replaced Paul Broca, well known for his research on Broca’s area in the frontal lobe, at Hospital Necker in 1880. In 1884, he was awarded a chair of surgery at ‘Hospital de la Charite’, replacing Leon Athanase Gosselin. Notable among his works is the description of the ‘Baizeau and Trélat method’ of surgical repair of cleft palate, and his book Clinique Chirurgicale. Leser and Trélat independently published papers describing skin lesions associated with mammary carcinoma and visceral malignancies. However, their description of cutaneous lesions was more in keeping with the appearance of senile angiomata or Campbell de Morgan spots. Therefore, the credit should go to Eugen Von Hollander (1867–1932), another German surgeon who accurately described the lesions in a paper published in 1900 titled ‘Contributions to the early diagnosis of intestinal carcinomas’. He observed skin changes associated with internal malignancies consisting of an eruption of flat, shiny, pigmented, glandular, epithelial growths similar to seborrhoeic warts or verrucae seniles in young patients with cancer. He hypothesized that there might be a link between abnormal epithelial proliferation in internal organs and skin keratinocyte proliferation. He is remembered for performing the first facelift, on a Polish aristocrat in 1912. The sign of Leser–Trélat is so deeply embedded in medical literature and the minds of modern practitioners that it is unlikely to ever be erased. However, the contribution of Eugen Von Hollander should not be forgotten.

Second opinion (external specialist referral) practice of breast pathology: the Nottingham experience.

Breast pathology is a challenging field, and discrepancies in diagnoses exist and can affect patient management. This study aims to review a breast referral practice and assess the pattern and frequency of breast lesions sent for an external expert review and evaluate potential impacts on patients' care. Seven hundred and forty cases that were referred to Nottingham City Hospital for a second opinion between 2019 and 2022 which have slides and reports were retrieved and reviewed. Reasons for referral, initial diagnosis, proffered specialist opinion and any discrepancy or potential impacts of management were assessed. The most frequent entities were papillary lesions (19%), fibroepithelial lesions (17%), invasive carcinomas that were sent for confirmation of the invasive diagnosis or subtyping of the invasive tumour (17%), intraductal epithelial proliferation with atypia (9%) and spindle cell lesions (8%). Other entities included biphasic tumours such as adenomyoepithelioma, as well as vascular and nipple lesions. Few cases were sent for prognostic classification or comments on the management, and in occasional cases no initial diagnosis was offered. After reviewing the cases by the expert pathologists, the initial diagnosis was confirmed or one of the suggested diagnoses was preferred in 79% of cases, including 129 cases (17%) in which the opinion resulted minor changes in the management. Significant changes in the classification of lesions were made in 132 cases (18%) which resulted in significant change in the patient management recommendation. In 14 cases (2%) a final classification was not possible, and further specialist opinion was obtained. Comments on the differential diagnosis and advice on further patient management were provided in most cases. This study demonstrates the value of external referral of challenging, rare and difficult to classify breast lesions. It also highlights the most common breast lesions that are likely to be challenging, and specialist opinion can refine their classification to improve patient care.

Ductular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver disease

Ductular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are largely unknown. Here, we identify neutrophils as drivers of biliary cell proliferation and the defective wound-healing response. The intrahepatic localization of neutrophils was evaluated in patients with chronic liver disease. Neutrophil dynamics were analyzed by intravital microscopy and neutrophil-labeling assays in DDC-treated mice. Neutrophil depletion or inhibition of recruitment was achieved using a Ly6g antibody or a CXCR1/2 inhibitor, respectively. Mice deficient in PAD4 (peptidyl arginine deiminase 4) and ELANE/NE (neutrophil elastase) were used to investigate the mechanisms underlying ductular reaction expansion. In this study we describe a population of ductular reaction-associated neutrophils (DRANs), which are in direct contact with biliary epithelial cells in chronic liver diseases and whose numbers increased in parallel with disease progression. We show that DRANs are immobilized at the site of ductular reaction for a prolonged period of time. In addition, liver neutrophils display a unique phenotypic and transcriptomic profile, showing a decreased phagocytic capacity and increased oxidative burst. Depletion of neutrophils or inhibition of their recruitment reduces DRANs and the expansion of ductular reaction, while mitigating liver fibrosis and angiogenesis. Mechanistically, neutrophils deficient in PAD4 and ELANE abrogate neutrophil-induced biliary cell proliferation, thus indicating the role of neutrophil extracellular traps and elastase release in ductular reaction expansion. Overall, our study reveals the accumulation of DRANs as a hallmark of advanced liver disease and a potential therapeutic target to mitigate ductular reaction and the maladaptive wound-healing response. Our results indicate that neutrophils are highly plastic and can have an extended lifespan. Moreover, we identify a new role of neutrophils as triggers of expansion of the biliary epithelium. Overall, the results of this study indicate that ductular reaction-associated neutrophils (or DRANs) are new players in the maladaptive tissue-healing response in chronic liver injury and may be a potential target for therapeutic interventions to reduce ductular reaction expansion and promote tissue repair in advanced liver disease.

Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions

Cell proliferation is a central process in tissue development, homeostasis, and disease, yet how proliferation is regulated in the tissue context remains poorly understood. Here, we introduce a quantitative framework to elucidate how tissue growth dynamics regulate cell proliferation. Using MDCK epithelial monolayers, we show that a limiting rate of tissue expansion creates confinement that suppresses cell growth; however, this confinement does not directly affect the cell cycle. This leads to uncoupling between rates of cell growth and division in epithelia and, thereby, reduces cell volume. Division becomes arrested at a minimal cell volume, which is consistent across diverse epithelia invivo. Here, the nucleus approaches the minimum volume capable of packaging the genome. Loss of cyclin D1-dependent cell-volume regulation results in an abnormally high nuclear-to-cytoplasmic volume ratio and DNA damage. Overall, we demonstrate how epithelial proliferation is regulated by the interplay between tissue confinement and cell-volume regulation.

Lobe-specific responses of TRAMP mice dorsolateral prostate following celecoxib and nintedanib therapy.

Delayed cancer progression in the ventral prostate of the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model has been previously reported upon celecoxib and nintedanib co-administration. Herein, we sought to further investigate the effects of these drugs association in some of their direct molecular targets (COX-2, VEGF and VEGFR-2) and in reactive stroma markers (TGF-β, αSMA, vimentin and pro-collagen 1) in the dorsolateral prostate, looking for lobe-specific responses. Male TRAMP mice were treated with celecoxib (10mg/Kg, i.o.) and/or nintedanib (15mg/Kg, i.o.) for 6weeks and prostate was harvested for morphological and protein expression analyses. Results showed that combined therapy resulted in unique antitumor effects in dorsolateral prostate, especially due to the respective stromal or epithelial antiproliferative actions of these drugs, which altogether led to a complete inversion in high-grade (HGPIN) versus low-grade (LGPIN) premalignant lesion incidences in relation to controls. At the molecular level, this duality in drug action was paralleled by the differential down/upregulation of TGF-β signaling by celecoxib/nintedanib, thus leading to associated changes in stroma composition towards regression or quiescence, respectively. Additionally, combined therapy was able to promote decreased expression of inflammatory (COX-2) and angiogenesis (VEGF/VEGFR-2) mediators. Overall, celecoxib and nintedanib association provided enhanced antitumor effects in TRAMP dorsolateral as compared to former registers in ventral prostate, thus demonstrating lobe-specific responses of this combined chemoprevention approach. Among these responses, we highlight the ability in promoting TGF-β signaling and its associated stromal maturation/stabilization, thus yielding a more quiescent stromal milieu and resulting in greater epithelial proliferation impairment.

CONVENTIONAL SQUAMOUS CELL CARCINOMA COEXISTING WITH A VERRUCOUS CARCINOMA: A HYBRID NEOPLASM

Verrucous carcinoma (VC) is a low-grade variant of squamous cell carcinoma (SCC) that lacks the cytological features of malignancy and does not metastasize, differently from the conventional SCC. Oral hybrid verrucous carcinoma is a rare neoplasm comprised of VC and conventional SCC. This study presents a case report of this hybrid neoplasm in an 81-year-old male former smoker. In the intraoral examination, the patient exhibited a white lesion with a verrucous surface in the maxillary alveolar ridge. Under clinical hypothesis of VC or conventional SCC, an incisional biopsy was performed. Microscopically, the tumor showed an endophytic proliferation of hyperkeratinized squamous epithelium with parakeratin plugging and bulbous rete ridges extending in depth. Areas of infiltration by trabeculae and islands of well-differentiated SCC were also observed. The final diagnosis was SCC coexisting with a hybrid verrucous carcinoma (VC). The patient was referred to a head and neck service and is undergoing treatment. Verrucous carcinoma (VC) is a low-grade variant of squamous cell carcinoma (SCC) that lacks the cytological features of malignancy and does not metastasize, differently from the conventional SCC. Oral hybrid verrucous carcinoma is a rare neoplasm comprised of VC and conventional SCC. This study presents a case report of this hybrid neoplasm in an 81-year-old male former smoker. In the intraoral examination, the patient exhibited a white lesion with a verrucous surface in the maxillary alveolar ridge. Under clinical hypothesis of VC or conventional SCC, an incisional biopsy was performed. Microscopically, the tumor showed an endophytic proliferation of hyperkeratinized squamous epithelium with parakeratin plugging and bulbous rete ridges extending in depth. Areas of infiltration by trabeculae and islands of well-differentiated SCC were also observed. The final diagnosis was SCC coexisting with a hybrid verrucous carcinoma (VC). The patient was referred to a head and neck service and is undergoing treatment.

ORAL VERRUCIFORM XANTHOMA: REPORT OF TWO CASES

Oral verruciform xanthoma (VX) is a benign lesion of unknown etiology, usually found in the gingiva and palate. This study reports on two cases of this uncommon lesion. The first is a nodule in the upper gingiva of an adult man, with the clinical diagnosis of squamous papilloma. The second is a white plaque on the tongue of a 64-year-old man, clinically diagnosed as leukoplakia or reactive hyperkeratosis. After excisional biopsy, both lesions presented a proliferation of squamous epithelium, with elongated rete ridges and numerous foamy macrophages (CD68+) within the connective tissue papillae, classified respectively as flat and verrucous. The first patient died during follow up, but the second showed no signs of recurrence one year after the biopsy. In a 60-year period, we have only 4 cases of VX (0.025%), a lesion that could be clinically misguided as other papillary or verrucous lesions. Oral verruciform xanthoma (VX) is a benign lesion of unknown etiology, usually found in the gingiva and palate. This study reports on two cases of this uncommon lesion. The first is a nodule in the upper gingiva of an adult man, with the clinical diagnosis of squamous papilloma. The second is a white plaque on the tongue of a 64-year-old man, clinically diagnosed as leukoplakia or reactive hyperkeratosis. After excisional biopsy, both lesions presented a proliferation of squamous epithelium, with elongated rete ridges and numerous foamy macrophages (CD68+) within the connective tissue papillae, classified respectively as flat and verrucous. The first patient died during follow up, but the second showed no signs of recurrence one year after the biopsy. In a 60-year period, we have only 4 cases of VX (0.025%), a lesion that could be clinically misguided as other papillary or verrucous lesions.

MOLLUSCUM CONTAGIOSUM AFFECTING THE LIPS

Molluscum contagiosum is a cutaneous and mucosal viral infection that can affect the oral cavity and lips on rare occasions. The aim of this study is to report a case of molluscum contagiosum affecting the lips. A 53-year-old female was referred for evaluation of multiple papules on the skin and lips. Oral and cutaneous examination revealed the presence of multiple yellowish papules in the skin of the shoulders and neck and in the vermillion border. Clinical diagnosis included molluscum contagiosum and impetigo and a biopsy of a lip lesion was performed under local anesthesia. Hematoxylin and eosin-stained histological slides showed a localized proliferation of the stratified squamous epithelium with keratinocytes presenting nuclear basophilic inclusions, compatible with molluscum contagiosum. The patient was submitted to surgical removal of additional lesions and remains in clinical follow-up. Molluscum contagiosum is a cutaneous and mucosal viral infection that can affect the oral cavity and lips on rare occasions. The aim of this study is to report a case of molluscum contagiosum affecting the lips. A 53-year-old female was referred for evaluation of multiple papules on the skin and lips. Oral and cutaneous examination revealed the presence of multiple yellowish papules in the skin of the shoulders and neck and in the vermillion border. Clinical diagnosis included molluscum contagiosum and impetigo and a biopsy of a lip lesion was performed under local anesthesia. Hematoxylin and eosin-stained histological slides showed a localized proliferation of the stratified squamous epithelium with keratinocytes presenting nuclear basophilic inclusions, compatible with molluscum contagiosum. The patient was submitted to surgical removal of additional lesions and remains in clinical follow-up.

#3679 ANOCTAMIN 1 INHIBITION SUPPRESSES CYSTOGENESIS BY ENHANCING CILIOGENESIS AND THE CILIARY DOSAGE OF POLYCYSTINS

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy which is characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel, which has recently been shown to be involved in ADPKD progression. However, how ANO1 contributes to ADPKD is largely unexplored. Method 1. Based on mRNA gene chips, the expression of ANO1 abnormally increased in human ADPKD kidneys. 2. Immunohistochemical staining showed ANO1 location. 3. Real-time PCR and Western blot showed mRNAs and protein of ANO1 in ADPKD patients and animal model-PKD1RC/RC mice. 4. Confocal immunofluorescence showed ANO1 and PC2 location in the cilia. 5. 3D gel culture to verify the function of ANO1 in cysts formation. 6. ANO1 inhibitors and siRNA to discover STAT3 and ERK pathway in ADPKD cell by WB. Results We found that ANO1 is consistently upregulated inhuman and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like patten at the ciliary base but not on the ciliary surface. ANO1 deficiency promotes both ciliogenesis and the ciliary dosage of polycystin-2 in human Pkd1-/- cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. Conclusion Our data indicate ANO1 may aggravate ADPKD by regulating the cilia length and PC2 expression. Moreover, ANO1 could support cyst growth by activating STAT3 and ERK pathways. Thus ANO1 is a negative regulator for both cilia formation and cilia trafficking of polycystins and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.

Mucin 4 is a cellular biomarker of necrotizing bronchiolitis in influenza A virus infection

Influenza A virus (IAV) in the human and swine host infects epithelial cells lining the respiratory tract causing a necrotizing bronchitis and bronchiolitis. These epithelial surfaces are protected by large glycoproteins called mucins. Mucin 4 (MUC4) is a transmembrane mucin that consists of an alpha subunit responsible for surface protection and intracellular beta subunit involved in signal transduction which repress apoptosis and stimulate epithelial proliferation. This study was designed to determine the expression and potential role of MUC4 during IAV infection. We used immunohistochemistry in combination with machine learning image analysis to quantify differential protein expression of MUC4 subunits in IAV-infected and uninfected lung in a porcine model. MUC4 protein basal expression in control animals varied significantly by litter. MUC4 protein expression was significantly increased in bronchioles with necrotizing bronchiolitis compared to histologically normal bronchioles, likely representing a regenerative response to restore mucosal integrity of conducting airways. Understanding the impact of differential MUC4 expression among healthy individuals and during IAV infection will facilitate control strategies by elucidating mechanisms associated with susceptibility to IAV that can be therapeutically or genetically regulated and may be extended to other respiratory diseases.

RIG-I contributes to keratinocyte proliferation and wound repair by inducing TIMP-1 expression through NF-κB signaling pathway.

Epithelial keratinocyte proliferation is an essential element of wound repair, and chronic wound conditions, such as diabetic foot, are characterized by aberrant re-epithelialization. In this study, we examined the functional role of retinoic acid inducible-gene I (RIG-I),a key regulator of epidermal keratinocyte proliferation, in promoting TIMP-1 expression. We found that RIG-Iis overexpressed in keratinocytes of skin injury and underexpressed in skin wound sites of diabetic foot and streptozotocin-induced diabetic mice. Moreover, mice lacking RIG-I developed an aggravated phenotype when subjected to skin injury. Mechanistically, RIG-I promoted keratinocyte proliferation and wound repair by inducing TIMP-1 via the NF-κB signaling pathway. Indeed, recombinant TIMP-1 directly accelerated HaCaT cell proliferation in vitro and promoted wound healing in Ddx58-/- and diabetic mice in vivo. In summary, we demonstrated that RIG-I is a crucial factor that mediates epidermal keratinocyte proliferation and may be a potential biomarker for skin injury severity, thus making it an attractive locally therapeutic target for the treatment of chronic wounds such as diabetic foot.

Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification

The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis. We used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis. We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis. Hypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.