Exploring the Role of the Gut Microbiota in Modulating Colorectal Cancer Immunity.

The gut microbiota plays an essential role in maintaining immune homeostasis and influencing the immune landscape within the tumor microenvironment. This review aims to elucidate the interactions between gut microbiota and tumor immune dynamics, with a focus on colorectal cancer (CRC). The review spans foundational concepts of immuno-microbial interplay, factors influencing microbiome composition, and evidence linking gut microbiota to cancer immunotherapy outcomes. Gut microbiota modulates anti-cancer immunity through several mechanisms, including enhancement of immune surveillance and modulation of inflammatory responses. Specific microbial species and their metabolic byproducts can significantly influence the efficacy of cancer immunotherapies. Furthermore, microbial diversity within the gut microbiota correlates with clinical outcomes in CRC, suggesting potential as a valuable biomarker for predicting response to immunotherapy. Conclusions: Understanding the relationship between gut microbiota and tumor immune responses offers potential for novel therapeutic strategies and biomarker development. The gut microbiota not only influences the natural history and treatment response of CRC but also serves as a critical modulator of immune homeostasis and anti-cancer activity. Further exploration into the microbiome's role could enhance the effectiveness of existing treatments and guide the development of new therapeutic modalities.

Doxorubicin-related cardiotoxicity: review of fundamental pathways of cardiovascular system injury.

Over the years, advancements in the field of oncology have made remarkable strides in enhancing the efficacy of medical care for patients with cancer. These modernizations have resulted in prolonged survival and improved the quality of life for these patients. However, this progress has also been accompanied by escalation in mortality rates associated with anthracycline chemotherapy. Anthracyclines, which are known for their potent antitumor properties, are notorious for their substantial cardiotoxic potential. Remarkably, even after 6 decades of research, a conclusive solution to protect the cardiovascular system against doxorubicin-induced damage has not yet been established. A comprehensive understanding of the pathophysiological processes driving cardiotoxicity combined with targeted research is crucial for developing innovative cardioprotective strategies. This review seeks to explain the mechanisms responsible for structural and functional alterations in doxorubicin-induced cardiomyopathy.

Circulating IgG Fragments for Gastric Cancer and Esophageal Cancer.

Blood serum of patients with gastric (n = 68) and esophageal (n = 43) cancer was assessed for proteolytic fragments of IgG. Serum samples of 20 healthy donors were used as a control. We analyzed indicators of hemostasis (prothrombin time, fibrinogen, plasminogen activity, a2-antiplasmin activity, protein C activity) in blood plasma and the level of total IgG in the blood serum. The median IgG-LysK of healthy donors was lower than in esophageal cancer and in patients with gastric cancer. ROC-analysis showed high sensitivity (91%) and specificity (85%) in the group with esophageal cancer but 68% and 85%, respectively, in patients with gastric cancer. Analysis of false negatives IgG-LysK in cancer patients showed that most patients had an advanced stage of cancer accompanied by metastases. Total IgG in the plasma of patients with false-negative IgG-LysK values was 30% lower than in samples with positive values, while the level of a2-antiplasmin was increased and the prothrombin time was shorter. These changes in blood homeostasis may be the reason for an increase in the proportion of false-negative values of the IgG-LysK coefficient. Circulatory IgG-LysK levels increase in the early stages of such cancers as gastric and esophageal cancers. Thus, when used in a panel with other more specific markers for these pathologies, this indicator can significantly increase the early detection of cancer.

Methotrexate & rheumatoid arthritis associated atherosclerosis: A narrative review of multidisciplinary approach for risk modification by the international board of experts.

Rheumatoid arthritis (RA) is an idiopathic, autoimmune connective tissue disorder that primarily affects the synovial joints, causing symmetric, erosive-deforming polyarthritis. It is also associated with extra-articular manifestations, particularly cardiovascular (CV) diseases (CVD). CV risk modification in RA remains unsolved despite recent advances in the management of RA. RA is an independent risk factor for atherosclerosis. RA and atherosclerosis share similar pathophysiological features (such as the pro-inflammatory cascade activation including interleukin-6) and risk factors (such as microflora dysbacteriosis and smoking). Patients with RA experience an exacerbation of atherogenesis, with atheromas destabilization, endothelial dysfunction, vasculitis, and hypercytokinemia. Consequently, the inflammatory response associated with RA is the basis for CVD development. The treat-to-target strategy not only improved RA control but also had a favorable effect on the morpho-functional state of the CV system in patients living with RA. Thus, disease-modifying antirheumatic drugs (DMARDs) - in particular methotrexate - may have a beneficial effect on the prevention of CV events in RA. It must be mentioned that RA is a serious multi-system disease, not only because of a window period during which the course of RA can be reversed, but also due to early damage to the heart and blood vessels. For this reason, a thorough cardiological assessment must be performed for all patients with RA, regardless of sex, age, disease stage, and disease activity score.

Diabetic Cardiomyopathy: 2023 Update by the International Multidisciplinary Board of Experts.

Diabetes mellitus (DM) is considered by many the pandemic of the 21st century and is associated with multiple organ damages. Among these, cardiovascular complications are responsible for an incredible burden of mortality and morbidity in Western Countries. The study of the pathological mechanisms responsible for the cardiovascular complications in DM patients is key for the development of new therapeutic strategies. The metabolic disorders caused by hyperglycemia, insulin resistance, and dyslipidemia, results in a cascade of pathomorphological changes favoring the atherosclerotic process and leading to myocardial remodeling. Parallel to this, oxidative stress, calcium overload, mitochondrial dysfunction, activation of protein kinase C signaling pathways, myocardial lipomatosis, and low-grade inflammation of the myocardium - are the main pathways responsible for the diabetic cardiomyopathy development. This review aims to appraise and discuss the pathogenetic mechanisms behind the diabetic cardiomyopathy development.

Pathomorphological Features of the Novel Coronavirus Disease in Patients with Systemic Amyloidosis.

Amyloidosis is one of the rare systemic illnesses characterized by the deposition of amyloid fibrils in various organs and tissues. There is a common point between COVID-19 and systemic amyloidosis regarding the multiorgan involvement in the pathological process which leads to a heightened risk for severe morbidity and mortality in amyloidosis patients who contracted COVID-19. We performed a pathomorphological analysis of the autopsy records of 22 patients who had COVID-19 and pre-existing systemic amyloidosis. The premortem diagnosis of systemic amyloidosis was established in 55% of patients, and in other 45% of cases, amyloidosis was found at autopsy. Based on the results of immunohistochemical amyloid typing, amyloid A (AA) amyloidosis was detected in 23%, amyloid light chain (AL) lambda in 32%, AL kappa-in 9%, and transthyretin (ATTR) amyloidosis-in 36% of observations. Immunohistochemical staining with an antibody against SARS-CoV-2 Spike (S) protein revealed positive immune reactions in type II alveolocytes in 59% of deceased persons. The analysis of autopsy findings indicates that patients with systemic amyloidosis are more likely to experience an aggressive clinical course of COVID-19 which leads to a multiorgan failure and a higher risk of fatal outcome.

Cellular and Molecular Mechanisms of the Tumor Stroma in Colorectal Cancer: Insights into Disease Progression and Therapeutic Targets.

Colorectal cancer (CRC) is a major health burden worldwide and is the third most common type of cancer. The early detection and diagnosis of CRC is critical to improve patient outcomes. This review explores the intricate interplay between the tumor microenvironment, stromal interactions, and the progression and metastasis of colorectal cancer. The review begins by assessing the gut microbiome's influence on CRC development, emphasizing its association with gut-associated lymphoid tissue (GALT). The role of the Wnt signaling pathway in CRC tumor stroma is scrutinized, elucidating its impact on disease progression. Tumor budding, its effect on tumor stroma, and the implications for patient prognosis are investigated. The review also identifies conserved oncogenic signatures (COS) within CRC stroma and explores their potential as therapeutic targets. Lastly, the seed and soil hypothesis is employed to contextualize metastasis, accentuating the significance of both tumor cells and the surrounding stroma in metastatic propensity. This review highlights the intricate interdependence between CRC cells and their microenvironment, providing valuable insights into prospective therapeutic approaches targeting tumor-stroma interactions.

Long Non-Coding RNAs in Colorectal Cancer: Navigating the Intersections of Immunity, Intercellular Communication, and Therapeutic Potential.

This comprehensive review elucidates the intricate roles of long non-coding RNAs (lncRNAs) within the colorectal cancer (CRC) microenvironment, intersecting the domains of immunity, intercellular communication, and therapeutic potential. lncRNAs, which are significantly involved in the pathogenesis of CRC, immune evasion, and the treatment response to CRC, have crucial implications in inflammation and serve as promising candidates for novel therapeutic strategies and biomarkers. This review scrutinizes the interaction of lncRNAs with the Consensus Molecular Subtypes (CMSs) of CRC, their complex interplay with the tumor stroma affecting immunity and inflammation, and their conveyance via extracellular vesicles, particularly exosomes. Furthermore, we delve into the intricate relationship between lncRNAs and other non-coding RNAs, including microRNAs and circular RNAs, in mediating cell-to-cell communication within the CRC microenvironment. Lastly, we propose potential strategies to manipulate lncRNAs to enhance anti-tumor immunity, thereby underlining the significance of lncRNAs in devising innovative therapeutic interventions in CRC.

Signaling Pathways in the Pathogenesis of Barrett's Esophagus and Esophageal Adenocarcinoma.

Barrett's esophagus (BE) is a premalignant lesion that can develop into esophageal adenocarcinoma (EAC). The development of Barrett's esophagus is caused by biliary reflux, which causes extensive mutagenesis in the stem cells of the epithelium in the distal esophagus and gastro-esophageal junction. Other possible cellular origins of BE include the stem cells of the mucosal esophageal glands and their ducts, the stem cells of the stomach, residual embryonic cells and circulating bone marrow stem cells. The classical concept of healing a caustic lesion has been replaced by the concept of a cytokine storm, which forms an inflammatory microenvironment eliciting a phenotypic shift toward intestinal metaplasia of the distal esophagus. This review describes the roles of the NOTCH, hedgehog, NF-κB and IL6/STAT3 molecular pathways in the pathogenesis of BE and EAC.

Novel Models of Crohn's Disease Pathogenesis Associated with the Occurrence of Mitochondrial Dysfunction in Intestinal Cells.

Crohn's disease remains one of the challenging problems of modern medicine, and the development of new and effective and safer treatments against it is a dynamic field of research. To make such developments possible, it is important to understand the pathologic processes underlying the onset and progression of Crohn's disease at the molecular and cellular levels. During the recent years, the involvement of mitochondrial dysfunction and associated chronic inflammation in these processes became evident. In this review, we discuss the published works on pathogenetic models of Crohn's disease. These models make studying the role of mitochondrial dysfunction in the disease pathogenesis possible and advances the development of novel therapies.

Mitochondrial mutations and mitoepigenetics: Focus on regulation of oxidative stress-induced responses in breast cancers.

Epigenetic regulation of mitochondrial DNA (mtDNA) is an emerging and fast-developing field of research. Compared to regulation of nucler DNA, mechanisms of mtDNA epigenetic regulation (mitoepigenetics) remain less investigated. However, mitochondrial signaling directs various vital intracellular processes including aerobic respiration, apoptosis, cell proliferation and survival, nucleic acid synthesis, and oxidative stress. The later process and associated mismanagement of reactive oxygen species (ROS) cascade were associated with cancer progression. It has been demonstrated that cancer cells contain ROS/oxidative stress-mediated defects in mtDNA repair system and mitochondrial nucleoid protection. Furthermore, mtDNA is vulnerable to damage caused by somatic mutations, resulting in the dysfunction of the mitochondrial respiratory chain and energy production, which fosters further generation of ROS and promotes oncogenicity. Mitochondrial proteins are encoded by the collective mitochondrial genome that comprises both nuclear and mitochondrial genomes coupled by crosstalk. Recent reports determined the defects in the collective mitochondrial genome that are conducive to breast cancer initiation and progression. Mutational damage to mtDNA, as well as its overproliferation and deletions, were reported to alter the nuclear epigenetic landscape. Unbalanced mitoepigenetics and adverse regulation of oxidative phosphorylation (OXPHOS) can efficiently facilitate cancer cell survival. Accordingly, several mitochondria-targeting therapeutic agents (biguanides, OXPHOS inhibitors, vitamin-E analogues, and antibiotic bedaquiline) were suggested for future clinical trials in breast cancer patients. However, crosstalk mechanisms between altered mitoepigenetics and cancer-associated mtDNA mutations remain largely unclear. Hence, mtDNA mutations and epigenetic modifications could be considered as potential molecular markers for early diagnosis and targeted therapy of breast cancer. This review discusses the role of mitoepigenetic regulation in cancer cells and potential employment of mtDNA modifications as novel anti-cancer targets.

Barrett's esophagus: The pathomorphological and molecular genetic keystones of neoplastic progression.

Barrett's esophagus is a widespread chronically progressing disease of heterogeneous nature. A life threatening complication of this condition is neoplastic transformation, which is often overlooked due to lack of standardized approaches in diagnosis, preventative measures and treatment. In this essay, we aim to stratify existing data to show specific associations between neoplastic transformation and the underlying processes which predate cancerous transition. We discuss pathomorphological, genetic, epigenetic, molecular and immunohistochemical methods related to neoplasia detection on the basis of Barrett's esophagus. Our review sheds light on pathways of such neoplastic progression in the distal esophagus, providing valuable insight into progression assessment, preventative targets and treatment modalities. Our results suggest that molecular, genetic and epigenetic alterations in the esophagus arise earlier than cancerous transformation, meaning the discussed targets can help form preventative strategies in at-risk patient groups.

Efficacy of da Vinci robot-assisted lymph node surgery than conventional axillary lymph node dissection in breast cancer - A comparative study.

BACKGROUND: da Vinci robot-assisted axillary lymph node dissection (dVALND) can be a minimally invasive technique to minimize post-operative complications. OBJECTIVE: To explore the clinical efficacy of dVALND in breast cancer (BC) patients for mitigating the postoperative complications than conventional ALND. METHODS: Total 60 female patients with BC were admitted to our hospitals since September 2018, and these patients segregated into two groups of 30 patients each. Modified radical mastectomy for BC was performed to the patients in both groups. In Group 1 (control group), ALND was performed using conventional mode of axillary lymph node surgery. In Group 2 (Test group), the dVALND was performed using da Vinci robot-assisted surgery. Wound healing, aesthetic effect and patient's satisfaction were evaluated after conventional method and dVALND. RESULTS: Postoperative complications viz., wound infection (1/30 (3.33%), p < 0.05), fat necrosis (3/30 (10%), p < 0.05) and lymphedema of upper limbs (2/30 (6.67%), p < 0.05) were observed in dVALND than conventional surgery. Local recurrence or metastasis was minimized and overall aesthetic effect not observed during follow-up. CONCLUSION: dVALND improved the overall patient's quality of life by mitigating postoperative complications than ALND.

Therapeutic Effects of hiPSC-Derived Glial and Neuronal Progenitor Cells-Conditioned Medium in Experimental Ischemic Stroke in Rats.

Transplantation of various types of stem cells as a possible therapy for stroke has been tested for years, and the results are promising. Recent investigations have shown that the administration of the conditioned media obtained after stem cell cultivation can also be effective in the therapy of the central nervous system pathology (hypothesis of their paracrine action). The aim of this study was to evaluate the therapeutic effects of the conditioned medium of hiPSC-derived glial and neuronal progenitor cells in the rat middle cerebral artery occlusion model of the ischemic stroke. Secretory activity of the cultured neuronal and glial progenitor cells was evaluated by proteomic and immunosorbent-based approaches. Therapeutic effects were assessed by overall survival, neurologic deficit and infarct volume dynamics, as well as by the end-point values of the apoptosis- and inflammation-related gene expression levels, the extent of microglia/macrophage infiltration and the numbers of formed blood vessels in the affected area of the brain. As a result, 31% of the protein species discovered in glial progenitor cells-conditioned medium and 45% in neuronal progenitor cells-conditioned medium were cell type specific. The glial progenitor cell-conditioned media showed a higher content of neurotrophins (BDNF, GDNF, CNTF and NGF). We showed that intra-arterial administration of glial progenitor cells-conditioned medium promoted a faster decrease in neurological deficit compared to the control group, reduced microglia/macrophage infiltration, reduced expression of pro-apoptotic gene Bax and pro-inflammatory cytokine gene Tnf, increased expression of anti-inflammatory cytokine genes (Il4, Il10, Il13) and promoted the formation of blood vessels within the damaged area. None of these effects were exerted by the neuronal progenitor cell-conditioned media. The results indicate pronounced cytoprotective, anti-inflammatory and angiogenic properties of soluble factors secreted by glial progenitor cells.

Health Science Community Will Miss This Bright and Uniting Star: In Memory of Professor Gjumrakch Aliev, M.D, Ph.D.

It is with deep sadness that we offer our memorial on the unexpected demise of our dear colleague, Professor Gjumrakch Aliev [...].

Expression of Estrogen Receptor α by Decidual Macrophages in Preeclampsia.

Preeclampsia is a gestation-associated hypertensive syndrome that threatens the life and health of the mother and the child. The condition is presumably caused by systemic failure with a strong involvement of innate immunity. In particular, it has been associated with flexible phenotypes of macrophages, which depend on the molecules circulating in the blood and tissue fluid, such as cytokines and hormones. This study aimed at a comparative evaluation of pro-inflammatory (TNFα) and anti-inflammatory (CD206, MMP9, HGF) markers, as well as the levels of estrogen receptor α, expressed by decidual macrophages in normal pregnancy and in patients with early- and late-onset preeclampsia. The tissue samples of decidua basalis were examined by immunohistochemistry and Western blotting. Isolation of decidual macrophages and their characterization were performed using cultural methods, flow cytometry and real-time PCR. Over 50% of the isolated decidual macrophages were positive for the pan-macrophage marker CD68. In the early-onset preeclampsia group, the levels of estrogen receptor α in decidua were significantly decreased. Furthermore, significantly decreased levels of HGF and CD206 were observed in both preeclampsia groups compared with the control group. The observed downregulation of estrogen receptor α, HGF and CD206 may contribute to the balance of pro- and anti-inflammatory macrophages and thereby to pathogenesis of preeclampsia.

Bladder Cancer: Update on Risk Factors, Molecular and Ultrastructural Patterns.

OBJECTIVE: The molecular mechanisms of bladder cancer development and progression are not clear. Bladder cancer is an important focus for epidemiological studies and understanding clinical implications. GOAL: The primary aim of prevention is achieved by limiting exposure to non-genetic risk factors, such as smoking, diet, arsenic in drinking water, or aromatic amines at work or elsewhere. Current therapies for bladder cancer are affected by tumor morphology and associated acquired genetic mutations. METHODS: A literature search was performed using PubMed, Scopus, ResearchGate, Google, MEDLINE, and ScienceDirect databases to find studies of bladder cancer published between 1984 and early 2020. The focus was articles that address epidemiological risk factors and underlying pathophysiological mechanisms. Articles were selected that enabled our review of these factors as well as molecular and structural patterns. RESULTS: There are multiple views of bladder cancer. The literature offers several novel insights regarding the development and progression of bladder cancer and possible biomarkers that may be useful in clinical and diagnostic practice. CONCLUSION: There are several molecular pathways associated with bladder cancer that are frequently updated. In addition, genetic subtypes of bladder tumors are not distinguished clearly which requires future more detailed analysis.

Histomorphological and Functional Features of the Eutopic Endometrium in Patients with Ovarian Endometriosis After Surgery-a Clinical Study.

Endometriosis causes infertility and the alterations in endometrial receptivity. Pinopodia in eutopic endometrial epithelium may have significant implications in the endometriosis-associated infertility. The aim of this study is to ascertain whether the surgical interventions to remove endometrioid ovarian cysts (EOCs) can improve endometrial receptivity. The study included 172 patients of reproductive age with EOC, who underwent laparoscopic cystectomy. Aspiration endometrial biopsy was performed at 6 and 12 months after the surgery during the proliferation and secretion phases. Histopathology analysis included H&E staining and IHC. Morphometric studies were performed on endometrial biopsies collected during the proliferation phase of 28 patients, and the secretion phase of 12 patients. The expression of IHC markers for estrogen receptors (ER) and progesterone receptors (PR) and the percentage of cells containing pinopodia were determined. A significant increase in the ER and PR expression was observed in the epithelium during the "middle stage, proliferation phase" and in the stroma and glands during "middle stage, secretion phase". A delay in endometrial secretory transformation and statistically significant decrease in the number of pinopodia was observed on the apical surface of the cells. These structural and functional alterations were observed both at 6 and 12 months after cystectomy. The endometriosis-associated infertility after surgical intervention of EOC could be due to the extensive expression of ER and PR during the proliferation and secretion phases, as well as the delayed secretory transformation and impaired formation of pinopodia in the eutopic endometrium in the patients at 6 and 12 months after surgery.