Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancer characterized by genomic complexity and therapeutic options limited to only standard chemotherapy. Although it has been suggested that stratifying TNBC patients by pathway-specific molecular alterations may predict benefit from specific therapeutic agents, application in routine clinical practice has not yet been established. There is a growing body of the literature supporting that epigenetic modifications comprised by DNA methylation, chromatin remodeling and non-coding RNAs play a fundamental role in TNBC pathogenesis. Extracellular matrix (ECM) is a highly dynamic 3D network of macromolecules with structural and cellular regulatory roles. Alterations in the expression of ECM components result in uncontrolled matrix remodeling, thus affecting its ability to regulate vital functions of cancer cells, including proliferation, migration, adhesion, invasion and epithelial-to-mesenchymal transition (EMT). Recent molecular data highlight the major role of tumor microenvironment and ECM alterations in TNBC and approaches for targeting tumor microenvironment have recently been recognized as potential therapeutic strategies. Notably, many of the ECM/EMT modifications in cancer are largely driven by epigenetic events, highlighting the pleiotropic effects of the epigenetic network in TNBC. This article presents and critically discusses the current knowledge on the epigenetic alterations correlated with TNBC pathogenesis, with emphasis on those associated with ECM/EMT modifications, their prognostic and predictive value and their use as therapeutic targets.

The BM, the major hematopoietic organ in humans, consists of a pleiomorphic environment of cellular, extracellular, and bioactive compounds with continuous and complex interactions between them, leading to the formation of mature blood cells found in the peripheral circulation. Systemic and local inflammation in the BM elicit stress hematopoiesis and drive hematopoietic stem cells (HSCs) out of their quiescent state, as part of a protective pathophysiologic process. However, sustained chronic inflammation impairs HSC function, favors mutagenesis, and predisposes the development of hematologic malignancies, such as myelodysplastic syndromes (MDS). Apart from intrinsic cellular mechanisms, various extrinsic factors of the BM immune microenvironment (IME) emerge as potential determinants of disease initiation and evolution. In MDS, the IME is reprogrammed, initially to prevent the development, but ultimately to support and provide a survival advantage to the dysplastic clone. Specific cellular elements, such as myeloid-derived suppressor cells (MDSCs) are recruited to support and enhance clonal expansion. The immune-mediated inhibition of normal hematopoiesis contributes to peripheral cytopenias of MDS patients, while immunosuppression in late-stage MDS enables immune evasion and disease progression towards acute myeloid leukemia (AML). In this review, we aim to elucidate the role of the mediators of immune response in the initial pathogenesis of MDS and the evolution of the disease.

Brown tumors represent a rare clinical manifestation reported in approximately 3% of patients with primary hyperparathyroidism and correspond to radiologically osteolytic lesions with well-defined borders in different parts of the skeleton. We report the case of a 53-year-old white man who presented to our hospital with osteolytic lesions of his distal ulna and radius, causing pain and swelling of 2-month duration. A subsequent biopsy revealed histological features consistent with giant cell tumor and a complete resection of his distal ulna was followed, along with curettage and cementoplasty of the distal radial metaphysis. Two weeks later, he was re-admitted with diffuse musculoskeletal soreness, anorexia, constipation, nausea, and localized abdominal pain and multiple osteolytic lesions on plain radiographs. A histopathological examination of the ulna and radius specimens showed similar findings and, given the multifocality, brown tumors related to primary or secondary hyperparathyroidism was included in the differential diagnosis. A laboratory examination showed high total serum calcium (14.5 mg/dl) and low serum phosphorus and 25-hydroxyvitamin D levels. Primary hyperparathyroidism was suspected and confirmed by the elevated parathyroid hormone levels of 1453 pg/mL. At radiological work-up, using computed tomography, ultrasonography, and parathyroid subtraction technetium-99m sestamibi scintigraphy, a 4.5 × 2.5 × 3.2 cm mass emanating from the right lobe of his thyroid gland was detected, displaying extensive uptake in the right lower parathyroid gland. After appropriate medical support including hyperhydration and high doses of diuretics and diphosphonates, his laboratory profile normalized and he underwent total thyroidectomy with removal of the parathyroid glands. Our patient is now recovering 12 months after surgery, with normal values of serum parathyroid hormone and calcium levels. The lytic bone lesions have almost disappeared and no other additional orthopedic intervention was necessary. The present case report emphasizes the need of inclusion of brown tumors in the differential diagnosis of multifocal osteolytic bone lesions, in order to avoid harmful surgical interventions. Laboratory testing of serum phosphate, calcium levels, and parathyroid hormone levels should always be included in the routine survey of patients with multifocal osteolytic lesions.

Breast carcinoma is currently considered as a group of diseases, differing not only in histopathologic phenotype, as indicated by histologic type and grade, but also in their protein, genetic and epigenetic molecular profile. The standard of care indicates that the core information for patient management includes data on Estrogen Receptor (ER), Progesterone Receptor (PgR) and Human Epidermal Growth Factor Receptor 2 (HER2), while there is an emerging role for the proliferation marker Ki67. These indices can be provided even in low resource settings and are indispensable for prognostication and therapeutic patient management. With the progress in molecular and translational research, there is a growing body of information on the molecular subtypes of breast carcinoma and their significance, and multigene signature assays are used to dictate prognosis and guide therapeutics in high resource settings. In addition, several cellular pathways involved in tumor growth and spread are dissected and targeted in clinical trials. Among these are the p53, RB, PI3K/Akt/mTOR and Ras/MAPK pathways, alterations associated with genetic instability and epigenetic alterations including histone methylation and acetylation, DNA methylation and microRNAs expression. The tumor immune microenvironment, including the tumor infiltrating lymphocytes (TILs) is attracting significant research interest. This review summarizes the mechanisms of function of the above factors in breast tumorigenesis with emphasis on their prognostic and predictive value and their use as therapeutic targets.

Background: Systemic inflammation in chronic kidney disease (CKD) is associated (as a cause or effect) with intestinal barrier dysfunction and increased gut permeability, with mechanisms not yet fully understood. This study investigated different parameters of the intestinal barrier in CKD patients, especially tight junction (TJ) proteins and their possible association with systemic endotoxemia and inflammation. Methods: Thirty-three patients with stage I–IV CKD (n = 17) or end-stage kidney disease (ESKD) (n = 16) and 11 healthy controls underwent duodenal biopsy. Samples were examined histologically, the presence of CD3+ T-lymphocytes and the expression of occludin and claudin-1 in the intestinal epithelium was evaluated by means of immunohistochemistry, circulating endotoxin concentrations were determined by means of ELISA and the concentrations of the cytokines IL-1β, IL-6, IL-8, IL-10 and TNF-α in serum were measured using flow cytometry. Results: Patients with stage I–IV CKD or ESKD had significantly higher serum endotoxin, IL-6, IL-8 and IL-10 levels compared to controls. Intestinal occludin and claudin-1 were significantly decreased, and their expression was inversely correlated with systemic endotoxemia. Regarding occludin, a specific expression pattern was observed, with a gradually increasing loss of its expression from the crypt to the tip of the villi. Conclusion: The expression of occludin and claudin-1 in enterocytes is significantly reduced in patients with CKD, contributing to systemic endotoxemia and inflammatory responses in these patients.

Aims: To look for correlations between expression of cell cycle regulatory proteins p34^cdc2, p21^WAF1, and p53 in node negative invasive ductal breast carcinoma, or between these proteins and clinicopathological parameters, and to assess their prognostic value. Methods: Immunohistochemistry using formalin fixed, paraffin wax embedded sections from 94 breast carcinomas. Adjacent benign epithelial breast tissue was available in 74 cases. Median follow up was 72 months. Results: Nuclear and cytoplasmic p34^cdc2 expression was seen in 80 and 62 tumours, respectively; nuclear expression was seen in adjacent benign epithelium in 12 cases. p21^WAF1 and p53 were positive in 48 and 21 tumours, respectively. High expression of p34^cdc2 in neoplastic nuclei was associated with higher histological grade and p53 expression, but not with tumour size, steroid receptor status, patient age, menopausal status, recurrence, metastasis, disease free survival (DFS), or overall survival (OS). p34^cdc2 in tumour cytoplasm was associated with p34^cdc2 nuclear positivity, high tumour grade, and DFS in univariate but not multivariate analysis. In contrast, p34^cdc2 expression in benign tissue independently predicted DFS and OS in univariate and multivariate analysis. Expression of p53 was associated with high tumour grade and negative steroid receptors, but not with recurrence, metastasis, DFS, or OS. p21^WAF1 expression was not associated with the examined parameters. Conclusions: p34^cdc2, p21^WAF1, and p53 expression does not predict outcome in node negative breast carcinoma, although p34^cdc2 expression in benign tissue is related to prognosis. The association between p34^cdc2 and p53 implicates p53 in G2–M cell cycle checkpoint control, possibly via mediators unrelated to p21^WAF1.