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May 2026 DOI 10.14302/issn.2572-3030.jcgb-26-6307
Faisst Arne-C.Corresponding author
The development of tumor biomarkers derived from blood, or its components, has become pivotal in advancing early cancer diagnosis. Malignant transformations induce cancer-specific alterations in the transcriptome, proteome, and secretome of tumor cells. Recent studies highlighted similar alterations in peripheral blood mononuclear cells (PBMCs) in cancer patients, which appear to mirror the state of transformation in tumor cells. These findings suggest an intercellular communication–driven mechanism rather than a systemic inflammatory response and, in addition to current ctDNA-based liquid biopsy biomarkers, point to a novel, simple, and highly robust approach for the early detection of cancer. Using this phenomenon to advance PBMC-based biomarker development, it will be essential to achieve 3D in vitro tumor models that reproduce a highly physiological tumor microenvironment (TME). Likewise, more enhanced 3D ex vivo models are required to enable the replication of cell-to-cell and organ-to-organ communication. These systems will guide the self-organization of mixed microenvironments derived from different tissues and enable them to accurately reproduce the molecular connections underlying these alterations. In this study, an innovative new modular 3D co-culturing approach was used to expose PBMCs to lung tumoroids, under physiologically relevant conditions. Changes in DNA fragmentation of PBMCs in the presence of lung cancer were quantified and used as a biomarker. To validate the predictiveness of this biomarker, our results were compared with clinical data from a clinical evaluation study. Similar to the clinical trial observations, PBMCs, when exposed to lung tumoroids, showed a significantly lower level of DNA fragmentation (37%). This modular 3D co-culturing model showed a predictiveness of the clinical data of > 90%, demonstrating its power to monitoring cell-to-cell communication effects and support the development of blood-based biomarkers.
Sep 2024 DOI 10.14302/issn.2692-1537.ijcv-24-5218
Luna-Rivero CesarCorresponding author
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often causes coagulation disorders that affect highly vascularized organs, such as the lungs and kidneys. Objective The objective of this study was to report the histopathological findings of variations in the fibrin pattern of pulmonary and renal microthrombi in patients who died from SARS-CoV-2 infection. Methods Minimally invasive autopsies were performed on 40 patients to collect lung (n=40) and kidney (n=16) tissue samples. Histochemical and immunohistochemical staining techniques were used for histopathological analyses. Premortem laboratory data were obtained from the patients' electronic medical records. Results The lung tissue showed a patchy pattern, characterized by areas of both minimal and severe damage. The most significant histopathological finding was the detection of thrombi with fibrin structures organized into discrete star-shaped units, which were more frequently observed in areas with severe lung injury than in those with minimal lung injury (p = 0.012). Star-shaped fibrin structures were also observed in the renal glomerular capillaries. Immunohistochemical staining revealed the presence of platelets and the procoagulant proteins von Willebrand factor (VWF) and Factor VIII within the star-shaped fibrin thrombi. Patients with star-shaped fibrin thrombi had higher levels of the systemic inflammatory indicators C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR). Conclusion Our observations suggest that the inflammatory microenvironment resulting from SARS-CoV-2 infection may contribute to the formation of star-shaped fibrin units in the pulmonary and renal microthrombi.
Jan 2022 DOI 10.14302/issn.2372-6601.jhor-22-4061
B. Danilova AnnaCorresponding author
N.N. Petrov National Medicine Research Center of Oncology, Department of Oncoimmunology, 197758, Leningradskaya str., 68, Pesochny, Saint-Petersburg, Russian Federation
Background Human malignant cell models which reflect the structural and physiological complexity of tumor tissue are of great importance for preclinical research in oncology. Spheroids/tumoroids derived from solid tumors are of great interest as cellular models mimicking the first vascular-free growth phase of a tumor node. The fact of the identity between artificially created tumor multicellular aggregates and the real tumor tissue, however, needs to be specified, described and validated in order to see how closely the spheroids are biologically similar to the malignized tissues in vivo compared to the monolayer cell cultures traditionally used. We present here a comparison study of the characteristics of solid tumor cells of different histogenesis (melanomas, soft tissue sarcomas and bone sarcomas, epithelial tumors) cultured in two dimensions (monolayer culture) and three dimensional space (spheroid), namely: spatial organization, multiplication, metabolic activity. Patients and Methods For the creation of 2 D and 3D cell models the cells isolated from the patient's solid tumor fragments obtained intraoperatively were used. 15 samples of skin melanoma, 20 samples of soft tissue and osteogenic sarcomas (STBS), and 9 samples of epithelial tumors (ET). The tumor cells were all cultivated for at least 10 passages. We used phase contrast, confocal microscopy, and immunohistochemistry to investigate spheroids and monolayer cultures. The supernatants of tumor cells grown in 2D and 3D cultures were studied using ELISA and multiplex analysis for the production of a spectrum of chemokines and cytokines supporting the immunosuppression, invasion and metastasis processes. Results Tumor specimens received were predominantly of metastatic origin (75%). In 100% of cases 2D cultures were received, in 88.6% of cases (39 out of 44) we succeeded in obtaining spheroids. There was no direct correlation between the efficiency of tumoroid formation and the tumor's histogenetic origin and the stage of the cancer process (primary tumor, recurrence, metastasis). The median size of spheroids by 4-5 days of cultivation with a starting concentration of 10000 cells per well was 657.14 μm for melanoma (min 400 - max 1000 μm), 571.42 μm (min 400 - max 700 μm), 507.14 μm (min 300 - max 600 μm) for soft tissue sarcomas, 650.0 μm (min 400 - max 900 μm) for osteogenic sarcomas. Immunochemical analysis of Ki-67, GLUT1, and Ecadherin markers was carried out for tumor tissue samples, single-layer tumor cultures, and tumoroids of every patient. The distribution of the stained groups in the spheroids was distinct from the monolayer cultures and more in accordance with the distribution of such in the tissue tumor, the number of Ki-67+ cells was increasing in the spheroids. We detected no dependence of Ki-67+ and GLUT1+ cell localization grade on spheroid size. We identified E-cadherin in tumor tissue and tumoroids of breast carcinoma and one melanoma culture. Monolayer cultures did not express it. The increase in secretory cell activity of the solid tumor cells from 2D to 3D system was observed when CCL2, CCL3, CXCL1, CXCL16, MIF, IL10, MICA (p<0.01) were investigated. Conclusion The presence of patient-specific cells of solid tumors in a 3D environment causes activation of the proliferative and metabolic processes as compared to monolayer cultures, which makes these models approximate the real world clinical picture. The production of chemokines that can attract to the tumor various types of immune system cells, to include their immature versions, as well as production of cytokines and Immunosuppression factors that, when present in the tumor microenvironment in the high concentrations, contribute to the formation of immune cells having suppressive capacities occurs in the 3D cell system. Three-dimensional model of the initial tumor nodule formation stage thus demonstrates the forming process of tumor cells favorable for them microenvironment. Construction of three-dimensional models - spheroids of tumor cells of differing histogenesis demands individual approach and more thorough investigation.
Jan 2021 DOI 10.14302/issn.2692-1537.ijcv-20-3685
Elkhenany HodaCorresponding author
Department of Surgery, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt.
The current uncontrollable outbreak of novel coronavirus (COVID-19) has unleashed severe global consequences in all aspects of life and society, bringing the whole world to a complete halt and has modeled significant threats to the global economy. The COVID-19 infection manifests with flu-like symptoms such as cough, cold, and fever resulting in acute respiratory distress syndrome (ARDS), lung dysfunction, and other systemic complications in critical patients are creating panic across the globe. However, the licensed vaccine has started to show up; some resulted in side effects that would limit its possibility in some circumstances as allergic personnel, for example. Moreover, the production and approval of new drugs is a very complicated process and takes a long time. On the other hand, stem cells have gone the extra mile and intensively investigated at preclinical and clinical studies in various degenerative diseases, including infectious ones. Stem cells are proposed as a broad-spectrum therapeutic agent, which may suppress the exaggerated immune response and promote endogenous repair by enhancing COVID-19 infected lung microenvironment. Also, stem cells have different application manners, either direct transplantation, exosome transplantation, or drug delivery of specific cytokines or nanoparticles with antiviral property by engineering stem cells. This review discusses and summarizes the possible emerging role of cell-based therapy, especially stem cell therapy, as an alternative promising therapeutic option for the treatment and control of novel COVID-19 and its potential role in tissue rejuvenation after COVID-19 infection.
Dec 2019 DOI 10.14302/issn.2372-6601.jhor-19-3092
S. Tsingotjidou AnastasiaCorresponding author
Laboratory of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, GR-541 24, Greece
Waldenström Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized mainly by uncontrolled accrual of M- immunoglobulin, secreted by malignant lymphoplasmatic cells. Mast cells interacting with malignant B-cells play an important role at the manifestation of the disease. Utilizing a previous xenotransplantation mouse model, this study evaluates long-term implant viability and quantifies distinct bone marrow mast cell populations along with their dynamics in non-WM and WM human bone implants. Non-WM bone implants were obtained from the femoral head of adult humans undergoing hip arthroplasty or hemiarthroplasty, whereas WM human bone implants originated from bone biopsies obtained from the posterior iliac crest of patients with active WM. All bone particles were implanted intramuscularly in twenty-four NOD/SCID mice. Following 3, 4 or 8 months postoperatively, xenografts were removed and studied using special histological techniques to identify mature and immature mast cells. Xenografts survived up to 8 months after implantation presenting normal cytoarchitecture (non-WM) or high-grade neoplastic infiltration and microresorption (WM bone biopsies). Statistical analysis of mast cell populations showed significant elevation regarding time progression and bone marrow microenvironment, thus suggesting the possible influence of malignant cells to the mast cell population in WM. This study presents the extended survival of intramuscular implantation of human adult bone xenografts into NOD/SCID mice and provides additional information on the interaction between mast cells and malignant B-cells.
Nov 2019 DOI 10.14302/issn.2689-5773.jcdp-19-3061
Bajaj AnubhaCorresponding author
MD. (Pathology) Panjab University, Department of Histopathology, A.B. Diagnostics, A-1, Ring Road , Rajouri Garden, New Delhi, 110027, India.
Novel cancer therapeutics are superior and prevalent in the current scenario although a subset may not be satisfactorily alleviated or undergo disease relapse with the adoption of conventional chemotherapeutic agents. Cancer cells can comfortably elude immune destruction as interaction of cancer cells with native immune cells within tissue microenvironment is a cogent factor in evasion of cancer cells from pertinent immune surveillance. Thus, cancer immunotherapy can be safely contemplated as an efficacious and contemporary treatment modality for managing various malignant disorders.
May 2019 DOI 10.14302/issn.2575-1212.jvhc-19-2722
Rodrigues Reina Moreira PamelaCorresponding author
Department of Veterinary Pathology, UNESP – FCAV – Faculdade de Ciências Agrárias e Veterinárias, Jaboticabal city, São Paulo State, Brazil.
Onychogryphosis is one of the main clinical findings in dogs with visceral leishmaniasis (VL); however, research focusing on the subungual area of infected dogs is scarce. This study aims to assess the subungual area of dogs with VL that presented or not onychogryphosis by means of histopathological analyses and immunohistochemical studies (parasite burden). The third digit of the thoracic and pelvic limbs of Leishmania infantum naturally infected dogs was collected regardless of sex, breed or age. The animals were split into two groups, dogs with onychogryphosis (G1; n=7) and without onychogryphosis (G2; n=9). The digits were evaluated in four areas (dorsal epidermis/dermis, ventral epidermis/dermis, dorsal matrix/dermis and ventral matrix/dermis). All lesions observed (mononuclear inflammatory infiltrate, vacuolar degeneration of basal keratinocytes, dermoepidermal clefting and pigmentary incontinence) were present in both groups, being more severe in the digits of G1 group. Immunostaining of the amastigote forms of Leishmania infantum were observed in the different areas of the digit, with statistical difference between the dorsal epidermis/dermis area and the dorsal matrix/dermis of G1 group. In conclusion, the main histopathological alteration of the digit of dogs with VL is mononuclear inflammatory infiltrate and parasite burden, especially in cutaneous tissue adjacent to the nail matrix. This aspect can influence the onychogryphosis development, due to the presence of the parasite and by inflammatory mediators released in the nail microenvironment.
Jul 2018
Ivanovska NinaCorresponding author
Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
Bone remodeling processes in rheumatoid arthritis (RA) depend mainly on the action of three types of cells. Osteoblasts are responsible for the formation of new bone, osteoclasts degrade mineralized bone and osteocytes regulate and maintain the bone homeostasis. Except, many other cell populations become pathologically activated in the inflamed microenvironment of the joint. The role of megakaryocytes and platelets in RA is poorly clarified. In the present study the presence of MK in the synovium and cartilage was observed in a model of arthritis induced in normal and complement depleted mice.
Jul 2017 DOI 10.14302/issn.2575-1212.jvhc-17-1586
Caroline ROSOLEM MayaraCorresponding author
Students of the Postgraduate Program in Veterinary Medicine, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp) Faculdade de Ciências Agrárias e Veterinárias (FCAV), Campus de Jaboticabal, São Paulo, Brasil.
The mammary tumor is one of the most common cancer in female dogs and, at the present days, there is a big focus on the study of the relation between this kind of tumor in animals and the cells that stay around them, like the inflammatory cells. The objective of this study was to evaluate and show where the inflammatory cells stay in simple mammary carcinomas in female dogs by immunohistochemistry. Samples of simple mammary carcinomas (tumor group; n=26) and mammary gland samples without tumor (control group; n=18) were submitted to immunohistochemical analysis for the detection of T lymphocytes, macrophages, plasma cells and the MHC-II molecule. The mast cells were evaluated by the histochemical technique (toluidine blue). Lymphocytes, macrophages and mast cells were observed distributed in the tumor stroma. MHC-II was detected in tumor cells and in the inflammatory infiltrate. Plasma cells predominated in the peritumoral stroma. Macrophages differed significantly between the two groups and predominated in the tumor group. In the comparison between histological types of mammary carcinomas, mast cells differed significantly between solid tumors of the tubular / papillary types. The cytoplasmic immunodetection of MHC-II was suggested an inefficient antigen presentation. Some of the leukocytes present in the tumor infiltrate, appear to be exerting a pro-tumor effect and allowing the progression of tubular and papillary carcinomas. But in solid carcinomas (may be poorly immunogenic), as they had the lowest proportion of leukocytes present in the tumor site. More studies are necessary to confirm these results, such as the determination of the cytokine profile and the predominant leukocyte subpopulations in the tumor microenvironment.
Mar 2014 DOI 10.14302/issn.2326-0793.jpgr-13-333
C. Ghosh ManikCorresponding author
Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN, 38163.
Carbofuran is a broad spectrum pesticide used in agricultural fields and domestic places throughout the world. It is one of the deadly toxic carbamate pesticide that kills the pest by inhibiting the crucial enzyme of nervous system known as acetyl cholinesterase. In the present study, we report how carbofuran increases the different spectrum of cholesterols, including free cholesterol and esterified cholesterol in the fish hepatocytes. It is observed that induced-cholesterol can inhibit the enzymatic activity such as Ca++-ATPase, which is a critical protein for maintaining the calcium homoeostasis in the cellular microenvironment. Carbofuran integrates into human body through foods and drinks. As trace of carbofuran is identified in our daily food and drinks, we examined the homology of Ca++-ATPase between the fish and human, so our data can illuminate the effects of carbofuran on this crucial enzyme. While studying the homology with the help of bioinformatics, we recognized that there is around 70% homology in the protein sequence of Ca++-ATPase between fish Heteropneustesfossilisand human (Homo sapiens), which appears as sufficient to simulate our fish-model data in human. This study demonstrates that carbofuran affects our day-to-day life by inhibiting Ca++-ATPase through modulation of lipid synthesis, a critical regulatory system that controls overall homeostasis in our body.
Feb 2014 DOI 10.14302/issn.2372-6601.jhor-13-346
E. Clapham ChloeCorresponding author
Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
Targeting cell metabolism is a therapeutic approach which has been used for the treatment of cancers with high levels of proliferation. Inhibition of metabolic processes in cancer cells has shown synergy with current therapeutic options to reduce refractory disease and relapse. In contrast, chronic lymphocytic leukaemia (CLL) is a disease where expansion of the malignant clone results from a combination of enhanced cell survival coupled with low level proliferation. The purpose of this article is to highlight how further research is needed to determine whether targeting cell metabolism may be a viable therapeutic strategy in this disease. We discuss how lymphocyte doubling time (LDT) remains a robust prognostic indicator used in the current clinical management of CLL, and how recognition of CLL as a proliferative disease has led to a greater understanding of the importance of energy-generating processes in its pathobiology. We summarize what is currently known about normal B cell metabolism and consider whether there is evidence of the Warburg effect in CLL cells. Finally, we speculate on how CLL cells may exploit protective mechanisms such as autophagy during times of metabolic stress and how they might influence or be influenced by metabolic characteristics of the microenvironment.