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Luteolin is a natural flavonoid with strong anti–oxidative properties that is reported to have an anti–cancer effect in several malignancies other than bladder cancer. In this study, we describe the effect of luteolin on a human bladder cancer cell line, T24, in the context of the regulation of p21, thioredoxin‐1 (TRX1) and the mechanistic target of rapamycin (mTOR) pathway. Luteolin inhibited cell survival and induced G2/M cell‐cycle arrest, p21 upregulation and downregulation of phospho(p)‐S6, which is downstream of mTOR signaling. Luteolin also upregulated TRX1 and reduced intracellular reactive oxygen species production. In a subcutaneous xenograft mouse model using the rat bladder cancer cell line, BC31, tumor volumes were significantly decreased in mice orally administered luteolin compared to control. Immunohistochemical analysis revealed that increased p21 and decreased p‐S6 expression were induced in the luteolin treatment group. Moreover, in another in vivo N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine (BBN)‐induced rat bladder cancer model, the oral administration of luteolin led to a trend of decreased bladder tumor dimension and significantly decreased the Ki67‐labeling index and p‐S6 expression. Furthermore, the major findings on the metabolism of luteolin suggest that both plasma and urine luteolin‐3ʹ‐O‐glucuronide concentrations are strongly associated with the inhibition of cell proliferation and mTOR signaling. Moreover, a significant decrease in the squamous differentiation of bladder cancer is attributed to plasma luteolin‐3ʹ‐glucuronide concentration. In conclusion, luteolin, and in particular its metabolized product, may represent another natural product‐derived therapeutic agent that acts against bladder cancer by upregulating p21 and inhibiting mTOR signaling. Luteolin suppresses cell proliferation through downregulation of mTOR signaling and upregulation of p21 in bladder cancers both in vitro and in vivo. mTOR activity is correlated with invasive ability in human bladder cancer cases. A metabolite of luteolin decreases cell viability and squamous differentiation in in vivo rat bladder cancer models.

Multi‐walled carbon nanotube‐7 (MWCNT‐7) fibers are biopersistent and have a structure similar to asbestos. MWCNT‐7 has been shown to induce malignant mesothelioma when administered by intrascrotal or intraperitoneal injection in rats and mice, and an inhalation study demonstrated that rats exposed to respirable MWCNT‐7 developed lung tumors. MWCNT‐N, which is similar to MWCNT‐7, was shown to induce both lung tumors and malignant mesothelioma in rats when administered by trans‐tracheal intrapulmonary spraying (TIPS). The present study was performed to investigate the carcinogenicity of MWCNT‐7 when administered by the TIPS method. Ten‐week‐old male F344/Crj rats were divided into 3 groups and administered 0.5 mL vehicle, 0.250 μg/mL MWCNT‐7 or 0.250 μg/mL crocidolite once a week for 12 weeks (total doses of 1.5 mg/rat) and then observed for up to 104 weeks. Rats in the MWCNT‐7 group began to die from pathologies associated with the development of malignant mesothelioma 35 weeks after the final TIPS administration. Overall, the incidence of malignant mesothelioma in the MWCNT‐7 group was significantly higher than in the vehicle or crocidolite groups.

Many prostate cancer patients develop resistance to treatment called castration‐resistant prostate cancer (CRPC) which is the major cause of recurrence and death. In the present study, four cyclohexanone curcumin analogs were synthesized. Additionally, their anticancer progression activity on CRPC cell lines, PC3 and PLS10 cells, was examined. We first determined their anti‐metastasis properties and found that 2,6‐bis‐(4‐hydroxy‐3‐methoxy‐benzylidene)‐cyclohexanone (2A) and 2,6‐bis‐(3,4‐dihydroxy‐benzylidene)‐cyclohexanone (2F) showed higher anti‐invasion properties against CRPC cells than curcumin. Analog 2A inhibited both MMP‐2 and MMP‐9 secretions and activities, whereas analog 2F reduced only MMP activities. These findings suggest that the compounds may inhibit CRPC cell metastasis by decreased extracellular matrix degradation. Analog 2A, the most potent analog, was then subjected to an in vivo study. Similar to curcumin, analog 2A was detectable in the serum of mice at 30 and 60 minutes after i.p. injections. Analog 2A and curcumin (30 mg/kg bodyweight) showed a similar ability to reduce tumor area in lungs of mice that were i.v. injected with PLS10 cells. Additionally, analog 2A showed superior growth inhibitory effect on PLS10 cells than that of curcumin both in vitro and in vivo. The compound inhibited PLS10 cells growth by induction of G1 phase arrest and apoptosis in vitro. Interestingly, analog 2A significantly decreased tumor growth with downregulation of cell proliferation and angiogenesis in PLS10‐bearing mice. Taken together, we could summarize that analog 2A showed promising activities in inhibiting CRPC progression both in vitro and in vivo. Our in vitro study showed that growth inhibitory effects of cyclohexanone curcumin analog 2A on PC3 and PLS10 cells is more potent than that of curcumin. Expression of cyclin D1 and survivin were downregulated after analog 2A treatment leading to induction of cell cycle arrest in G1 phase and apoptosis in PLS10 cells. In the in vivo study, analog 2A showed a significant inhibitory effect on tumor volume whereas curcumin did not. In anti‐metastasis studies, analog 2A showed similar effects to curcumin in vivo, although analog 2A had more pronounced anti‐invasion effects on PC3 and PLS10 cells in in vitro studies.

POU5F1-expressing cells can self-renew and differentiate, contributing to metastasis formation in colorectal cancer (CRC), but it plays an important role in normal pluripotent stem cells. Here, we identified the CRC-specific gene, HNF1A, which is the downstream of POU5F1. HNF1A associates with fatty acid and glucose metabolism, and CRC cells highly expressed it. In 198 CRC patients, high HNF1A expression was an independent predictor of disease-free ( P  = 0.031) and overall ( P  = 0.007) survival. HNF1A-knockdown showed significantly reduced cell growth, increased apoptosis, and improved anticancer drug sensitivity. We revealed that HNF1A regulated controlled GLUT1 expression via HIF1A and multidrug resistance protein function to suppress SRI. HNF1A expression was elevated in persister cells after exposure to anticancer drugs, and anticancer drug sensitivity was also improved in persister cells via the inhibition of HNF1A. In conclusion, HNF1A expression can reflect resistance to anticancer drug treatment, and its suppression improves anticancer drug sensitivity as a new therapeutic target.

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide with high morbidity and mortality rates. The discovery of small molecule anticancer reagents has significantly affected cancer therapy. However, the anticancer effects of these therapies are not sufficient to completely cure CRC. PDZ-binding kinase (PBK) was initially identified as a mitotic kinase for mitogen-activated protein kinase and is involved in cytokinesis and spermatogenesis. Aberrant expression of PBK has been reported to be closely associated with malignant phenotypes of many cancers and/or patient survival. However, the expression of PBK and its association to patient survival in CRC have not been fully elucidated. In the present study, 269 primary CRCs were evaluated immunohistochemically for PBK expression to assess its ability as a prognostic factor. CRC tumor cells variably expressed PBK (range, 0–100%; median, 32%) in the nucleus and cytoplasm. Univariate analyses identified a significant inverse correlation between PBK expression and pT stage (P<0.0001). Furthermore, patients carrying CRC with higher PBK expression showed significantly favorable survival (P=0.0094). Multivariate Cox proportional hazards regression analysis revealed high PBK expression (HR, 0.52; P=0.015) as one of the potential favorable factors for CRC patients. PBK expression showed significant correlation to Ki-67 labeling indices (ρ=0.488, P<0.0001). In vitro, the PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells with PBK expression through downregulation of P-ERK and induction of apoptosis. These results suggest that PBK-targeting therapeutics may be useful for the treatment of PBK-expressing CRC patients.

Cbln1, secreted from cerebellar granule cells, and the orphan glutamate receptor δ2 (GluD2), expressed by Purkinje cells, are essential for synapse integrity between these neurons in adult mice. Nevertheless, no endogenous binding partners for these molecules have been identified. We found that Cbln1 binds directly to the N-terminal domain of GluD2. GluD2 expression by postsynaptic cells, combined with exogenously applied Cbln1, was necessary and sufficient to induce new synapses in vitro and in the adult cerebellum in vivo. Further, beads coated with recombinant Cbln1 directly induced presynaptic differentiation and indirectly caused clustering of postsynaptic molecules via GluD2. These results indicate that the Cbln1-GluD2 complex is a unique synapse organizer that acts bidirectionally on both pre- and postsynaptic components.

PurposeDetecting bladder cancer (BC) in routine CT images is important but is sometimes difficult when cancer is small. We evaluated the ability of 40-keV advanced monoenergetic images to depict BC. Materials and methodsFifty-two patients with a median age of 74 years (range 45–92) who were diagnosed as BC with transurethral resection or cystectomy, were included. They were examined with contrast-enhanced dual-energy CT (DE-CT) and advanced virtual monoenergetic images (40 keV) were reconstructed. For evaluating depictability of BC on 40-keV or virtual-120-kVp images, the difference in CT number between the cancer and bladder wall (BC–BW value) were calculated. We also subjectively assessed depictability of BC in virtual-120-kVp and 40-keV images using a 4-grade Likert scale (3: clear, 0: not visualized). ResultsIn 42 of 52 patients, BC–BW values could be calculated because BC was detected on CT images. The mean BC–BW value at 40 keV was significantly higher than that of virtual 120 kVp [80.5 ± 54 (SD) vs. 11.4 ± 12.5 HU, P < 0.01]. Average scores of subjective evaluations in the virtual-120-kVp and 40-keV images were 1.7 ± 1.2 and 2.1 ± 1.2, respectively (P < 0.001).ConclusionThe advanced monoenergetic reconstruction technique reconstructed using DE-CT image is useful to depict BC.

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome. Rett syndrome is a childhood brain disorder that mainly affects girls and causes symptoms including anxiety, tremors, uncoordinated movements and breathing difficulties. Rett syndrome is caused by mutations in a gene called MECP2, which is found on the X chromosome. Males with MECP2 mutations are rare but have more severe symptoms and die young. Many researchers who study Rett syndrome use mice as a model of the disorder. In particular, male mice with the mouse equivalent of the human MECP2 gene switched off in every cell in the body (also known as Mecp2-null mice) show many of the features of Rett syndrome and die at a young age. The MECP2 gene is important for healthy brain activity. The brain contains two major types of neurons: excitatory neurons, which encourage other neurons to be active; and inhibitory neurons, which stop or dampen the activity of other neurons. In 2010, researchers reported that mice lacking Mecp2 in only their inhibitory neurons develop most of the same problems as those mice with no Mecp2 at all. This discovery led Ure et al. – including a researcher involved in the 2010 study – to ask if activating Mecp2 in the same neurons in otherwise Mecp2-null mice was enough to prevent some of their Rett syndrome-like symptoms. The experiments showed that male mice that only have Mecp2 activated in their inhibitory neurons lived several months longer than male Mecp2-null mice. These male “rescue mice” also moved normally and had a normal body weight, though they still experienced anxiety, tremors and breathing difficulties. Female mice represent a better model of human Rett syndrome patients, and Ure et al. found that female rescue mice showed smaller improvements than the males. These data suggest that when a brain is missing Mecp2 everywhere, as in male Mecp2-null mice, turning on Mecp2 in inhibitory neurons can make the brain network nearly normal and prevent most Rett-syndrome-like symptoms. However, the brains of female rescue mice contain both normal cells and cells with mutated Mecp2. This mixture of normal and abnormal cells appears to cause abnormalities that cannot be overcome by rescuing just the activity of the inhibitory neurons. These findings also highlight the importance of doing future studies in female mice to better understand the development of Rett syndrome. The next challenge is to test different ways of activating the inhibitory neurons in the female mouse brain, for example by using drugs that target these neurons. It is hoped these methods will help researchers to refine a path toward potential new treatments for Rett syndrome patients. Finally, in a related study, Meng et al. asked how deleting or activating Mecp2 only in the excitatory neurons of mice affected Rett-syndrome-like symptoms.

Introduction Patients with metastatic renal cell carcinoma have a poor prognosis and its specific pathogenesis remains unelucidated. Case presentation At 78 years of age, a Japanese male patient was diagnosed with metastatic renal cell carcinoma (cT3N2M1 stage) and multiple brain metastases that were responsive to stereotactic radiation therapy followed by systemic combination induction therapy of pembrolizumab plus lenvatinib. Adverse events, including grade 3 hypertension, grade 2 eruption, and elevated grade 2 fever, were controlled by a dose reduction or suspension of drugs. The patient eventually showed a tolerance for continuing with 8 mg lenvatinib. Fourteen months after the initiation of treatment, and on 8 mg lenvatinib, this patient showed no sign of disease progression at the last follow‐up. Conclusion We detail the absence of disease progression in a metastatic renal cell carcinoma case with multiple brain metastases more than 1 year after stereotactic radiation therapy followed by first‐line pembrolizumab plus lenvatinib.

Purple corn color is a widely used food colorant that was reported to have attenuating effects on hypertension, diabetes, and to have anti‐cancer effects on colon and breast cancer. Our study is the first on its possible chemoprevention effects against prostate cancer. For this purpose an androgen‐dependent prostate cancer cell line, LNCaP, was used to examine effects in vitro. Purple corn color inhibited the proliferation of LNCaP cells by decreasing the expression of Cyclin D1 and inhibiting the G1 stage of the cell cycle. Thirty‐six male transgenic rats for adenocarcinoma of prostate were fed basic diet or diet with purple corn color for 8 weeks. Purple corn color decreased the incidence of adenocarcinoma in the lateral prostate and slowed down the progression of prostate cancer. A lower Ki67 positive rate, a decrease of the expression of Cyclin D1, and downregulation of the activation of Erk1/2 and p38 MAPK were observed in the group consuming purple corn color in the diet. Since purple corn color is a mixture, determining its active component should help in the understanding and usage of purple corn color for prostate cancer chemoprevention. Therefore, the three major anthocyanins in purple corn color, cyanidin‐3‐glucoside, pelargonidin‐3‐glucoside and peonidin‐3‐glucoside, were tested with LNCaP cells. The results suggested that cyanidin‐3‐glucoside and pelargonidin‐3‐glucoside are the active compounds.