Secondary Nodules Research Articles

Clinical impact of EGFR and KRAS mutations in surgically treated unifocal and multifocal lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) are the two most common oncogenic drivers in lung adenocarcinoma, and their roles still need further exploration. Here we aimed to compare the clinical impact of EGFR and KRAS mutations on disease progression in resected unifocal and multifocal lung adenocarcinoma. Clinicopathologic and genomic data were collected for patients who underwent resection of lung adenocarcinoma from 2008 to 2022 at Stanford University Hospital. Retrospective review was performed in 241 patients whose tumors harbored EGFR (n=150, 62.2%) or KRAS (n=91, 37.8%) mutations. Clinical outcome was analyzed with special attention to the natural history of secondary nodules in multifocal cases wherein the dominant tumor had been resected. We confirm that compared with EGFR mutations, patients with KRAS mutations had more smokers, larger tumor size, higher TNM stage, higher positron emission tomography (PET)/computed tomography (CT) standard uptake value max, higher tumor mutation burden, and worse disease-free survival and overall survival on univariate analysis. For patients with multifocal pulmonary nodules, the median follow-up of unresected secondary nodules was 55 months. Secondary nodule progression-free survival (SNPFS) was significantly worse for patients with KRAS mutations than those with EGFR mutations (mean 40.3±6.6 vs. 67.7±6.5 months, P=0.004). Univariate analysis showed tumor size, tumor morphology, pathologic TNM stage, and KRAS mutations were significantly associated with SNPFS, while multivariate analysis showed only KRAS mutations were independently associated with worse SNPFS (hazard ratio 1.752, 95% confidence interval: 1.017-3.018, P=0.043). Resected lung adenocarcinomas with KRAS mutations have more aggressive clinicopathological features and confer worse prognosis than those with EGFR mutations. Secondary pulmonary nodules in multifocal cases with dominant KRAS-mutant tumors have more rapid progression of the secondary nodules.

The Chemistry and Mineralogy (CheMin) X-ray Diffractometer on the MSL Curiosity Rover: A Decade of Mineralogy from Gale Crater, Mars

For more than a decade, the CheMin X-ray diffraction instrument on the Mars Science Laboratory rover, Curiosity, has been returning definitive and quantitative mineralogical and mineral–chemistry data from ~3.5-billion-year-old (Ga) sediments in Gale crater, Mars. To date, 40 drilled rock samples and three scooped soil samples have been analyzed during the rover’s 30+ km transit. These samples document the mineralogy of over 800 m of flat-lying fluvial, lacustrine, and aeolian sedimentary rocks that comprise the lower strata of the central mound of Gale crater (Aeolis Mons, informally known as Mt. Sharp) and the surrounding plains (Aeolis Palus, informally known as the Bradbury Rise). The principal mineralogy of the sedimentary rocks is of basaltic composition, with evidence of post-depositional diagenetic overprinting. The rocks in many cases preserve much of their primary mineralogy and sedimentary features, suggesting that they were never strongly heated or deformed. Using aeolian soil composition as a proxy for the composition of the deposited and lithified sediment, it appears that, in many cases, the diagenetic changes observed are principally isochemical. Exceptions to this trend include secondary nodules, calcium sulfate veining, and rare Si-rich alteration halos. A surprising and yet poorly understood observation is that nearly all of the ~3.5 Ga sedimentary rocks analyzed to date contain 15–70 wt.% of X-ray amorphous material. Overall, this >800 m section of sedimentary rock explored in lower Mt. Sharp documents a perennial shallow lake environment grading upward into alternating lacustrine/fluvial and aeolian environments, many of which would have been habitable to microbial life.

Spleen white pulp structural and cellular composition in experimental furosemide-­induced hypomagnesemia

Relevance. Magnesium deficiency in the blood (hypomagnesemia) is due to many reasons, among which loop diuretics (furosemide) occupy acertain place. The role of the spleen in this process has not been determined. The aim of the work was to elucidate the effect of furosemide-­induced hypomagnesemia on the immune structures of the white pulp of rat spleen. Materials and Methods. Furosemide (Lasix® Aventis Pharma Ltd, India) was injected daily intraperitoneally at adose of 30 mg/kg to the experimental group of white outbred rats for 6 days, animals of the control group received an injection of 0.9% NaCl. Investigated: blood serum for the content of magnesium, calcium, sodium and iron; serial sections of the white pulp of the spleen after staining with hematoxylin and eosin to assess the structure and azure-­II-eosin to assess the cellular composition. With amicroscope magnification of 280 times, the ratio (in%) of primary (PLNS) and secondary lymphoid nodules of the spleen (SLNS) was calculated, the following were measured (µm): the diameter of the germinal center (GC), the width of the mantle and marginal zone, the diameter of the periarteriolar lymphoid sheath (PALS). In GC, the peripheral zone of lymphoid nodules, PALS at amagnification of 1500 times per field of view (100 μm2) was counted and presented as apercentage of the number of lymphocytes; macrophages; cells, mitotic and apoptotic elements. Morphometric analysis was carried out using Image ProPlus6.0 software (Media Cybernetics, USA). Statistical processing was carried out using the Statistica 10.0 software package with the determination of the arithmetic mean (M) and its error (m). Results and Discussion. The administration of furosemide led to adecrease in magnesium in the blood serum by 1.6 times (p0.05). In the white pulp of the spleen of animals of the experimental group, the proportion of SLNS decreased by 18.14%, the number of SLNS increased by 42.5% (p0.05). The diameter of SLNS increased insignificantly, the diameter of GC and the width of the marginal zone significantly increased by 27.1 and 24.8%, respectively. The proportion of macrophages increased by 20.6% in GC SLNS, and by 17.0% in PALS. The highest increase in the proportion of cells with signs of apoptosis was found in the periarteriolar lymphoid sheath of experimental animals - 34.6% (p0.05). Conclusion. Furosemide loading causes the development of dyselementosis, with the most significant loss of magnesium (hypomagnesemia) and has apronounced effect on the immune parameters of the spleen, represented by white pulp structures. Therefore, correction of the elemental status and monitoring of the state of the spleen in hypomagnesemia caused by the use of loop diuretics is anecessary element in the prevention of complications associated with the use of diuretic drugs.

Regression of metastatic malignant melanoma with dupilumab: A case report

AbstractExcoriated pruritus can be an intolerable symptom in patients with cancer where Type 2 inflammation and its associated cytokines IL‐4 and IL‐13 play major roles in the pruritus. Dupilumab, an antibody blocking IL‐4 and IL‐13, is approved for treating moderate to severe atopic dermatitis (AD) where itching is a significant symptom. We present a case report of intractable malignancy‐associated AD and pruritus with eosinophilia in a patient with stage IV malignant melanoma who was treated with dupilumab. Biweekly treatment with dupilumab led to an immediate improvement in itching and resolution of the AD, which subsided after a few doses and without significant adverse effects. Routine radiologic monitoring of the malignant melanoma showed concomitant resolution of secondary nodules in the lung, liver, and pleura. It was concluded that dupilumab may be a safe and effective treatment for intractable malignancy‐associated AD with pruritus and may have potential for moderating metastatic malignant melanoma.

Age-dependent distribution and size of lymphatic nodules as components of extrahepatic bile duct-associated lymphatic tissue in domestic swine - a micromorphometric study

Due to the biological and immunological similarity between pigs and humans, pigs are used in medical research. Many morphological studies regarding the structure of the components of mucosal associated lymphatic tissue have been performed in animals including pigs as well as in humans. However, no any information about the existence of extrahepatic bile duct-associated lymphoid tissue (EHBDALT) is available in pigs. The aim of this work was to study the distribution and size of lymphatic nodules in the wall of extrahepatic bile ducts of immature and mature pigs in order to describe the structure of EHBDALT as component of mucosa-associated lymphoid tissue. It was found out that EHBDALT consisted of diffuse lymphatic tissue, solitary and aggregated lymphatic nodules. In 2-month-old pigs, diffuse lymphatic tissue predominated but single lymphatic nodules were found as inactive homogenous encapsulated aggregates of lymphocytes. In mature animals, diffuse lymphatic tissue, primary and secondary nodules were observed. The present micromorphometric study allowed evaluating the age-dependent distribution and size of lymphatic nodules in porcine extrahepatic bile ducts. It provides original data on the presence and age-dependent structure of bile duct MALT in domestic pigs.

Reaction of regional lymph nodes of the middle ear during ultrasound lymphotropic therapy of exudative otitis media (experimental study)

The article is devoted to structural changes in the regional lymph nodes of the middle ear (superficial, facial and deep cervical lymph nodes) in experimental animals (30 male Wistar rats) when modeling exudative otitis media and after a 7-day course of local ultrasound lymphotropic therapy. The method of conducting the experiment is described. Comparative morphological and morphometric studies of lymph nodes were carried out on the 12th day from the beginning of otitis modeling and evaluated according to 19 criteria: node cut-off area, capsule area, marginal sinus, interstitial part, paracortical area, cerebral sinuses, brain cords, area number and area of primary and secondary lymphoid nodules, area of germinal centers, specific areas of the cortex and medulla oblongata, sinus system, T-dependent and B-dependent zones, cortical-cerebral index. With exudative otitis media in the regional lymph nodes of the middle ear, compared with the physiological norm, a reaction from the intra-nodular structures was observed, indicating inhibition of drainage and detoxification in the lymph catchment area, which was considered as the morphological equivalent of the insufficiency of their lymphocyte function. Regional lymphotropic therapy using low-frequency ultrasound contributed to the positive dynamics of the structural components of the lymph nodes and the normalization of most of their indicators, which is a prerequisite for the development and use of this technology in clinical practice.

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination.

Epithelial ovarian cancer (EOC) is considered the deadliest gynecological disease and is normally diagnosed at late stages, at which point metastasis has already occurred. Throughout disease progression, EOC will encounter various ecosystems and the communication between cancer cells and these microenvironments will promote the survival and dissemination of EOC. The primary tumor is thought to develop within the ovaries or the fallopian tubes, both of which provide a microenvironment with high risk of causing DNA damage and enhanced proliferation. EOC disseminates by direct extension from the primary tumors, as single cells or multicellular aggregates. Under the influence of cellular and non-cellular factors, EOC spheroids use the natural flow of peritoneal fluid to reach distant organs within the peritoneal cavity. These cells can then implant and seed distant organs or tissues, which develop rapidly into secondary tumor nodules. The peritoneal tissue and the omentum are two common sites of EOC metastasis, providing a microenvironment that supports EOC invasion and survival. Current treatment for EOC involves debulking surgery followed by platinum-taxane combination chemotherapy; however, most patients will relapse with a chemoresistant disease with tumors developed within the peritoneum. Therefore, understanding the role of the unique microenvironments that promote EOC transcoelomic dissemination is important in improving patient outcomes from this disease. In this review article, we address the process of ovarian cancer cellular fate at the site of its origin in the secretory cells of the fallopian tube or in the ovarian surface epithelial cells, their detachment process, how the cells survive in the peritoneal fluid avoiding cell death triggers, and how cancer- associated cells help them in the process. Finally, we report the mechanisms used by the ovarian cancer cells to adhere and migrate through the mesothelial monolayer lining the peritoneum. We also discuss the involvement of the transcoelomic ecosystem on the development of chemoresistance of EOC.

Морфология регионарных лимфатических узлов при экспериментальном канцерогенезе предстательной железы

Background: the migration of tumor cells into blood and lymphatic vessels is a key stage of the metastatic process in malignant neoplasms. Moreover, the presence of tumor cells in the lymph nodes is an indicator of cancer aggressiveness, and the histopathological characteristics of the lymph nodes are one of the important parameters for the treatment prognosis and patient survival Aim: to evaluate changes in the lymph nodes of mice during experimental carcinogenesis in the prostate gland. Material and Methods: the study was conducted on CBA inbred 3-month-old male mice (n=30). To create a model of malignant tumor growth in the prostate gland, a diluted cell strain of transplantable Ehrlich ascites carcinoma was inoculated into the prostate parenchyma. A model of prostate carcinogenesis was created in 18 days by transplanting Ehrlich ascites carcinoma into prostate tissue in mice (n=15; main group). The remaining 15 mice were in the control group. All manipulations with animals were carried out in compliance with the basic ethical principles. After the animals were removed from the experiment, a morphological analysis of the prostate and regional (pelvic) lymph nodes was performed. The area and cellular composition concerning the main structural and functional zones of the pelvic lymph nodes in both groups of animals were evaluated Results: this study showed that the cellular composition changed in the setting of prostate carcinogenesis in the pelvic lymph nodes. In the main group of animals, the number of immunoblasts significantly prevailed in the germinal center of secondary lymphoid nodules versus the control group (p<0,05). An increase in immunoblasts by almost 2 times in mice (experimental group) indicated the inhibition of humoral immunity in prostate carcinogenesis. Also, in the main group, the area of the cortical substance decreased by 14.5% and the area of the paracortex increased by 28.4% versus the control group (p<0,05). Conclusion: the first metastases of prostate cancer appear in regional lymph nodes. On the 18th day of prostate carcinogenesis, the structure of regional lymph nodes undergoes changes: paracortical hyperplasia, a decrease in the area of medullary cords and medullary substance, a decrease in cerebral sinuses KEYWORDS: prostate cancer, carcinogenesis, experiment, Ehrlich ascites carcinoma, lymphangiogenesis, lymph node, regional metastases. FOR CITATION: Astashov V.V., Lomshakov A.A., Tsekhmistrenko T.A. et al. Morphology of regional lymph nodes in experimental prostate carcinogenesis. Russian Medical Inquiry. 2022;6(4):171–176 (in Russ.). DOI: 10.32364/2587-6821-2022-6-4-171-176.

A systematic review and meta-analysis of the correlation between hyperuricemia and thyroid nodules in adults.

In recent years, thyroid nodules have gradually become one of the important factors endangering people's health, and we hope to recognize the association between hyperuricemia and thyroid nodulogenesis by this meta-analysis study. Literatures related to hyperuricemia and thyroid nodules were searched in the Chinese biomedical databases Chinese National Knowledge Infrastructure (CNKI), VIP, Wanfang, and the Chinese Biomedical Literature Database (CBM), as well as the English databases PubMed, EMBASE, and the Cochrane Library from establishment of the databases to September 2021. Duplicate literatures were identified using Endnote X9 software and excluded. All studies were screened according to the inclusion and exclusion criteria, and the quality of the included literature was assessed. Data were recorded and meta-analyzed using the Stata 15.1 software. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated using the fixed effects or random effects models. Finally, sensitivity analyses were performed to assess the reliability of the results. Funnel plots were constructed to evaluate the publication bias of the literatures. A total of 16 articles, with a total sample size of 126,907, were included in this study. Meta-analysis showed that there was no correlation between the incidence of thyroid nodules and the presence or absence of hyperuricemia in the overall population. Interestingly, hyperuricemia was found to be a protective factor for the incidence of thyroid nodules in the male population (OR =0.91; 95% CI: 0.86 to 0.97; P<0.05). However, hyperuricemia was identified as a risk factor for the incidence of thyroid nodules in the female population (OR =1.14; 95% CI: 1.04 to 1.25; P<0.05). Serum uric acid has a bidirectional regulatory effect in different genders and female patients should be wary of secondary thyroid nodules.

Morphofunctional Features of Limphoid Tissue of the Stomach in Some Wild Bird Species

The article presents the results of histological studies of topography, microstructure and functional features of the stomach lymphoid tissue in birds. The research was carried out on 12 species of wild birds belonging to 6 orders. Classical methods of histological specimens staining with hematoxylin and eosin, according to Weigert, Van Gieson, and argentum nitrate impregnation according to Kelemen were used when performing the work. It has been confirmed that the birds' stomach has glandular (proventriculus), muscular (ventriculus, gizzard) and pyloric parts, which are not equally expressed in separate species. In all parts of the stomach, lymphoid tissue is represented by local clusters, which in birds of the orders Galliiformes (P. colchicus, B. bonasia, P. crictatus); Anseriformes (B. canadensis); Passeriformes (P. pica, C. cornix); Gruiformes (G. chloropus, F. atra); Ciconiiformes (C. ciconia) and Columbiiformes (C. livia) are located in the tunica mucosa and submucosa, and in B. canadensis, F. atra, G. chloropus also in the tunica muscularis and tunica serosa. In L. lagopus and G. glandarius, lymphoid tissue has been found only in the proventriculus and its intermediate zone. Structural levels of lymphoid tissue (diffuse form, prenodules, primary and secondary lymphoid nodules) are unequally expressed in the birds' stomach. In B. bonasia, B. canadensis, P. pica, C. cornix, C. ciconia, C. livia, only a diffuse form appears in all its parts. This form of lymphoid tissue is registered in the ventriculus of other birds species and proventriculus in L. lagopus and G. glandarius. All levels of the lymphoid tissue structural organization are detected in the proventriculus in P. crictatus, G. chloropus and in the proventriculus and pyloric part of the stomach in P. colchicus and F. atra. The content of lymphoid tissue is different in parts of the birds' stomach. Most of all it is contained in the intermediate zone of the proventriculus and the pyloric part of the stomach. Diffuse form is the most common among the levels of lymphoid tissue structural organization. The research results make it possible to more fully assess the morphofunctional status of wild birds and, accordingly, to find out the state of their immune system

Content and location of lymphocyte subpopulations with markers CD4+, CD8+ and CD20+ in the esophageal tonsil of chickens and the Meckel diverticulum of ducks

Immune formations of birds' digestive organs, including the esophageal tonsil and Meckel’s diverticulum, protect the body from foreign antigens that enter the body with food and water and play an important role in maintaining the genetic constancy of its internal environment. This unique property of the immune system is formed during ontogenesis and is associated with maintaining the selection of lymphocyte clones that are able to respond to foreign antigens and carry out a specific immune response of two types: humoral and cellular. This article presents the results of a study of T- and B-lymphocyte subpopulations of the esophageal tonsil of Shever 579 cross chickens at the age of 25, 180 and 300 days, the Meckel diverticulum of the Blagovarsky cross ducks at the age of 30, 150 and 180 days. Immunohistochemical and statistical research methods were used to determine the localization and quantitative parameters of cell populations of lymphocytes (CD4+, CD8+, CD20+) using monoclonal antibodies and the DAKO EnVision FLEX+ imaging system (Dako Cytomation, Denmark). Separate subpopulations of T-lymphocytes (CD4+ - helpers, CD8+ -cytotoxic / T-suppressors) and mature B-lymphocytes (CD20+) were found in the esophageal tonsil and Meckel diverticulum of birds. Their presence confirms that antigen-independent proliferation and differentiation of lymphocytes into effector cells occur in the immune formations of the digestive system. The lymphoid tissue of these formations is represented mainly by a well-defined diffuse form and nodules with light centers (secondary). In the esophageal tonsil of chickens, these structures are located in the tunica mucosa and tela submucosa, and in the Meckel diverticulum of ducks – also in the tunica muscularis. The content of lymphocytes with these markers predominates in diffuse lymphoid tissue compared to that in secondary lymphoid nodules. In the diffuse lymphoid tissue of the esophageal tonsil, lymphocytes are located mainly near the adenomeres and excretory ducts of the esophageal glands, blood vessels, and under the surface epithelium, and in Meckel’s diverticulum – around the crypts, in their epithelium and in the epithelium of the villi. They are also found in the light centers of lymphoid nodules and on their periphery. The indices of the content of lymphocytes with the indicated markers in the esophageal tonsil and Meckel diverticulum which we determined were associated with age characteristics of the poultry in the postnatal period of ontogenesis. According to our observations, the content of CD20+ lymphocytes was the highest, while the populations of CD4+ and CD8+ lymphocytes were much smaller. This indicates an increase in the activity and predominance of the humoral immunity over the cellular one. The content of CD20+ lymphocytes was highest in birds at the age of 180 days, that is, during their sexual maturity. The data presented in the work can be used by morphologists researching the organs of the immune system, immunologists, poultry specialists involved in breeding, using and raising poultry and in educational work.

Effects of Current Density on Surface Morphology and Coating Thickness of Nickel Plating on Copper Surface

Nickel (Ni) thin film was deposited on commercial pure copper using electrodeposition method. To understand the growth behavior of Ni nodules, deposition was done by varying the coating current density. The topography of coating was analyzed using Scanning Electron Microscope (SEM). The coatings were also analyzed for variation in amount of coating, cathode current efficiency and thickness of coating. The deposited Ni thin film was observed to be of coffee bean kind of secondary nodules with size varying from 400 to 800 nm and almost spherical primary nodules with size varying from 100 to 250 nm varying as a function of coating current density. At higher current density, the coatings were observed to be of multiple layers of nodules. This suggests the presence of defects like twins, dislocations and stacking faults. The nodules are observed to have fine crystallites in the nano range.

CHANGES IN THE STRUCTURAL ORGANIZATION OF THE SPLEEN UNDER THE INFLUENCE OF MONOSODIUM GLUTAMATE AND AFTER ITS ABOLITION

Актуальність. Глутамат натрію є однією з найпоширеніших харчових добавок в світі. В статті наведено та проаналізовано дані експериментального дослідження, яке проводено на 52 білих щурах самцях та самках репродуктивного віку.&#x0D; Мета дослідження – вивчити морфометричні, гістологічні та електронно-мікроскопічні зміни паренхіми селезінки щурів за умов впливу глутамату натрію та після його відміни.&#x0D; Методи. Мікроанатомію компонентів селезінки білих щурів за умов фізіологічної норми дослідили на 10 інтактних тваринах. Експериментальні тварини поділені на 3 групи. Статистичну обробку цифрових даних проводили за допомогою програмного забезпечення «Excel» та «STATISTICA» 6.0 з використанням параметричного методу.&#x0D; Результати. Через вісім тижнів дії глутамату натрію виявлено достовірне зменшення відносної площі білої пульпи в паренхімі селезінки білих щурів самців та самок, збільшення кількості вторинних лімфоїдних вузликів, зростання кількості моноцитів, макрофагів, плазматичних клітин та клітин мієлоїдного ряду, зростання частки ретикулярної сполучної тканини в складі селезінкових тяжів червоної пульпи. Еритроцити та тромбоцити заповнюють не лише просвіт пазух селезінки, але й накопичуються в пульпарних тяжах, велика кількість лімфоцитів на різних стадіях апоптозу. Венозні пазухи червоної пульпи повнокровні, їхні просвіти розширені та дещо деформовані. Навколо судин та венозних пазух наявні ознаки набряку. Збільшення кількості плазматичних клітин свідчить про пришвидшення проліферації активованих лімфоцитів, яке є ознакою iмуноіндукуючого ефекту. Через чотири тижні після відміни глутамату натрію гістологічна та електронно-мікроскопічна будова органа майже не відрізняється від попередньої групи тварин. Зростає повнокрів’я судин паренхіми селезінки, щільність клітин зменшується. Збільшується кількість апоптично змінених клітин.&#x0D; Підсумок. Через вісім тижнів після відміни глутамату натрію зворотніх змін у структурі паренхіми селезінки не виявлено. Отже, відміна введення глутамату натрію після його тривалого впливу не «покращує» морфометричних показників паренхіми селезінки щурів та не призводить до відновлення структурної організації органа.

Hypertension Editors' Picks: Hyperaldosteronism.

Hypertension Editors' Picks: Hyperaldosteronism.

EMT-Induced Gemcitabine Resistance in Pancreatic Cancer Involves the Functional Loss of Equilibrative Nucleoside Transporter 1.

Epithelial-mesenchymal transition (EMT) in cancer cells drives cancer chemoresistance, yet the molecular events of EMT that underpin the acquisition of chemoresistance are poorly understood. Here, we demonstrate a loss of gemcitabine chemosensitivity facilitated by human equilibrative nucleoside transporter 1 (ENT1) during EMT in pancreatic cancer and identify that cadherin switching from the epithelial (E) to neuronal (N) type, a hallmark of EMT, contributes to this loss. Our findings demonstrate that N-cadherin decreases ENT1 expression, membrane localization, and gemcitabine transport, while E-cadherin augments each of these. Besides E- and N-cadherin, another epithelial cell adhesion molecule, EpCAM, played a more prominent role in determining ENT1 membrane localization. Forced expression of EpCAM opposed cadherin switching with restored ENT1 expression, membrane localization, and gemcitabine transport in EMT-committed pancreatic cancer cells. In gemcitabine-treated mice, EpCAM-positive tumors had high ENT1 expression and reduced metastasis, whereas tumors with N-cadherin expression resisted gemcitabine treatment and formed extensive secondary metastatic nodules. Tissue microarray profiling and multiplexed IHC analysis of pancreatic cancer patient-derived primary tumors revealed EpCAM and ENT1 cell surface coexpression is favored, and ENT1 plasma membrane expression positively predicted median overall survival times in patients treated with adjuvant gemcitabine. Together, our findings identify ENT1 as an inadvertent target of EMT signaling mediated by cadherin switching and provide a mechanism by which mesenchymal pancreatic cancer cells evade gemcitabine therapy during EMT.

Функціональні зони плямки Пейєра сліпої кишки кролів

A feature of rabbit gut-associated lymphoid tissue is that its structure is more developed than in other animal species. In rabbits it is composed of sacculus rotundus, vermiform appendix and Peyer’s patches. These immune formations contain an organized component of lymphoid tissue – lymphoid nodules (B-cell zone) and interfollicular region (T-cell). Secondary lymphoid nodules with germinal centers presented in them are formed due to antigen stimulation. The caecum of Hyplus rabbits at the age of 30 -, 60 - and 90-days was investigated. Each age group consisted of 5 rabbits. Experimental rabbits are clinically healthy, unvaccinated and untreated against ecto- and endoparasites. Peyer’s patches of the caecum were selected for the study and fixed in 10% of formalin. Subsequently, the specimens stained with hematoxylin-eosin were prepared from the obtained samples. On the 30th day of life, Peyer’s patches in the cecum were detected by gross examination. On the histological level, they had formed interfollicular region and lymphoid nodules. In turn, lymphoid nodules were divided into primary and secondary ones. A well-defined mantle zone and germinal centers were observed in the secondary lymphoid nodules. The regularities of their area indicators increase (mean value, median and interquartile range (IQR)) and their correlation were studied. The most intensive growth of the mantle area and the germinal center was observed from the 30th to the 60th day. The relative area of the mantle zone and the germinal center as part of the secondary lymphoid nodule was determined. Its value did not change during the experimental period.

К вопросу о патогенезе затянувшегося течения экссудативного среднего отита

The article is devoted to the role of the regional lymphatic system of the middle ear, from the point of view of the pathogenesis of the prolonged presence of fluid in the air cavities of the temporal bone with a prolonged course of serous otitis media. The study was carried out in an experiment on a model of exudative otitis media in laboratory animals (20 sexually mature male Wistar rats). Studied the state of regional (superficial, facial, and deep) lymph nodes collecting lymph from the mastoid process, tympanic cavity; external auditory canal, auditory tube. Comparative morphological and morphometric studies of lymph nodes were carried out on the 12th day of experimental otitis media and were assessed according to 19 criteria: total area of the node section, area of the capsule, marginal sinus, cortex, paracortex, medullary sinuses, medullary cords, number and area of primary and secondary lymphoid nodules, area of germinal centers, specific areas of cortical and medullary substance, sinus system, cortical/medullary ratio (C/M index), T- and B-dependent areas. Disorders of lymph outflow in the middle ear area, different nature, and degree of response of regional lymph nodes of different groups to the exudative process were revealed. It is assumed that the restructuring of the structural organization of the nodes, reflecting the inhibition of their protective and drainage functions, can prolong the phenomena of lymphostasis in the area of the primary focus and lead to the protracted course of exudative otitis media in clinical practice.

Long-Term Electrodeposition under a Uniform Parallel Magnetic Field. 2. Flow-Mode Transition from Laminar MHD Flow to Convection Cells with Two-Dimensional (2D) Nucleation.

Following the analysis of the self-organization of two-dimensional (2D) nuclei in Part 1, the flow-mode transition from laminar magnetohydrodynamics (MHD) flow to convection cells accompanied by 2D nucleation under a uniform parallel magnetic field was theoretically examined using the statistical mechanics of nonequilibrium fluctuation. As a result, it was clarified that secondary nodules of 2D nuclei develop with multiple nucleations during the transition, forming a one-upon-another structure. Then, the evolution of the convection cells as well as the secondary nodules requires unstable growth of the asymmetrical fluctuations by the specific adsorption of an ion. As predicted by the theory, the electrolytic current in copper deposition with specific adsorption of hydrogen ions under a parallel magnetic field developed with time, resulting in a nonlinear steplike curve in a 1200 s deposition time.

Long-Term Electrodeposition under a Uniform Parallel Magnetic Field. 1. Instability of Two-Dimensional Nucleation in an Electric Double Layer.

Under a parallel magnetic field, after long-term copper deposition from an acidic copper sulfate solution, numerous spherical secondary nodules of 10 to 100 μm diameters were formed one upon another in dendritic mode. This is a new type of micro-magnetohydrodynamic (MHD) effect arising from the unstable growth of three-dimensional (3D) and two-dimensional (2D) nuclei by specific adsorption of hydrogen ions (second micro-MHD effect). From the viewpoint of instability in electrodeposition, though 3D nucleation in the diffusion layer is always unstable, with ionic specific adsorption such as hydrogen ions, stable 2D nucleation turns unstable after long-term deposition. The resultant competitive growth of 3D and 2D nuclei produces spherical nodules as their composite, leading to their dendritic growth. Furthermore, though negligibly small, nonequilibrium fluctuations occurring in 2D nucleation migrate with the laminar solution flow caused by Lorentz force (MHD flow). Depending on whether the ionic adsorption is specific or nonspecific, the traveling asymmetrical fluctuation changes the direction to the upstream or downstream side, respectively.

Abstract PO-062: EMT-induced gemcitabine resistance in pancreatic cancer involves the functional loss of equilibrative nucleoside transporter 1

Abstract Epithelial-mesenchymal transition (EMT) in cancer cells drives cancer chemoresistance, yet the molecular events of EMT that underpin the acquisition of chemoresistance are poorly understood. Here, we demonstrate a significant loss of gemcitabine chemosensitivity facilitated by human equilibrative nucleoside transporter 1 (ENT1) during EMT in pancreatic cancer and identify that cadherin switching from the epithelial (E) to neuronal (N) type, a hallmark of EMT, contributes to this loss. Our findings demonstrate that N-cadherin decreases ENT1 expression, basolateral membrane localization and gemcitabine transport, while E-cadherin augments each of these. Besides E- and N-cadherin, another epithelial cell adhesion molecule, EpCAM, played a more prominent role in determining ENT1 membrane localization. Forced expression of EpCAM opposed cadherin switching with restored ENT1 expression, basolateral localization and gemcitabine transport in EMT-committed pancreatic cancer cells. In gemcitabine-treated mice, EpCAM positive tumors had high ENT1 expression and reduced metastasis, whereas tumors with N-cadherin expression resisted gemcitabine treatment and formed extensive secondary metastatic nodules. Tissue microarray profiling and multiplexed immunohistochemical analysis of pancreatic cancer patient-derived primary tumors revealed EpCAM and ENT1 cell surface co-expression is favored, and ENT1 plasma membrane expression positively predicted median overall survival times in patients treated with adjuvant gemcitabine. Together, our findings identify ENT1 as an inadvertent target of EMT signaling mediated by cadherin switching and provide a mechanism by which mesenchymal pancreatic cancer cells evade gemcitabine therapy during EMT. Citation Format: Brenna Weadick, Debasis Nayak, Avinash K. Persaud, Sau Wai Hung, Radhika Raj, Wei Chen, Junan Li, Terence M. Williams, Rajgopal Govindarajan. EMT-induced gemcitabine resistance in pancreatic cancer involves the functional loss of equilibrative nucleoside transporter 1 [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-062.