Pathological evaluation of bladder cancer typically reveals great tumour heterogeneity, and therefore the common observation of urothelial carcinoma exhibiting a wide variety of histopathological patterns is not surprising. Some of these patterns are so distinctive that they have been recognised as specific variants of urothelial carcinoma. Classifications have recently been revised in the 2016 World Health Organisation (WHO) classification of tumours of the urinary system and male genital organs. The current WHO classifications clarify terminological issues and provide better definition criteria, but also incorporate some new entities. Many of these variants have important prognostic or therapeutic implications worth knowing by the urologist and oncologist, but also represent diagnostic challenges in daily pathology practice. This review will discuss the features of variants of urothelial carcinoma in the context of our current clinical practice. Histological variations and new entities of bladder cancer not included in the current WHO classification of urothelial tumours will be briefly discussed.

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The glial cells astrocytes have long been recognized as important neuron-supporting elements in brain development, homeostasis, and metabolism. After the discovery that the reciprocal communication between astrocytes and neurons is a fundamental mechanism in the modulation of neuronal synaptic communication, over the last two decades astrocytes became a hot topic in neuroscience research. Crucial to their functional interactions with neurons are the cytosolic Ca2+ elevations that mediate gliotransmission. Large attention has been posed to the so-called Ca2+microdomains, dynamic Ca2+ changes spatially restricted to fine astrocytic processes including perisynaptic astrocytic processes (PAPs). With presynaptic terminals and postsynaptic neuronal membranes, PAPs compose the tripartite synapse. The distinct spatial-temporal features and functional roles of astrocyte microdomain Ca2+ activity remain poorly defined. However, thanks to the development of genetically encoded Ca2+ indicators (GECIs), advanced microscopy techniques, and innovative analytical approaches, Ca2+ transients in astrocyte microdomains were recently studied in unprecedented detail. These events have been observed to occur much more frequently (∼50–100-fold) and dynamically than somatic Ca2+ elevations with mechanisms that likely involve both IP3-dependent and -independent pathways. Further progress aimed to clarify the complex, dynamic machinery responsible for astrocytic Ca2+ activity at microdomains is a crucial step in our understanding of the astrocyte role in brain function and may also reveal astrocytes as novel therapeutic targets for different brain diseases. Here, we review the most recent studies that improve our mechanistic understanding of the essential features of astrocyte Ca2+ microdomains.

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The recent approval of several agents have revolutionized the scenario of therapeutic management of metastatic renal cell carcinoma (RCC) allowing us to reach important clinical end points with extended patients' survival. Actually, every new drug approved has represented an important step forward to the improvement of patient's survival. On the other hand, we now understand that RCC includes a large group of tumor entities, each of them with different genetic and mutational alterations, but also showing different clinical behavior; a reason behind the needs of subtype specific personalized approach to therapy of RCC. Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with locally advanced or metastatic RCC. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors (ICI), gathering prognostic and predictive information about FDA-indicated tumors seems to be prudent. Robust and reliable biomarkers are crucial for patient's selection of treatments with immunomodulatory drugs. PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC. Each FDA approved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers in daily practice. IHC staining appears in membranous fashion. The atezolizumab approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in RCC. A single biomarker for patient selection may not be feasible, given that immune responses are dynamic and evolve over time. Biomarker development for ICI drugs will likely require integration of multiple biologic components like PD-L1 expression, TILs and mutational load. New methodological approaches based on digital pathology may be relevant since they will allow recognition of the biomarker and to objectively quantitate its expression, and therefore might produce objective and reproducible cut-off assessment. Multidisciplinary approach is very much needed to fully develop the current and future value of ICI in clinical practice.

Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.

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Cancers exhibit a remarkable degree of intratumoral heterogeneity (ITH), which results from complex cellular interactions amongst various cell types. This phenomenon provides an opportunity for clonal selection and growth advantages to aggressive cancer cell types, resulting in worse prognosis and challenges to anti-cancer therapy. Cell competition is a conserved mechanism operational in cellular and organ systems, which allows neighboring cells to compare their relative fitness levels and results in the elimination of viable but suboptimal cells. By abuse of this conserved homeostasis mechanism, aggressive cancer cell types gain an advantage over normal cell types by achieving traits like increased proliferation, de-differentiation, and stemness. This review presents recent evidence that cell competition mechanisms actively participate in the regulation of intratumoral cell-cell interactions and thus contribute to ITH, and this process is essential for cancer development and progression. Classical concepts of cell competitionThroughout the development and life of an organism, cells are subjected to compromising pressures that impact overall intrinsic health, culminating in viable, but suboptimal cells. Cell competition is an evolutionarily conserved fitness sensing mechanism that functions to ensure optimum tissue health and homeostasis. Neighboring competing cells compare their relative fitness status resulting in the elimination of the suboptimal, less fit cells, "Losers," by the more fit cells, "Winners." Cell competition was first identified in Drosophila by Morata and colleagues through a series of landmark experiments on a class of dominant mutations called Minutes, which encode ribosomal proteins [1]. The homozygous mutation of Minute gene was observed to be lethal, and the heterozygous mutation renders animals viable, but with reduced growth rates and reduced cellular proliferation. Mosaic wing disc studies revealed that although viable on their own, Minute +/clones were eliminated from the disc when surrounded by Minute wildtype cells. These results suggested that competing cells can sense growth rates and that competition results in the elimination of the slower-growing cells. Interestingly, the final wing compartment size was not affected by cell competition, indicating that Minute wildtype clones grew at the expense of mutant clones [2,3]. Additional investigations revealed that elimination of Minute +/clones by wildtype clones was, in fact, apoptosis dependent [4]. Similar to the Drosophila findings, studies in a chimeric mouse model found that cells with a heterozygous mutation in the ribosomal protein-encoding L24 gene display impaired ribosome biogenesis, and although viable on their own, were eliminated when confronted by wildtype cells [5]. These original findings carved the biological foundation of cell competition, and the most recent decades have uncovered several fitness sensing mechanisms and downstream signaling networks governing competitive interactions. We now understand that cellular ...