Epithelial Proliferation Research Articles

Solitary Peutz-Jeghers polyp harboring a focus of high-grade dysplasia in the colon: a case report and literature review.

A solitary Peutz-Jeghers (PJ) polyp is a rare hamartomatous lesion without an associated PJ syndrome. However, little is known regarding malignancy arising in solitary PJ polyps. Here, we report a case of a solitary colonic PJ polyp with focal dysplasia. A 45-year-old asymptomatic man underwent total colonoscopy following a positive fecal occult blood test. The patient had no history of mucocutaneous pigmentation or family history of PJ syndrome. A 20mm erythematous pedunculated polyp was observed in the sigmoid colon. Magnified endoscopy revealed a tubular or branch-like pit pattern with localized areas of irregular pits. These findings were suggestive of colorectal adenoma with high-grade dysplasia, and endoscopic mucosal resection was performed. Histopathological examination revealed arborizing proliferation of hyperplastic epithelia with smooth muscle bundles. In addition, a small number of irregular crypts with high-grade dysplasia were observed in the hyperplastic epithelium. Based on these histological findings, we finally diagnosed the patient with a solitary colonic PJ polyp with high-grade dysplasia. The present case suggests that solitary colonic PJ polyps may harbor dysplastic changes and require pathological evaluation with en bloc resection of the polyps.

Shear stress effects on epididymal epithelial cell via primary cilia mechanosensory signaling.

Shear stress, resulting from fluid flow, is a fundamental mechanical stimulus affecting various cellular functions. The epididymis, essential for sperm maturation, offers a compelling model to study the effects of shear stress on cellular behavior. This organ undergoes extensive proliferation and differentiation until puberty, achieving full functionality as spermatozoa commence their post-testicular maturation. Although the mechanical tension exerted by testicular fluid is hypothesized to drive epithelial proliferation and differentiation, the precise mechanisms remain unclear. Here we assessed whether the responsiveness of the epididymal cells to shear stress depends on functional primary cilia by combining microfluidic strategies on immortalized epididymal cells, calcium signaling assays, and high-throughput gene expression analysis. We identified 97 genes overexpressed in response to shear stress, including early growth response (Egr) 2/3, cellular communication network factor (Ccn) 1/2, and Fos proto-oncogene (Fos). While shear stress triggered a rapid increase of intracellular Ca2+, this response was abrogated following the impairment of primary ciliogenesis through pharmacological and siRNA approaches. Overall, our findings provide valuable insights into how mechanical forces influence the development of the male reproductive system, a requisite to sperm maturation.

Assessment of optical coherence tomography and optical coherence microscope for oral cancer diagnosis: a clinical accuracy study

Objective: To explore and evaluate the feasibility and accuracy of using optical coherence tomography and optical coherence microscope (OCT/OCM) for diagnosis of oral cancer. Methods: In this study, OCT/OCM was utilized to image the oral mucosa specimens. A total of 289 ex vivo oral mucosa specimens were collected from 68 patients with oral cancer who were hospitalized at Department of Oral and Maxillofacial Head and Neck Tumors, Capital Medical University School of Stomatology, between January 2021 and February 2023, resulting in a dataset of 1 445 OCT/OCM images. By observing the characteristic patterns in the OCT/OCM images, including normal oral mucosa, epithelial abnormal proliferation (mild, moderate, severe), and oral cancer, these patterns were matched with corresponding pathological images. A diagnostic study was conducted, employing pathological diagnosis as the gold standard and utilizing a double-blind experimental design involving three diagnostic evaluators who participated in the analysis and diagnosis of OCT/OCM images. Results: The OCT/OCM images demonstrated good correlation with the corresponding pathological images, and diagnostic criteria were established based on the comparative results. In the diagnostic study involving three investigators, the accuracy was 82%, sensitivity was 84% (95%CI: 80%-88%), and specificity was 81% (95%CI: 77%-85%). There was a high level of agreement among the observers (κ=0.614), indicating substantial concordance in the diagnostic results among the three investigators. Conclusions: This study demonstrates the potential of OCT/OCM for diagnosis of oral cancer. The technology accurately distinguishes between normal oral mucosa, epithelial abnormal proliferation and oral cancer.

RELATO DE CASO: HIPERPLASIA MAMÁRIA EM FELINO MACHO

Feline mammary fibroepithelial hyperplasia (FMFH) is a benign, non-neoplastic condition that primarily affects young female cats, usually less than two years old. It is characterized by the proliferation of mammary duct epithelium and periductal connective tissue, associated with the hormonal effects of endogenous and exogenous progestogens. Although more common in females during pregnancy, pseudopregnancy, or early estrus, it can also occur in males after prolonged treatment with progestogens. This report describes the case of an uncastrated male cat in which two small nodules were found in the abdominal region, and subsequently, five more nodules were detected in the mammary region via ultrasound. These nodules underwent fine-needle aspiration cytology, revealing well-differentiated epithelial and mesenchymal cells, suggestive of fibroadenomatous mammary hyperplasia. The animal then underwent castration and, the next day after the procedure, the nodules completely disappeared.

Candida tropicalis-derived vitamin B3 exerts protective effects against intestinal inflammation by promoting IL-17A/IL-22-dependent epithelial barrier function

ABSTRACT Candida tropicalis-a prevalent gut commensal fungus in healthy individuals – contributes to intestinal health and disease. However, how commensal C. tropicalis influences intestinal homeostasis and barrier function is poorly understood. Here, we demonstrated that the reference strain of C. tropicalis (MYA-3404) ameliorated intestinal inflammation in murine models of chemically induced colitis and bacterial infection. Intestinal colonization of C. tropicalis robustly upregulated the expression of IL-17A and IL-22 to increase barrier function and promote proliferation of intestinal epithelial cells in the mouse colon. Metabolomics analysis of fecal samples from mice colonized with C. tropicalis revealed alterations in vitamin B3 metabolism, promoting conversion of nicotinamide to nicotinic acid. Although nicotinamide worsened colitis, treatment with nicotinic acid alleviated disease symptoms and enhanced epithelial proliferation and Th17 cell differentiation. Oral gavage of C. tropicalis mitigated nicotinamide-induced intestinal dysfunction in experimental colitis. Blockade of nicotinic acid production with nicotinamidase inhibitors lowered the protective effects against colitis in mice treated with C. tropicalis. Notably, a clinical C. tropicalis strain isolated from patients with candidemia lacked the protective effects against murine colitis observed with the reference strain. Together, our results highlight a novel role for C. tropicalis in resolving intestinal inflammation through the modulation of vitamin B3 metabolism.

Utilizing Ziziphus spina-christi for eco-friendly synthesis of silver nanoparticles: Antimicrobial activity and promising application in wound healing

Abstract Wound healing is a critical process essential for the body’s recovery from injuries, often complicated by bacterial infections. Silver nanoparticles (AgNPs) have gained attention due to their antibacterial and tissue-regenerative properties. However, conventional chemical synthesis methods for AgNPs pose environmental risks. This study utilizes Ziziphus spina-christi (ZSC) extract for the eco-friendly synthesis of AgNPs, evaluating their antibacterial and wound-healing capabilities. The AgNPs-ZSC showed an absorption maximum at λ max of 460 nm, a particle size of 111.2 ± 1.09 nm, a polydispersity index of 0.38 ± 0.006, and a zeta potential of −27.0 ± 0.231 mV. The synthesized AgNPs-ZSC were spherical, non-aggregated, and exhibited potent antibacterial activity superior to chloramphenicol. Furthermore, the AgNPs-ZSC cream significantly promoted wound closure, epithelial tissue proliferation, and granulation tissue formation in rats, showing no signs of toxicity or adverse reactions. In conclusion, AgNPs-ZSC cream demonstrates excellent antibacterial and wound-healing properties, presenting a sustainable alternative to conventional chemical methods for AgNP synthesis.

Suppression of epithelial proliferation and tumourigenesis by immunoglobulin A.

Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis 1 . Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function 2,3 with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities 4-8 . Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have increased susceptibility to endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to both reduce steady-state proliferation and protect mice from tumours, but this function was due to antibody structure rather than binding specificity. In both organoid and monolayer culture systems, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and a targeted CRISPR screen identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 regulate Notch signalling and tune the normal cycling of absorptive colonocyte progenitors. In mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 or blocking Notch signalling was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.

Management of a labial pleomorphic adenoma in the odontostomatology department of the Idrissa Pouye general hospital in Dakar

Pleomorphic adenoma of the salivary glands (formerly called mixed tumor) represents 60% of oral salivary tumors. The accessory salivary glands have their preferential location at the palate, the lips of the cheek and the oropharynx. At the level of the lips, this tumor most often affects the right upper lip.We report a case of pleomorphic adenoma of the right upper lip evolving for more than 4 years in a 70-year-old melanoderm patient who was referred to the odontostomatology department of the Idrissa Pouye General Hospital (HOGIP).The swelling was large, slightly exceeding the midline of the upper lip. The swelling measured approximately 20 cm from its long axis. It was firm, painless and did not bleed on contact and covered with a healthy-looking mucosa. The management was surgical under local anesthesia and the postoperative course was simple.Histological analysis specified that it was a well-limited nodular lesion, corresponding to a mixed epithelial and mesenchymal proliferation with a thin capsule in favor of a pleomorphic adenoma. No recurrence was observed 4 months after the operation.

The diagnostic challenge of a Papillary lesion of the breast in a patient with Peutz-Jeghers syndrome

Abstract Introduction/Objective Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder with elevated risk of various neoplasms, including breast cancer. The incidence of cancer among PJS patients is estimated to be 15-fold higher than the general population. The spectrum of breast lesions in PJS varies from benign papillomas to invasive carcinomas, presenting significant diagnostic complexities. The case presented here revolves around a unique papillary lesion in a PJS patient. Methods/Case Report A 40-year-old African American female, with PJS presented with a palpable abnormality in the right subareolar region with sanguineous nipple discharge. Multiple prior biopsies revealed intraductal papillomas with no atypia. Imaging showed a 7.0 cm complex solid and cystic subareolar mass, which had increased in size by 42% within a short period. Given the rapid increase in size, malignant transformation was clinically suspected. The patient underwent bilateral mastectomy. Macroscopic examination showed a 9.0 cm tan firm subareolar nodule with solid and cystic components. Histopathology revealed areas consistent with intraductal papilloma, however, additional complexities, including epithelial and myoepithelial proliferations with mild cytologic atypia, squamous, apocrine, and sebaceous metaplasia made the diagnosis challenging. No necrosis or increased mitotic activity was identified. Immunostaining for CK5/6 and p63 highlighted the myoepithelial layer, while estrogen receptor demonstrated heterogeneous positive staining. This picture raised suspicion of adenomyoepithelioma, but there was a significant overlap with intraductal papilloma. A final diagnosis of intraductal papillary neoplasm with epithelial and focal myoepithelial atypia was rendered. Results (if a Case Study enter NA) NA Conclusion This case presented a complex diagnostic dilemma. The rapid growth of the lesion, coupled with cytological atypia, raised significant concern necessitating precise differentiation between adenomyoepithelioma and intraductal papilloma. Further research is imperative to explore the pathophysiology of breast lesions in PJS, their impact on surveillance, management, potential for malignancy, and prognosis. Investigating additional diagnostic modalities and molecular markers to aid in accurate differentiation between benign and malignant papillary neoplasms in PJS patients warrants consideration.

Involvement of autophagy and gut dysbiosis in ambient particulate matter-induced colonic inflammation

Ambient fine particulate matter (PM2.5), a vital environmental toxicant, not only adversely affects the cardiovascular and respiratory systems but also potentially exhibits an association with intestinal inflammation and colorectal cancer (CRC). The underlying molecular mechanisms of PM2.5 impacts on CRC are still unclear. In this study, we utilized collected ambient PM2.5 and standard reference material SRM2786 to investigate the toxic effects on the colon through in vivo chronic exposure mouse and in vitro cell culture models. We employed a chronic mouse exposure model to clarify the colonic injury and gut microbiome biomarkers. Prolonged exposure to PM2.5 via oropharyngeal aspiration led to a significant rise in colonic epithelial proliferation and reduced colon length in mice. It triggered characteristics indicative of gut microbiota dysbiosis linked to inflammatory bowel disease. The gut microbiome alternations may serve as a biomarker indicating the colonic health impacts of PM2.5 exposure. PM2.5 and SRM2786-induced cytotoxicity manifested as autophagy dysregulation-mediated abnormal proliferation, IL-8 production, p62/SQSTM1 accumulation, and lysosomal membrane damage in human colon cells WiDr and Caco-2. Both PM2.5 and SRM2786 exposures led to the accumulation of p62/SQSTM1 and compromised lysosomal membrane integrity, showing impaired autophagic flux in WiDr and Caco-2 cells. Finally, we examined the correlations between atmospheric PM2.5 data and biomarkers of colonic inflammation in human population. The serum level of IL-8 was significantly correlated with regional anthropogenic pollutants. In conclusion, our findings elucidate that ambient PM2.5 exhibits adverse effects on colon health manifested as inflammation, aberrant proliferation, and gut dysbiosis, potentially mediated through autophagy dysregulation, thereby highlighting the importance of further research on the impact of environmental pollutants on gastrointestinal health.

Vasoactive intestinal peptide promotes secretory differentiation and mitigates radiation-induced intestinal injury

BackgroundVasoactive intestinal peptide (VIP) is a neuronal peptide with prominent distribution along the enteric nervous system. While effects of VIP on intestinal motility, mucosal vasodilation, secretion, and mucosal immune cell function are well-studied, the direct impact of VIP on intestinal epithelial cell turnover and differentiation remains less understood. Intestinal stem and progenitor cells are essential for the maintenance of intestinal homeostasis and regeneration, and their functions can be modulated by factors of the stem cell niche, including neuronal mediators. Here, we investigated the role of VIP in regulating intestinal epithelial homeostasis and regeneration following irradiation-induced injury.MethodsJejunal organoids were derived from male and female C57Bl6/J, Lgr5-EGFP-IRES-CreERT2 or Lgr5-EGFP-IRES-CreERT2/R26R-LSL-TdTomato mice and treated with VIP prior to analysis. Injury conditions were induced by exposing organoids to 6 Gy of irradiation (IR). To investigate protective effects of VIP in vivo, mice received 12 Gy of abdominal IR followed by intraperitoneal injections of VIP.ResultsWe observed that VIP promotes epithelial differentiation towards a secretory phenotype predominantly via the p38 MAPK pathway. Moreover, VIP prominently modulated epithelial proliferation as well as the number and proliferative activity of Lgr5-EGFP+ progenitor cells under homeostatic conditions. In the context of acute irradiation injury in vitro, we observed that IR injury renders Lgr5-EGFP+ progenitor cells more susceptible to VIP-induced modulations, which coincided with the strong promotion of epithelial regeneration by VIP. Finally, the observed effects translate into an in vivo model of abdominal irradiation, where VIP showed to prominently mitigate radiation-induced injury.ConclusionsVIP prominently governs intestinal homeostasis by regulating epithelial progenitor cell proliferation and differentiation and promotes intestinal regeneration following acute irradiation injury.

7862 The Paradoxical Role Of ERFFI1 In Breast Cancer Progression Is Supported By Its Dynamic Protein Interactome

Abstract Disclosure: A. Ocampo: None. P.D. Bagamasbad: None. In breast cancer (BCa), glucocorticoid (GC) therapy is used in anti-emetic and palliative care. However, the effects of GC therapy in BCa are conflicting as it is beneficial for hormone-responsive luminal subtypes while it promotes tumor progression in more aggressive triple-negative BCa (TNBCs). A factor implicated in this paradoxical shift is the feedback inhibitor of epidermal growth factor receptor (EGFR) signaling, ERBB receptor feedback inhibitor 1 (ERRFI1). In BCa cell lines, ERRFI1 expression is directly regulated by GC receptor (GR). More interestingly, ERRFI1 was found to restrict the GC-enhanced proliferation in normal breast epithelia but enhances the GC-mediated pro-tumorigenic effects in highly aggressive TNBC. To identify the mechanism behind the shift in ERFFI1 function through BCa progression, ERRFI1 protein interactions in the luminal, HER2, and TNBC subtypes were analyzed by identifying differentially expressed proteins from each subtype using available proteome and interactome datasets from Integrated Interactions Database and followed by network and clustering analyses through STRING. The ERRFI1 interactome varied across the subtypes, and gene ontology analysis of the protein networks revealed progressive tumorigenic effects from the least aggressive luminal subtype to the most aggressive TNBC. The luminal BCa-ERRFI1 interactome showed metastatic potential that is countered by negative regulation of receptor tyrosine kinase (RTK) signaling. The HER2-ERRFI1 interactome highlighted the amplification of RTK signaling and its possible modulation through SRC while the TNBC-ERRFI1 interactome presents pro-oncogenic proteins implicated in drug resistance, angiogenesis, and EMT. Interestingly, the interactome also revealed a link between EGFR signaling and GR signaling possibly through ERRFI1, EGFR, and SFN. To determine the function of ERFFI1 in EGFR signaling in BCa, we generated stable ERRFI1 knockdown in different breast epithelial cell models through lentiviral transduction. Cells were then treated with EGF followed by gene expression analysis of known EGF-upregulated genes such as MYC, GSK3B, MCL1, and MMP9. We found that ERRFI1 knockdown enhanced the EGF-dependent induction of MYC and MMP9 in normal MCF10A cells and this effect was not observed in the TNBC MDA-MB-468 line, suggesting the loss of ERRFI1-mediated inhibition of EGFR signaling with BCa tumorigenic potential. Taken together, our findings suggest that the progressive loss of anti-tumorigenic function of ERRFI1 may be explained by its changing interactome in BCa molecular subtypes. Presentation: 6/3/2024

7862 The Paradoxical Role of ERFFI1 in Breast Cancer Progression Is Supported by Its Dynamic Protein Interactome

Abstract Disclosure: A. Ocampo: None. P.D. Bagamasbad: None. In breast cancer (BCa), glucocorticoid (GC) therapy is used in anti-emetic and palliative care. However, the effects of GC therapy in BCa are conflicting as it is beneficial for hormone-responsive luminal subtypes while it promotes tumor progression in more aggressive triple-negative BCa (TNBCs). A factor implicated in this paradoxical shift is the feedback inhibitor of epidermal growth factor receptor (EGFR) signaling, ERBB receptor feedback inhibitor 1 (ERRFI1). In BCa cell lines, ERRFI1 expression is directly regulated by GC receptor (GR). More interestingly, ERRFI1 was found to restrict the GC-enhanced proliferation in normal breast epithelia but enhances the GC-mediated pro-tumorigenic effects in highly aggressive TNBC. To identify the mechanism behind the shift in ERFFI1 function through BCa progression, ERRFI1 protein interactions in the luminal, HER2, and TNBC subtypes were analyzed by identifying differentially expressed proteins from each subtype using available proteome and interactome datasets from Integrated Interactions Database and followed by network and clustering analyses through STRING. The ERRFI1 interactome varied across the subtypes, and gene ontology analysis of the protein networks revealed progressive tumorigenic effects from the least aggressive luminal subtype to the most aggressive TNBC. The luminal BCa-ERRFI1 interactome showed metastatic potential that is countered by negative regulation of receptor tyrosine kinase (RTK) signaling. The HER2-ERRFI1 interactome highlighted the amplification of RTK signaling and its possible modulation through SRC while the TNBC-ERRFI1 interactome presents pro-oncogenic proteins implicated in drug resistance, angiogenesis, and EMT. Interestingly, the interactome also revealed a link between EGFR signaling and GR signaling possibly through ERRFI1, EGFR, and SFN. To determine the function of ERFFI1 in EGFR signaling in BCa, we generated stable ERRFI1 knockdown in different breast epithelial cell models through lentiviral transduction. Cells were then treated with EGF followed by gene expression analysis of known EGF-upregulated genes such as MYC, GSK3B, MCL1, and MMP9. We found that ERRFI1 knockdown enhanced the EGF-dependent induction of MYC and MMP9 in normal MCF10A cells and this effect was not observed in the TNBC MDA-MB-468 line, suggesting the loss of ERRFI1-mediated inhibition of EGFR signaling with BCa tumorigenic potential. Taken together, our findings suggest that the progressive loss of anti-tumorigenic function of ERRFI1 may be explained by its changing interactome in BCa molecular subtypes. Presentation: 6/3/2024

Novel adomavirus associated with proliferative skin lesions affecting the dermal denticles of a sand tiger shark (Carcharias taurus).

A captive sand tiger shark (Carcharias taurus) presented with progressive, hard, raised, miliary skin lesions localized to the lateral trunk and peduncle. Histopathologic evaluation of biopsy samples revealed dysplastic proliferation of odontogenic epithelium with the production of collagenous material. Inclusion bodies and viral particles were not observed with light or transmission electron microscopy, respectively. However, using next generation sequencing with Illumina MiSeq and PCR followed by Sanger sequencing, the complete genome of a novel adomavirus, tentatively named sand tiger shark adomavirus (STAdoV), was obtained from the affected tissue. The genome was circular and 18.5 kilobases with bidirectionally transcribed genes, namely EO1, EO2 & 4, EO3, LO4, LO5, LO6, LO7, LO8, and SET. In situ hybridization using RNAscope® technology and a STAdoV specific probe localized viral DNA to the nuclei of proliferating epithelial cells. Adomaviruses are an emerging viral group with structural and replicative genes sharing a complex evolutionary history with adenoviruses and small circular DNA tumor viruses including papillomaviruses and polyomaviruses. Adomaviruses are described in a number of fish species in association with both necrotizing and proliferative diseases. BLAST analysis of the viral genome revealed greatest nucleotide identity (71.29%) to guitarfish adomavirus (GAdoV), another elasmobranch virus associated with proliferative (epidermal) skin lesions. Lesions in the index animal persisted for approximately 1 year during which time four conspecifics developed similar proliferations. Ultimately, lesions in all sharks regressed spontaneously without recurrence for 2 years.

P2X4 receptor mediates macrophage infiltration leading to endometriotic cyst epithelium proliferation and hyperalgesia in mouse model

To evaluate the effects of a P2X4 receptor (P2X4R)-specific antagonist on murine endometriotic-like lesions and human endometriotic stromal cells. Experimental study using an in vivo mouse endometriosis model and in vitro primary culture of human endometriotic stromal cells. NC-2600, an antagonist of the P2X4 ionotropic ATP receptor (P2X4R), was orally administered to the mice and cells. Gene expression analyses for cytokines were conducted in the endometriotic-like cysts and vaginal portion of mice, and immunohistochemistry was performed to evaluate the proliferative activity and localization of macrophages in addition to cytokine expression. The sensation of murine vaginal pain was evaluated using visceromotor responses. The study was performed in academic and hospital research laboratories. NC-2600 reduced the proliferation of the cyst epithelium and vaginal pain sensation. In both cysts and vaginas, P2X4R is mainly expressed in macrophages, and NC-2600 reduces the number of tissue macrophages and reverses the elevated expression of InterleukinL-33 and cyclooxygenase-2 in animals with endometriosis. These results indicate unknown pathophysiological roles of P2X4R expressed in local macrophages at the injury site of endometriosis and in the vagina, suggesting the potential therapeutic effects of orally administered P2X4R inhibitors for alleviating the symptoms of endometriosis.

Pulmonary epithelial wound healing and the immune system. Mathematical modelling and bifurcation analysis of a bistable system

Respiratory diseases such as asthma, acute respiratory distress syndrome (ARDS), influenza or COVID-19 often directly target the epithelium. Elevated immune levels and a ‘cytokine storm’ are directly associated with defective healing dynamics of lung diseases such as COVID-19 or ARDS. The infected cells leave wounded regions in the epithelium which must be healed for the lung to return to a healthy state and carry out its main function of gas-exchange. Due to the complexity of the various interactions between cells of the lung epithelium and surrounding tissue, it is necessary to develop models that can complement experiments to fully understand the healing dynamics. In this mathematical study we model the mechanism of epithelial regeneration. We assume that healing is exclusively driven by progenitor cell proliferation, induced by a chemical activator such as epithelial growth factor (EGF) and cytokines such as interleukin-22 (IL22). Contrary to previous studies of wound healing, we consider the immune system, specifically the T effector cells TH1, TH17, TH22 and Treg to strongly contribute to the healing process, by producing IL22 or regulating the immune response. We therefore obtain a coupled system of two ordinary differential equations for the epithelial and immune cell densities and two functions for the levels of chemicals that either induce epithelial proliferation or recruit immune cells. These functions link the two cell equations. We find that to allow the epithelium to regenerate to a healthy state, the immune system must not exceed a threshold value at the onset of the healing phase. This immune threshold is supported experimentally but was not explicitly built into our equations. Our assumptions are therefore sufficient to reproduce experimental results concerning the ratio TH17/Treg cells as a threshold to predict higher mortality rates in patients. This immune threshold can be controlled by parameters of the model, specifically the base-level growth factor concentration. This conclusion is based on a mathematical bifurcation analysis and linearization of the model equations. Our results suggest treatment of severe cases of lung injury by reducing or suppressing the immune response, in an individual patient, assessed by their disease parameters such as course of lung injury and immune response levels.

Midkine as a driver of age-related changes and increase in mammary tumorigenesis

Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and Tcells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.

Corneal Epithelial Remodeling Following Cylinder Correction With SMILE or FS-LASIK: A Contralateral Comparative Study.

To compare the corneal epithelial remodeling in eyes with high astigmatism that had small incision lenticule extraction (SMILE) and femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK). Seventy-four patients with myopic astigmatism of greater than -2.00 diopters (D) and little binocular difference in spherical equivalent were included in this contralateral comparative study. All patients received SMILE in one eye and FS-LASIK in the other eye randomly. The corneal epithelial remodeling pattern was mapped using the latest RTVue spectral-domain optical coherence tomographer (Optovue) by region. Satisfactory refractive correction was achieved in all enrolled eyes with either SMILE or FS-LASIK. The corneal epithelium gradually thickened following surgical cylinder correction, distributing mainly along the flat medium. The corneal epithelium proliferation is milder centrally but more pronounced in the mid-peripheral area after SMILE, compared with FS-LASIK. The flat-steep difference in corneal epithelial thickness (CET) is evident in the mid-peripheral and peripheral areas, which is more obvious in SMILE. Residual cylinder was positively correlated with CET in eyes that had FS-LASIK, but not SMILE. More importantly, these epithelial changes were positively correlated with the ablation depth and higher order aberrations following surgical refractive correction. The postoperative CET map varied between SMILE and FS-LASIK. In eyes with high astigmatism, SMILE surgery is followed by milder and more stable corneal epithelial thickening. Moreover, the corneal epithelium is sensitive to stromal ablation and corneal remodeling is crucial to the postoperative visual quality. This study rigorously distinguished the CET difference between SMILE and FS-LASIK in astigmatic eyes and shed light on subsequent research. [J Refract Surg. 2024;40(10);e728-e741.].

Anti-tumor property of Argemone mexicana leaves methanol extracts against 7, 12- Dimethylbenz[a]anthracene (DMBA) induced mammary tumors in experimental rats

Background: Breast cancer is a complex and multistage process. Many natural compounds are available for an effective and efficient alternative method against breast cancer. This study focused on the anti-cancer activity of Argemone mexicana leaf extract on Dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in experimental rats. Materials and Methods: Argemone mexicana Leaves (AML) were collected, extracted by soxhlet apparatus with methanol solvent, and analyzed by Gas Chromatography and Mass-Spectroscopy (GCMS). Healthy Female Sprague-Dawley rats (7-8 weeks and 100 ± 20 g) were divided in five groups and used to induce mammary tumors by DMBA [25 mg/kg/ Subcutaneous (s.c.)]. After developing a palpable nodule (10-12 weeks after DMBA), the rats were treated with AML extract [200 and 400 mg/kg/Body Weight (b.w.)] and Tamoxifen (TAM 10 mg/kg) orally for 12 weeks. Body weight, tumor weight and volume measurements, lipid peroxidation, antioxidant and tumor marker [Carcinoembryonic Antigen (CEA)] levels, and histological investigations were assessed. Results: Following AML treatment, there was a reduction in weight and volume (P< 0.01) of breast tumor, as well as a significant decrease in levels of lipid peroxidation and tumor marker CEA (P < 0.001) and improved Superoxide Dismutase (SOD), Reduced glutathione (GSH), and caspase levels (P < 0.001). In cytological results, AML improved the cellular architecture, and significant restoration in histopathological examinations revealed a tumor with minimal glandular epithelium proliferation, a decrease in mitotic figures, and nuclear alterations. Conclusion: The study suggests that AML extract has a chemoprotective effect against DMBA-induced mammary tumors in experimental animals, specifying its possibility as a therapeutic agent for breast cancer treatment.

The Influence of Non-Pharmacological and Pharmacological Interventions on the Course of Autosomal Dominant Polycystic Kidney Disease.

Polycystic kidney disease (PKD) includes autosomal dominant (ADPKD) and autosomal recessive (ARPKD) forms, both of which are primary genetic causes of kidney disease in adults and children. ADPKD is the most common hereditary kidney disease, with a prevalence of 329 cases per million in Europe. This condition accounts for 5-15% of end-stage chronic kidney disease (ESKD) cases, and in developed countries such as Poland, 8-10% of all dialysis patients have ESKD due to ADPKD. The disease is caused by mutations in the PKD1 and PKD2 genes, with PKD1 mutations responsible for 85% of cases, leading to a more aggressive disease course. Recent research suggests that ADPKD involves a metabolic defect contributing to cystic epithelial proliferation and cyst growth. Aim: This review explores the interplay between metabolism, obesity, and ADPKD, discussing dietary and pharmacological strategies that target these metabolic abnormalities to slow disease progression. Conclusion: Metabolic reprogramming therapies, including GLP-1 analogs and dual agonists of GIP/GLP-1 or glucagon/GLP-1 receptors, show promise, though further research is needed to understand their potential in ADPKD treatment fully.