Interferon-γ/Janus kinase 1/STAT1 Signaling Represses Forkhead Box A1 and Drives a Basal Transcriptional State in Muscle-Invasive Bladder Cancer.

During progression, luminal muscle-invasive bladder cancer (MIBC) can transition to the aggressive basal-squamous (Ba/Sq) subtype. Reduced expression of forkhead box A1 (FOXA1) in the urothelium is a hallmark and driver of the Ba/Sq transcriptional state and squamous differentiation. Ba/Sq tumors are highly inflamed; however, the specific inflammatory pathways contributing to the Ba/Sq state are unknown.

Integrating spin-dependent emission and dielectric switching in Fe catenated metal-organic frameworks.

Mechanically interlocked molecules (MIMs) including famous catenanes show switchable physical properties and attract continuous research interest due to their potential application in molecular devices. The advantages of using spin crossover (SCO) materials here are enormous, allowing for control through diverse stimuli and highly specific functions, and enabling the transfer of the internal dynamics of MIMs from solution to solid state, leading to macroscopic applications. Herein, we report the efficient self-assembly of catenated metal-organic frameworks (termed catena-MOFs) induced by stacking interactions, through the combination of rationally selected flexible and conjugated naphthalene diimide-based bis-pyridyl ligand (BPND), [M(CN)] (M = Ag or Au) and Fe in a one-step strategy.

Urothelium-Specific Expression of Mutationally Activated Pik3ca Initiates Early Lesions of Noninvasive Bladder Cancer.

Although approximately 70% of bladder cancers are noninvasive and have high recurrence rates, early-stage disease is understudied. The lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. Although mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable.

The Potent Anti-Tumor Effects of Rhodiola Drinking Are Associated with the Inhibition of the mTOR Pathway and Modification of Tumor Metabolism in the UPII-Mutant Ha-Ras Model.

SHR-5 has been used as an "adaptogen" for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the underlying mechanisms of action. UPII-mutant Ha-ras bladder-cancer-transgenic mice, that developed low-grade and noninvasive papillary transitional urothelial cell carcinoma, were fed with 1.

Kawain Inhibits Urinary Bladder Carcinogenesis through Epigenetic Inhibition of LSD1 and Upregulation of H3K4 Methylation.

Epidemiological evidence suggests that kava () drinks may reduce the risk of cancer in South Pacific Island smokers. However, little is known about the anti-carcinogenic effects of kava on tobacco smoking-related bladder cancer and its underlying mechanisms. Here we show that dietary feeding of kawain (a major active component in kava root extracts) to mice either before or after hydroxy butyl(butyl) nitrosamine (OH-BBN) carcinogen exposure slows down urinary bladder carcinogenesis and prolongs the survival of the OH-BBN-exposed mice.

Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism.

UPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcinoma in these mice. The mice were fed at six weeks of age with vehicle control or kawain (6 g/kg) formulated food for approximately five months.

Structural or functional defects of PTEN in urothelial cells lacking P53 drive basal/squamous-subtype muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) exhibits strong inter- and intra-tumor heterogeneity that affects biological behaviors, therapeutic responses, and prognoses. Mutations that activate RTK-RAS-PI3K and inactivate P19-P53-P21 coexist in 60-70% of MIBC. By time-controlled ablation of Tp53 and Pten, singly or combined, in adult mouse urothelium, we found that Tp53 loss alone produced no abnormality.

DNMT3A//Rac1 Is an Effector Pathway for to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells.

The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that , a long non-coding RNA that is over-expressed in ~95% of human muscle-invasive bladder cancers (MIBCs), induces stem-cell-like sphere formation and the invasion of cultured bladder cancer cells by upregulating Rho GTPase, Rac1.

Assembly of a Heterotrimetallic ZnDyIr Pentanuclear Complex toward Multifunctional Molecular Materials.

Rational selection of metal ions and organic ligands to synthesize metal-organic complexes (MOCs) is necessary for constructing multifunctional materials. Herein, we have obtained a novel heterotrimetallic ZnDyIr pentanuclear MOC by the assembly of Dy, luminescent Zn(valpn), and [Ir(HL)(ppy)]Cl metalloligands (Hppy = 2-phenylpyridine, HL = 2,2'-bipyridine-5,5'-di--benzoic acid). Single-crystal structural analysis shows that the central [Ir(L)(ppy)] bridges two ZnDy moieties using two carboxylates of L.

The kidney protects against sepsis by producing systemic uromodulin.

Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. Although electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI.

DNA damage, DNA repair and carcinogenicity: Tobacco smoke versus electronic cigarette aerosol.

The allure of tobacco smoking is linked to the instant gratification provided by inhaled nicotine. Unfortunately, tobacco curing and burning generates many mutagens including more than 70 carcinogens. There are two types of mutagens and carcinogens in tobacco smoke (TS): direct DNA damaging carcinogens and procarcinogens, which require metabolic activation to become DNA damaging.

Magnetooptical Properties of Lanthanide(III) Metal-Organic Frameworks Based on an Iridium(III) Metalloligand.

Integrating magnetic and optical properties into a metal-organic framework (MOF) remains a great challenge. Herein, we have reasonably constructed two 3D magnetooptical MOFs by incorporating a [Ir(ppy)(bpy)]-based fluorescent metalloligand and magnetic Ln centers. The alternating arrangements of Δ- or Λ-[Ir(ppy)(bpy)] endow these MOFs with enhanced optical properties.

PKM2 Is Essential for Bladder Cancer Growth and Maintenance.

Unlabelled: Pyruvate kinase M2 (PKM2) has been shown to promote tumorigenesis by facilitating the Warburg effect and enhancing the activities of oncoproteins. However, this paradigm has recently been challenged by studies in which the absence of PKM2 failed to inhibit and instead accelerated tumorigenesis in mouse models. These results seem inconsistent with the fact that most human tumors overexpress PKM2.

The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells.

It has long been recognized that non-muscle-invasive bladder cancer (NMIBC) has a low propensity (20%) of becoming muscle-invasive (MIBC), and that MIBC carry many more p53 point mutations (p53m) than NMIBC (50% vs 10%). MIBC also has a higher mutation burden than NMIBC. These results suggest that DNA repair capacities, mutational susceptibility and p53m are crucial for MIBC development.

Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis.

Human chromosome 9p21.3 is susceptible to inactivation in cell immortalization and diseases, such as cancer, coronary artery disease and type-2 diabetes. Although this locus encodes three cyclin-dependent kinase (CDK) inhibitors (p15, p14 and p16), our understanding of their functions and modes of action is limited to the latter two.

Episodic Aspiration with Oral Commensals Induces a MyD88-dependent, Pulmonary T-Helper Cell Type 17 Response that Mitigates Susceptibility to .

Cross-sectional human data suggest that enrichment of oral anaerobic bacteria in the lung is associated with an increased T-helper cell type 17 (Th17) inflammatory phenotype. In this study, we evaluated the microbial and host immune-response dynamics after aspiration with oral commensals using a preclinical mouse model. Aspiration with a mixture of human oral commensals (MOC; , , and ) was modeled in mice followed by variable time of killing.

Hypermethylation of FOXA1 and allelic loss of PTEN drive squamous differentiation and promote heterogeneity in bladder cancer.

Intratumoral heterogeneity in bladder cancer is a barrier to accurate molecular sub-classification and treatment efficacy. However, individual cellular and mechanistic contributions to tumor heterogeneity are controversial. We examined potential mechanisms of FOXA1 and PTEN inactivation in bladder cancer and their contribution to tumor heterogeneity.

Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice.

Electronic-cigarettes (E-cigs) are marketed as a safe alternative to tobacco to deliver the stimulant nicotine, and their use is gaining in popularity, particularly among the younger population. We recently showed that mice exposed to short-term (12 wk) E-cig smoke (ECS) sustained extensive DNA damage in lungs, heart, and bladder mucosa and diminished DNA repair in lungs. Nicotine and its nitrosation product, nicotine-derived nitrosamine ketone, cause the same deleterious effects in human lung epithelial and bladder urothelial cells.

Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel.

High serum concentrations of kidney-derived protein uromodulin [Tamm-Horsfall protein (THP)] have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage.

Mitochondrial lipid droplet formation as a detoxification mechanism to sequester and degrade excessive urothelial membranes.

The apical surface of the terminally differentiated mammalian urothelial umbrella cell is mechanically stable and highly impermeable, in part due to its coverage by urothelial plaques consisting of 2D crystals of uroplakin particles. The mechanism for regulating the uroplakin/plaque level is unclear. We found that genetic ablation of the highly tissue-specific sorting nexin Snx31, which localizes to plaques lining the multivesicular bodies (MVBs) in urothelial umbrella cells, abolishes MVBs suggesting that Snx31 plays a role in stabilizing the MVB-associated plaques by allowing them to achieve a greater curvature.

Downregulation of miR-200c stabilizes XIAP mRNA and contributes to invasion and lung metastasis of bladder cancer.

Our previous studies have demonstrated that XIAP promotes bladder cancer metastasis through upregulating RhoGDIβ/MMP-2 pathway. However, the molecular mechanisms leading to the XIAP upregulation was unclear. In current studies, we found that XIAP was overexpressed in human high grade BCs, high metastatic human BCs, and in mouse invasive BCs.

Characterization of Histone Deacetylase Expression Within In Vitro and In Vivo Bladder Cancer Model Systems.

Epigenetic aberrations are prominent in bladder cancer (BC) and contribute to disease pathogenesis. We characterized histone deacetylase (HDAC) expression, a family of deacetylation enzymes, in both in vitro and in vivo BC model systems and analyzed expression data from The Cancer Genome Atlas (TCGA). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis was used to determine the expression status of Class I and II HDACs in ten human BC cell lines, while qRT-PCR was used to determine HDAC expression in 24 human tumor specimens.

ATG7 Promotes Bladder Cancer Invasion via Autophagy-Mediated Increased ARHGDIB mRNA Stability.

Since invasive bladder cancer (BC) can progress to life threatening metastases, understanding the molecular mechanisms underlying BC invasion is crucial for potentially decreasing the mortality of this disease. Herein, it is discovered that autophagy-related gene 7 (ATG7) is remarkably overexpressed in human invasive BC tissues. The knockdown of ATG7 in human BC cells dramatically inhibits cancer cell invasion, revealing that ATG7 is a key player in regulating BC invasion.

MEG3, as a Competing Endogenous RNA, Binds with miR-27a to Promote PHLPP2 Protein Translation and Impairs Bladder Cancer Invasion.

Muscle-invasive and metastatic bladder cancer have an extremely poor 5-year survival rate of 5%. In comparison, all other bladder cancers (BCs) have a 5-year survival rate of 77%. This striking contrast indicates that one of the therapeutic kernels for bladder cancer is to elucidate the molecular mechanisms underlying its invasiveness and metastasis.