Artificial intelligence: A promising frontier in bladder cancer diagnosis and outcome prediction.

Bladder cancer (BCa) is the most common malignancy of the urinary tract and the most expensive malignancy to treat over the patients' lifetime. In recent years a number of studies have utilized Artificial Intelligence (AI) algorithms to perform certain clinical tasks involved in BCa diagnosis and outcome prediction. These tasks include automatic tumor detection, staging, and grading, bladder wall segmentation, as well as prediction of recurrence, response to chemotherapy, and overall survival. Despite the promising results reported, AI algorithms have not been fully integrated into the clinical workflow. In this article we (1) provide an accessible introduction to the fundamental nomenclature and concepts in AI, (2) review the literature to explore how AI is used for BCa diagnosis and outcome prediction, and (3) present our perspective on the obstacles that must be removed before AI algorithms can enter the mainstream of cancer management.

FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML.

Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear. Here we demonstrate that AKT and FOXM1 constitute a positive autoregulatory loop in AML cells that sustains high activity of both pro-oncogenic regulators. Inactivation of either AKT or FOXM1 signaling results in disruption of whole loop, coordinated suppression of FOXM1 or AKT, respectively, and similar transcriptomic changes. AML cells with inhibited AKT activity or stable FOXM1 knockdown display increase in HOXA genes expression and BCL2L1 suppression that are associated with prominent sensitization to treatment with Bcl-2 inhibitor venetoclax. Taken together, our data indicate that AKT and FOXM1 in AML cells should not be evaluated as single independent regulators but as two parts of a common FOXM1-AKT positive feedback circuit. We also report for the first time that FOXM1 inactivation can overcome AML venetoclax resistance. Thus, targeting FOXM1-AKT loop may open new possibilities in overcoming AML drug resistance and improving outcomes for AML patients.

Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells.

FOXM1 transcription factor is an oncogene and a master regulator of chemoresistance in multiple cancers. Pharmacological inhibition of FOXM1 is a promising approach but has proven to be challenging. We performed a network-centric transcriptomic analysis to identify a novel compound STL427944 that selectively suppresses FOXM1 by inducing the relocalization of nuclear FOXM1 protein to the cytoplasm and promoting its subsequent degradation by autophagosomes. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic treatments (platinum-based agents, 5-fluorouracil, and taxanes). RNA-seq analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 toward the FOXM1 pathway. Collectively, the novel autophagy-dependent mode of FOXM1 suppression by STL427944 validates a unique pathway to overcome tumor chemoresistance and improve the efficacy of treatment with conventional cancer drugs.

FOXM1: a potential therapeutic target in human solid cancers.

Introduction: FOXM1 is one of the most frequently overexpressed proteins in human solid cancers. Here, we discuss novel direct targets of FOXM1 as well as new pathways involving FOXM1, through which this protein exerts its oncogenic activity.Areas covered: We give a detailed review of FOXM1 transcriptional targets involved in 16 different types of human cancer as published in the literature in the last 5 years. We also discuss a novel positive feedback loop between FOXM1 and AKT - both well-established master regulators of cancer.Expert opinion: Despite the discovery of several FOXM1 inhibitors over the years (by our team and others), their therapeutic use is limited by their adverse off-target effects.Newly-discovered proteins regulated by FOXM1 present a promising alternative approach to target its pro-cancer activity. In addition, targeting regulating proteins that take part in the positive feedback loop between FOXM1/AKT has the double advantage of suppressing both, and can lead to developing novel anti-cancer drugs.

Adenosine A2A receptor (A2AR) activation triggers Akt signaling and enhances nuclear localization of ß-catenin in osteoblasts.

Osteoblast differentiation and proliferation are regulated by several modulators, among which are adenosine A2A receptors (A2ARs) and Wingless/Integrated-ß-catenin pathways. Cytosolic ß-catenin stabilization promotes its nuclear translocation and transcriptional activity. In the present study, we seek to determine whether there is a connection between A2AR stimulation and cellular ß-catenin levels in osteoblasts. Osteoblast precursor cell line (MC3T3-E1) and primary murine osteoblasts were treated with CGS21680, a highly selective A2AR agonist. We analyzed cellular content and nuclear translocation of phosphorylated (p)-serine 552 (S552) ß-catenin in response to A2AR stimulation in MC3T3-E1 cells, in both wild-type and A2AR knockout (A2AKO) mice. Moreover, we measured cellular ß-catenin levels in MC3T3-E1 cells transfected with scrambled or protein kinase B (Akt) small interfering RNA following A2AR activation. CGS21680 (1 µM) stimulated an increase in both the cellular content and nuclear translocation of p-S552 ß-catenin after 15 min of incubation. A2AR activation had no tangible effect on the cellular ß-catenin level either in A2AKO mice or in osteoblasts with diminished Akt content. Our findings demonstrate an interaction between A2AR, ß-catenin, and Akt signaling in osteoblasts. The existence of such a crosstalk has significant repercussions in the development of novel therapeutic approaches targeting medical conditions associated with reduced bone density.-Borhani, S., Corciulo, C., Larranaga-Vera, A., Cronstein, B. N. Adenosine A2A receptor (A2AR) activation triggers Akt signaling and enhances nuclear localization of ß-catenin in osteoblasts.

Clinical significance of positive platelet immunofluorescence assay in adult immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a relatively common hematologic disorder manifested by low platelet count due to immune-mediated platelet destruction and/or suppression of platelet production. This study aim was to evaluate characteristics and clinical presentation of adult patients with ITP and exploring the clinical value of platelet antibodies assay in proposed cases in Iranian population. In this prospective case series 46 adult patients with ITP and platelet count of <100 × 10(9)/L, referred to the Taleghani Medical Center, Tehran, Iran between 2007 and 2009 were evaluated. There were 26 females and 20 males (1.3:1) with mean age of 38.9 ± 19.7 years. The platelet autoantibodies were measured by means of indirect platelet suspension immunofluorescence test. According to our results, 7 patients (15.2 %) displayed a positive platelet antibody assay. There was a significant negative correlation between platelet count and antibody level (r = -0 0.59; p < 0.001). Additionally, a positive correlation between platelet count and patients' age (r = 0.302; p = 0.042) was detected. 20 patients (56.5 %) were symptomatic at presentation and the most common bleeding signs were petechia, purpura and epistaxis. Results indicated no significant correlation between increased platelet antibody level and bleeding manifestations except for hematuria (r = 0.435; p = 0.02) and epistaxis (r = 0.382; p = 0.015). Disclosure of platelet autoantibodies and the consequential thrombocytopenia associated to some extent but not completely with the propensity to bleed which necessitates more factors to be evaluated.

Effect of 830-nm diode laser irradiation on human sperm motility.

Sperm motility is known as an effective parameter in male fertility, and it depends on energy consumption. Low-level laser irradiation could increase energy supply to the cell by producing adenosine triphosphate. The purpose of this study is to evaluate how the low-level laser irradiation affects the human sperm motility. Fresh human semen specimens of asthenospermic patients were divided into four equal portions and irradiated by 830-nm GaAlAs laser irradiation with varying doses as: 0 (control), 4, 6 and 10 J/cm(2). At the times of 0, 30, 45 and 60 min following irradiation, sperm motilities are assessed by means of computer-aided sperm analysis in all samples. Two additional tests [HOS and sperm chromatin dispersion (SCD) tests] were also performed on the control and high irradiated groups as well. Sperm motility of the control groups significantly decreased after 30, 45 and 60 min of irradiation, while those of irradiated groups remained constant or slightly increased by passing of time. Significant increases have been observed in doses of 4 and 6 J/cm(2) at the times of 60 and 45 min, respectively. SCD test also revealed a non-significant difference. Our results showed that irradiating human sperms with low-level 830-nm diode laser can improve their progressive motility depending on both laser density and post-exposure time.