Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl
extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading ...to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2-immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of α- and β-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca
-dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia.
ALK rearranged renal cell carcinoma (ALK-RCC) has recently been included in 2016 WHO classification as a provisional entity. In this study, we describe 12 ALK-RCCs from 8 institutions, with detailed ...clinical, pathological, immunohistochemical (IHC), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) analyses. Patients' age ranged from 25 to 68 years (mean, 46.3 years). Seven patients were females and five were males (M:F = 1:1.4). Tumor size ranged from 17 to 70 mm (mean 31.5, median 25 mm). The pTNM stage included: pT1a (n = 7), pT1b (n = 1), and pT3a (n = 4). Follow-up was available for 9/12 patients (range: 2 to 153 months; mean 37.6 months); 8 patients were alive without disease and one was alive with distant metastases. The tumors demonstrated heterogeneous, ‘difficult to classify' morphology in 10/12 cases, typically showing diverse architectural and cellular morphologies, including papillary, tubular, tubulocystic, solid, sarcomatoid (spindle cell), rhabdoid, signet-ring cell, and intracytoplasmic vacuoles, often set in a mucinous background. Of the remaining two tumors, one showed morphology resembling mucinous tubular and spindle cell renal cell carcinoma (MTSC RCC-like) and one was indistinguishable from metanephric adenoma. One additional case also showed a focal metanephric adenoma-like area, in an otherwise heterogeneous tumor. By IHC, all tumors were diffusely positive for ALK and PAX8. In both cases with metanephric adenoma-like features, WT1 and ALK were coexpressed. ALK rearrangement was identified in 9/11 tumors by FISH. ALK fusion partners were identified by NGS in all 12 cases, including the previously reported: STRN (n = 3), TPM3 (n = 3), EML4 (n = 2), and PLEKHA7 (n = 1), and also three novel fusion partners: CLIP1 (n = 1), KIF5B (n = 1), and KIAA1217 (n = 1). ALK-RCC represents a genetically distinct entity showing a heterogeneous histomorphology, expanded herein to include unreported metanephric adenoma-like and MTSC RCC-like variants. We advocate a routine ALK IHC screening for “unclassifiable RCCs” with heterogeneous features.
Tumori testisa čine 1% neoplazmi u odraslih muškaraca i 5% svih uroloških tumora u svijetu. Čak 95% svih tumora testisa čine tumori zametnih stanica, dok se manji dio tumora razvija iz ...paratestikularnih struktura uključujući rete testisa, epididimis i funikulus spermatikus. Tumori rete testisa dijele se u cistične promjene, neneoplastične proliferacije, benigne i maligne tumore. Sertoliformni cistadenom rete testisa rijedak je benigni tumor. Pojavljuje se u svim dobnim skupinama, a klinički se očituje u obliku bezbolne palpabilne mase u skrotumu. Histološki je najčešće solidne arhitekture, građen od gusto zbijenih tubula obloženih kubičnim do cilindričnim epitelnim stanicama obilnih svijetlih citoplazmi i bazalno smještenih jezgara te mjestimično naglašenih nukleola, nalik Sertolijevim stanicama. Imunohistokemijski tumorske stanice pokazuju pozitivnu reakciju na PAX8, a mogu biti pozitivne i na markere strome te spolnog tračka testisa kao što su inhibin, kalretinin i SOX9. Radikalna ili parcijalna ingvinalna orhidektomija dovode do potpunog izlječenja pa dodatno onkološko liječenje nije potrebno, a recidivi nisu zabilježeni. Ovdje donosimo prikaz bolesnika sa sertoliformnim cistadenomom rete testisa koji je liječen radikalnom ingvinalnom orhidektomijom.
Reactive stromal changes that occur in different human cancers might play a role in local tumor spreading and progression. Studies done on various human cancers have shown activated stromal cell ...phenotypes, modified extracellular matrix (ECM) composition, and increased microvessel density. Furthermore, they exhibit biological markers consistent with stroma at the site of wound repair. In prostate cancer, stroma is composed of fibroblasts, myofibroblasts, endothelial cells and immune cells. Predominant cells in the tumorous stroma are, however, fibroblasts/ myofibroblasts. They are responsible for the synthesis, deposition and remodeling of the ECM. Epithelial tumorous cells, in interaction with stromal cells and with the help of various molecules of ECM, create a microenvironment suitable for cancer cell proliferation, movement, and differentiation. In this review, we discussed the role of different stromal components in prostate cancer as well as their potential prognostic and therapeutic significance.
Chronic inflammation is associated with both benign conditions and cancer. Likewise, inflammatory cells are quite common in benign prostatic hyperplasia (BPH) and prostatic tissue harboring cancer. ...Triggers that activate inflammatory pathways in the prostate remain a subject of argument and are likely to be multifactorial, some of these being bacterial antigens, different chemical irritations, and metabolic disorders. Acute and chronic inflammation in prostate leads to accumulation of immunocompetent cells, mainly T lymphocytes and macrophages, but also neutrophils, eosinophils, and mast cells, depending on the type of offending agent. Inflammatory processes activate hyperproliferative programs resulting in nodules seen in BPH, but are also important in creating suitable microenvironment for cancer growth and progression. Inflammatory cells have mostly been shown to have a protumoral effect such as tumor-associated macrophages, but some cell types such as mast cells have antitumoral effects. This review outlines the recent findings and theories supporting the role of inflammatory responses as drivers of both benign and malignant epithelial processes in the prostate gland.
Background:
Testicular germ cell tumors (TGCTs) are the most common young male malignancy with a steadily rising incidence. Standard clinical practice is radical orchidectomy of suspicious lumps ...followed by histopathological diagnosis and tumor subtyping. This practice can lead to complications and quality of life issues for the patients. Liquid biopsies, especially cell-free DNA (cfDNA), promised to be true surrogates for tissue biopsies, which are considered dangerous to perform in cases of testicular tumors. In this study, we have performed a systematic review on the potential of cfDNA in TGCT patient management, its potential challenges in translation to clinical application and possible approaches in further research.
Materials & Methods:
The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines on EuropePMC and PUBMED electronic databases, with the last update being on October 21, 2021. Due to the high heterogeneity in identified research articles, we have performed an overview of their efficacy.
Results:
Eight original articles have been identified on cfDNA in TGCT patients published from 2004 to 2021, of which six had more than one TGCT patient enrolled and were included in the final analysis. Three studies investigated cfDNA methylation, one has investigated mutations in cfDNA, two have investigated cfDNA amount, and one has investigated cfDNA integrity in TGCT. The sensitivity of cfDNA for TGCT was found to be higher than in serum tumor markers and lower than miR-371a-3p, with comparable specificity. cfDNA methylation analysis has managed to accurately detect teratoma in TGCT patients.
Conclusion:
Potential challenges in cfDNA application to TGCT patient management were identified. The challenges relating to the biology of TGCT with its low mutational burden and low cfDNA amounts in blood plasma make next-generation sequencing (NGS) methods especially challenging. We have also proposed possible approaches to help find clinical application, including a focus on cfDNA methylation analysis, and potentially solving the challenge of teratoma detection.
RASSF1A represents one of the eight isoforms of the RASSF1 gene. RASSF1A is a tumor suppressor gene whose inactivation influences tumor initiation and development. In cancer, RASSF1A is frequently ...inactivated by mutations, loss of heterozygosity and, most commonly, by promoter hypermethylation. As epigenetic inactivation of RASSF1A was detected in various cancer types, it was extensively investigated and nowadays, the research on RASSF1A promoter methylation proceeds in the light of an epigenetic tumor biomarker. Analyses of DNA methylation of genes involved in carcinogenesis such as RASSF1A are currently done mostly on genomic DNA (gDNA). Simultaneously, cell-free DNA (cfDNA) from liquid biopsies has lately been developed as an early cancer diagnostic tool. This review discusses the evidence on aberrantly methylated RASSF1A in gDNA and cfDNA from different cancer types and its utility for early cancer diagnosis, prognosis, and surveillance. Furthermore, methylation frequencies of RASSF1A in gDNA and cfDNA were compared in various cancer types. The weaknesses and strengths of the investigations mentioned above are discussed. In conclusion, although the importance of RASSSF1A methylation in relation to cancer was established, and it became included in several diagnostic panels, the evidence of its diagnostic utility is still experimental and not yet implemented in standard clinical health care.
Breast cancer, the most frequent disease amongst women worldwide, accounts for the highest cancer-related mortality rate. Triple-negative breast cancer (TNBC) subtype encompasses ~15% of all breast ...cancers and lack estrogen, progesterone, and HER2 receptors. Although risk factors for breast cancer are well-known, factors underpinning breast cancer onset and progression remain unknown. Recent studies suggest the plausible role of oncoviruses including human papillomaviruses (HPVs), Epstein-Barr virus (EBV), and mouse mammary tumor virus (MMTV) in breast cancer pathogenesis. However, the role of these oncoviruses in TNBC is still unclear. In the current study, we explored the status of high-risk HPVs, EBV, and MMTV in a well-defined TNBC cohort from Croatia in comparison to 16 normal/non TNBC samples (controls) using polymerase chain reaction assay. We found high-risk HPVs and EBV present in 37/70 (53%) and 25/70 (36%) of the cases, respectively. The most common HPV types are 52, 45, 31, 58 and 68. We found 16% of the samples positive for co-presence of high-risk HPVs and EBV. Moreover, our data revealed that 5/70 (7%) samples are positive for MMTV. In addition, only 2/70 (3%) samples had co-presence of HPVs, EBV, and MMTV without any significant association with the clinicopathological variables. While, 6/16 (37.5%) controls were positive for HPV (p = .4), EBV was absent in all controls (0/16, 0%) (p = .01). In addition, we did not find the co-presence of the oncoviruses in the controls (p > .05). Nevertheless, further investigations are essential to understand the underlying mechanisms of multiple-oncogenic viruses' interaction in breast carcinogenesis, especially TNBC.
Prostate Cancer—Focus on Cholesterol Škara, Lucija; Huđek Turković, Ana; Pezelj, Ivan ...
Cancers,
09/2021, Volume:
13, Issue:
18
Journal Article
Peer reviewed
Open access
Prostate cancer (PC) is the most common malignancy in men. Common characteristic involved in PC pathogenesis are disturbed lipid metabolism and abnormal cholesterol accumulation. Cholesterol can be ...further utilized for membrane or hormone synthesis while cholesterol biosynthesis intermediates are important for oncogene membrane anchoring, nucleotide synthesis and mitochondrial electron transport. Since cholesterol and its biosynthesis intermediates influence numerous cellular processes, in this review we have described cholesterol homeostasis in a normal cell. Additionally, we have illustrated how commonly deregulated signaling pathways in PC (PI3K/AKT/MTOR, MAPK, AR and p53) are linked with cholesterol homeostasis regulation.
The choice of therapy for muscle-invasive bladder cancer (MIBC) could be influenced by the tumor's molecular subtype. Currently, well-defined consensus subtypes are based on tumor microarray mRNA ...data. Clearly defined and easy-to-use surrogate molecular subtypes, based on immunohistochemistry (IHC) performed on whole slides, are needed to make subtyping cost-effective and useful in routine work and future research. To aid in the development of a simple immunohistochemical classifier, a retrospective single-center series of 92 cases of localized bladder cancer was identified. Routine IHC for GATA3, cytokeratins 5 and 6 (CK5/6), and p16 was performed on whole tissue blocks containing muscle-invasive disease. Electronic medical records were retrieved and searched for clinical variables, treatment, and survival data. The mean age was 69.6 years, and 73% were males. Conservative treatment was used in 55% of cases, while cystectomy with chemotherapy was used in 45%. GATA3 and CK5/6 expression divided cases into broad luminal and basal subtypes, respectively, while p16 expression was used to subclassify luminal cases into luminal papillary and luminal unstable types according to the consensus molecular classification. When subtyped in this way, GATA3 and CK5/6 negative cases showed worse overall survival. Molecular subtyping of MIBC on whole slides containing muscle-invasive tumor using only three commonly used, consensus-based antibodies, is a feasible and cost-effective method for detecting subtypes of invasive bladder cancer. Future work combining morphological analysis and IHC is needed to fully translate the consensus molecular classification into a comprehensive, cost-effective subtyping strategy.
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