Specialized protrusions coordinate migratory border cell cluster cohesion via Scribble, Cdep, and Rac

Apicobasal polarity is a defining characteristic of epithelial cells and its disruption is a cancer hallmark. Distinct apical and basolateral protein modules antagonize each other to establish separate membrane domains. These modules interact with dozens of potential effector proteins. Here we describe polarity protein localization and function within a migrating epithelial cell cluster and identify a functionally significant effector protein. In Drosophila egg chambers, border cells delaminate from the follicular epithelium and migrate collectively. We report that the basolateral protein Scribble is required for border cell cluster cohesion and migration. The basolateral module localizes the Rac guanine nucleotide exchange factor Cdep to membranes, and Cdep knockdown phenocopies Scribble cluster cohesion defects. Remarkably, membrane targeting of Cdep is sufficient to partially suppress multiple Scribble phenotypes. We describe specialized basolateral protrusions that promote cluster cohesion. Scribble restricts these protrusions from encroaching onto the apical domain. Thus, a major function of the basolateral module is to localize Cdep, promoting specialized protrusions, cluster cohesion, and collective migration.

Atypical Papillary Thyroid Carcinoma with Squamous Metaplasia and RET/NRAS/TERT/PIK3CA Mutations: A Case Report

Background: Papillary thyroid carcinoma (PTC) with squamous metaplasia is a relatively rare and special subtype adenocarcinoma of thyroid which involves multiple genetic changes. We reported a rare case of atypical PTC with squamous metaplasia and RET/NRAS/TERT/PIK3CA mutations which was confirmed after surgical resection pathologically. Case summary: A 2.5×2.5×2 cm3, smooth, hard, clear boundaries and solid nodule on the left thyroid gland was found on relevant physical examination of the patient. And then, the unilateral radical resection of thyroid carcinoma was performed after diagnosing. The tumor cells were squamous metaplasia and arranged in structures with diffuse growth pattern microscopically. At high magnification, stretched nucleus, nuclear grooves and internuclear pseudoinclusions in tumor cells were detected, and the follicular epithelium cells were atypical. Immunohistochemical staining shown strong positiveness of CK19, TTF-1, P40 and Galectin-3, partial positiveness of TG of tumor cells and negativeness of Calcitonin, which could exclude medullary thyroid carcinoma (MTC). Furthermore, first generation sequencing of 18 PTC related genes techniques shown RET, NRAS, TERT and PIK3CA was mutated. Conclusion: Genetic detection is vital to the diagnosis of thyroid adenocarcinoma, especially for the PTC with atypical morphology or rare metaplasia

Effect of the prenatal action of fulvestrant on the ovaries of the offspring of laboratory mice

Relevance. Fulvestrant is used for the treatment of breast cancer in combination with other drugs. The aim of the study was to determine the effect of the prenatal action of fulvestrant on the ovaries of the offspring of laboratory mice. Materials and Methods. The experimental animals were divided into 4 groups: intact, control and 2 experimental, 5 animals in each group. Injections were administered to females after fertilization at the gestational stage E 11.5 once intramuscularly. In the control group (n=5), sterile castor oil was administered at a dose of 0.8 mcg/kg. In the first experimental group (n=5), an antiestrogen was introduced in the form of an oil solution of fulvestrant 0.08 ml 0.0005% at a dose of 20 mcg/kg. In the second group (n=5), an antiestrogen was introduced in the form of an oil solution of fulvestrant 0.4 ml 0.0005% at a dose of 100 mcg/kg. Results and Discussion . The study revealed that in the ovaries when the drug was administered at a dose of 20 mcg/kg (F-20), the number of primordial follicles was reduced. Accordingly, the number of follicles of subsequent generations decreased. With the introduction of the drug fulvestrant 100 mcg/kg (F-100) on the section of the ovary, sclerosis of the stromal component is observed, accompanied by a rearrangement of the vascular network with signs of atresia and cystic degeneration of the follicular epithelium in the secondary and tertiary follicles, formed cysts are observed in the ovarian parenchyma. Conclusion. The prenatal effect of the drug fulvestrant on the maternal body during pregnancy leads to persistent structural changes in the ovaries of the offspring, manifested in the late stages of ontogenesis, which, in turn, can lead to violations of reproductive function. The depth and scale of these changes are dose-dependent.

Subcellular spatial transcriptomics identifies three mechanistically different classes of localizing RNAs

Intracellular RNA localization is a widespread and dynamic phenomenon that compartmentalizes gene expression and contributes to the functional polarization of cells. Thus far, mechanisms of RNA localization identified in Drosophila have been based on a few RNAs in different tissues, and a comprehensive mechanistic analysis of RNA localization in a single tissue is lacking. Here, by subcellular spatial transcriptomics we identify RNAs localized in the apical and basal domains of the columnar follicular epithelium (FE) and we analyze the mechanisms mediating their localization. Whereas the dynein/BicD/Egl machinery controls apical RNA localization, basally-targeted RNAs require kinesin-1 to overcome a “default” dynein-mediated transport. Moreover, a non-canonical, translation- and dynein-dependent mechanism mediates apical localization of a subgroup of dynein-activating adaptor RNAs (BicD, Bsg25D, hook). Altogether, our study identifies at least three mechanisms underlying RNA localization in the FE, and suggests a possible link between RNA localization and dynein/dynactin/adaptor complex formation in vivo.

Radioiodine Ablation for Thyroid Cancer. Historical and Modern Aspects. Literature Review

Thyroid cancer is the most common oncological pathology of the endocrine system organs with a continuing trend towards an increase in the incidence. Radioiodine therapy (RIT) is the second stage of combined treatment, it is carried out only as an adjuvant treatment, it is an uncontested method of radio-targeted therapy for distant metastases of differentiated thyroid cancer (DTC). The method of radioiodine therapy is based on the unique natural affinity of iodine atoms for the follicular epithelium of the thyroid gland and DTC cells. Determination of indications for RIT is based on stratification of recurrence risk, persistence, and disease prevalence. Over the past 15 years, the world’s leading professional communities have repeatedly revised approaches to risk stratification. Consideration of the mutational profile of the tumor and the theranostic approach have become significant innovations.Radioiodine therapy can be presented in the form of three modes: ablation of residual thyroid tissue, treatment of residual tumor and treatment of distant metastases. These regimens differ in the administered therapeutic activity of 131I, which looks logical from the point of view of the necessary personalization of the treatment. At the same time, in scientific circles, disputes about the absence of significant differences in the used therapeutic activities of 131I prescribed for radioiodine ablation outside the personalized approach do not subside.

Colchicine Improves Clinical Outcomes and Quality of Life in Hidradenitis Suppurativa Patients: A Retrospective Study

Introduction: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder of the follicular epithelium. The aim of the study was to investigate the effectiveness of colchicine on the clinical outcomes of HS patients, and to evaluate wither colchicine as monotherapy or in combination with doxycycline would provide better outcomes. Methods: A retrospective study was conducted including 44 patients with established HS, divided into three groups. The first group (n = 15 patients) received colchicine as monotherapy, the second group (n = 14 patients) received colchicine and doxycycline 100 mg/d, while the third group (n = 15 patients) received colchicine and doxycycline 40 mg/d. Disease severity during treatment was assessed at baseline and follow-up, using the Hurley Scoring System and the International Hidradenitis Suppurativa Severity Score System (IHS4). All patients were also asked to complete a Dermatology Life Quality Index (DLQI) questionnaire. These scores were compared among the study groups. Results: The DLQI and IHS4 scores significantly improved after treatment with colchicine (p < 0.001) in all groups. All colchicine regimes, including the single colchicine regime, colchicine plus doxycycline 100 mg regime, and colchicine plus doxycycline 40 mg regime, resulted in significant improvements in the DLQI and IHS4 scores (p < 0.001). Clinical improvement based on DLQI and IHS4 scores was similar in all groups. None of the patients had to discontinue the treatment due to adverse events. Discussion: In conclusion, our findings suggest that colchicine may improve clinical severity and quality of life in HS patients, either as monotherapy or in combination with doxycycline, both at antimicrobial (100 mg) and sub-antimicrobial (40 mg) doses.

Atypical Papillary Thyroid Carcinoma with Squamous Metaplasia and RET/NRAS/TERT/PIK3CA Mutations: A Case Report

Background: Papillary thyroid carcinoma (PTC) with squamous metaplasia is a relatively rare and special subtype adenocarcinoma of thyroid which involves multiple genetic changes. We reported a rare case of atypical PTC with squamous metaplasia and RET/NRAS/TERT/PIK3CA mutations which was confirmed after surgical resection pathologically. Case summary: A 2.5×2.5×2 cm3, smooth, hard, clear boundaries and solid nodule on the left thyroid gland was found on relevant physical examination of the patient. And then, the unilateral radical resection of thyroid carcinoma was performed after diagnosing. The tumor cells were squamous metaplasia and arranged in structures with diffuse growth pattern microscopically. At high magnification, stretched nucleus, nuclear grooves and internuclear pseudoinclusions in tumor cells were detected, and the follicular epithelium cells were atypical. Immunohistochemical staining shown strong positiveness of CK19, TTF-1, P40 and Galectin-3, partial positiveness of TG of tumor cells and negativeness of Calcitonin, which could exclude medullary thyroid carcinoma (MTC). Furthermore, first generation sequencing of 18 PTC related genes techniques shown RET, NRAS, TERT and PIK3CA was mutated. Conclusion: Genetic detection is vital to the diagnosis of thyroid adenocarcinoma, especially for the PTC with atypical morphology or rare metaplasia

Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation

Notch is a conserved developmental signaling pathway that is dysregulated in many cancer types, most often through constitutive activation. Tumor cells with nuclear accumulation of the active Notch receptor, NICD, generally exhibit enhanced survival while patients experience poorer outcomes. To understand the impact of NICD accumulation during tumorigenesis, we developed a tumor model using the Drosophila ovarian follicular epithelium. Using this system we demonstrated that NICD accumulation contributed to larger tumor growth, reduced apoptosis, increased nuclear size, and fewer incidents of DNA damage without altering ploidy. Using bulk RNA sequencing we identified key genes involved in both a pre- and post- tumor response to NICD accumulation. Among these are genes involved in regulating double-strand break repair, chromosome organization, metabolism, like raptor, which we experimentally validated contributes to early Notch-induced tumor growth. Finally, using single-cell RNA sequencing we identified follicle cell-specific targets in NICD-overexpressing cells which contribute to DNA repair and negative regulation of apoptosis. This valuable tumor model for nuclear NICD accumulation in adult Drosophila follicle cells has allowed us to better understand the specific contribution of nuclear NICD accumulation to cell survival in tumorigenesis and tumor progression.

THE FOLLICLEGENESIS IN THE THYROID GLAND IN THE POSTNATAL PERIOD OF ONTOGENESIS UNDER PRENATAL ANTIGENIC INFLUENCE

Antigenic influence at critical terms of ontogenesis can cause significant changes in the child's immune system. It is known that the entry of antigens into the fetus causes premature release of T-lymphocytes from the thymus and their migration to various organs. The paper was aimed at the study of the folliclegenesis of the thyroid gland in postnatal period at norm and after prenatal influence of staphylococcal toxoid. In the experimental research as a material were thyroid glands of Wistar rats aged 1 to 60 days of postnatal development (162 animals), about 6 animals in each group. Three animals groups were studied on 1, 3, 7, 11, 14, 21, 30, 45, 60 days after bith. I gr. - intact animals (norm); ІІ gr. - control, animals which were injected intrauterine 0.9% NaCl solution; III - experimental animals injected with staphylococcal toxoid liquid purified adsorbed (10-14 units of binding in 1 ml, diluted 10 portions) by operation intrauterinely on the 18th day of dated pregnancy. Histological sections 3-5 μm thick were stained by hematoxylin and eosin, histochemicaly by alcian blue and azan staining. Immunohistochemical study was performed according to the protocol recommended for a particular antibody of the manufacturer. Used ki-67 (Ki-67), TTF-1 (8G7G3/1), Fox-1 (A-12) monoclonal antibodies by Santa Cruz Biotechnology, Inc. A set of morphometric studies was performed by microscope Carl Zeiss Primo Star equipped with the Axiocam digital microphoto attachment with using program complex Zeiss Zen 2011. The results were considered reliable at p≤0,05. For processing of statistical material was used the standard software package Microsoft Office Excel and Statistica 10.0.The results were obtained about morphogenesis of rat’s thyroid after intrauterine antigenic action of staphylococcal toxoid. Morphofunctional homeostasis and stromal-parenchymal proportional relationship to thyroid gland closely associated with the activity of immune cells, including special role of lymphocytes, macrophages, and mast cells. Prenatal influence of staphylococcal toxoid led to the formation of a more pronounced structure of the parenchyma and stroma, but they showed signs of functional immaturity after birth. During the sucking period, the simultaneous presence of intra-, extrafollicular, septal and intramural types of folliculogesis is determined, which is a local reaction to systemic antigenic irritation with activation of compensatory-adaptive reactive folliclegenesis. The revealed changes in the process of folliclegenesis, accompanied by venous plethora, the formation of intraorgan diffuse lymphoid tissue and nodules, desquamation of the follicular epithelium, redistribution of the follicle diameter is a reaction to the systemic antigenic effect on the body during the critical period of prenatal development and normalizes by 45 days.Keywords: morphogenesis, thyroid gland, antigen, staphylococcal toxoid, experiment.