The Antimicrobial Peptide Tilapia Piscidin 4 Induced the Apoptosis of Bladder Cancer Through ERK/SIRT1/PGC-1α Signaling Pathway.

Marine antimicrobial peptides have been demonstrated in numerous studies to possess anti-cancer properties. This research investigation aimed to explore the fundamental molecular mechanisms underlying the antitumor activity of Tilapia piscidin 4 (TP4), an antimicrobial peptide, in human bladder cancer. TP4 exhibited a remarkable inhibitory effect on the proliferation of bladder cancer cells through cell cycle arrest at the G2/M phase. Additionally, TP4 upregulated the expression of cleaved caspase-3, caspase-9, and PARP, leading to the activation of apoptotic pathways in bladder cancer cells. TP4 exhibit a marked rise in mitochondria reactive oxygen species, leading to the subsequent loss of potential for the mitochondrial membrane. Furthermore, the inhibition of mitochondrial oxidative phosphorylation resulted in a decrease in downstream ATP production. Meanwhile, TP4-treated bladder cancer cells showed an increase in Bax and ERK but a decrease in SIRT1, PGC-1α, and Bcl2. ERK activation, SIRT1/PGC-1α-axis, and TP4-induced apoptosis were all significantly reversed by the ERK inhibitor SCH772984. Finally, the inhibitory effect of TP4 on tumor growth has been confirmed in a zebrafish bladder cancer xenotransplantation model. These findings suggest that TP4 may be a potential agents for human bladder cancer through apoptosis induction, ERK activation, and the promotion of SIRT1-mediated signaling pathways.

Machine Learning Prediction of Prediabetes in a Young Male Chinese Cohort with 5.8-Year Follow-Up.

The identification of risk factors for future prediabetes in young men remains largely unexamined. This study enrolled 6247 young ethnic Chinese men with normal fasting plasma glucose at the baseline (FPGbase), and used machine learning (Mach-L) methods to predict prediabetes after 5.8 years. The study seeks to achieve the following: 1. Evaluate whether Mach-L outperformed traditional multiple linear regression (MLR). 2. Identify the most important risk factors. The baseline data included demographic, biochemistry, and lifestyle information. Two models were built, where Model 1 included all variables and Model 2 excluded FPGbase, since it had the most profound effect on prediction. Random forest, stochastic gradient boosting, eXtreme gradient boosting, and elastic net were used, and the model performance was compared using different error metrics. All the Mach-L errors were smaller than those for MLR, thus Mach-L provided the most accurate results. In descending order of importance, the key factors for Model 1 were FPGbase, body fat (BF), creatinine (Cr), thyroid stimulating hormone (TSH), WBC, and age, while those for Model 2 were BF, white blood cell, age, TSH, TG, and LDL-C. We concluded that FPGbase was the most important factor to predict future prediabetes. However, after removing FPGbase, WBC, TSH, BF, HDL-C, and age were the key factors after 5.8 years.

Roles of biochemistry data, lifestyle, and inflammation in identifying abnormal renal function in old Chinese.

BACKGROUND: The incidence of chronic kidney disease (CKD) has dramatically increased in recent years, with significant impacts on patient mortality rates. Previous studies have identified multiple risk factors for CKD, but they mostly relied on the use of traditional statistical methods such as logistic regression and only focused on a few risk factors. AIM: To determine factors that can be used to identify subjects with a low estimated glomerular filtration rate (L-eGFR < 60 mL/min per 1.73 m2) in a cohort of 1236 Chinese people aged over 65. METHODS: Twenty risk factors were divided into three models. Model 1 consisted of demographic and biochemistry data. Model 2 added lifestyle data to Model 1, and Model 3 added inflammatory markers to Model 2. Five machine learning methods were used: Multivariate adaptive regression splines, eXtreme Gradient Boosting, stochastic gradient boosting, Light Gradient Boosting Machine, and Categorical Features + Gradient Boosting. Evaluation criteria included accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), F-1 score, and balanced accuracy. RESULTS: A trend of increasing AUC of each was observed from Model 1 to Model 3 and reached statistical significance. Model 3 selected uric acid as the most important risk factor, followed by age, hemoglobin (Hb), body mass index (BMI), sport hours, and systolic blood pressure (SBP). CONCLUSION: Among all the risk factors including demographic, biochemistry, and lifestyle risk factors, along with inflammation markers, UA is the most important risk factor to identify L-eGFR, followed by age, Hb, BMI, sport hours, and SBP in a cohort of elderly Chinese people.

Green-Solvent-Processable Organic Photovoltaics with High Performances Enabled by Asymmetric Non-Fullerene Acceptors.

In this work, two asymmetric non-fullerene acceptors (NFAs), BTP-EHBO-4F and BTP-PHD-4F, are designed to be applied in green-solvent-processable organic photovoltaics (OPVs). BTP-EHBO-4F and BTP-PHD-4F show good solubilities in green solvent o-xylene. As a result, PM6:BTP-EHBO-4F-based devices exhibit outstanding photovoltaic performances using o-xylene as a solvent. By comparison, due to the poor solubility of Y6 in o-xylene, PM6:Y6-based devices show poor performances. Owing to the favorable phase separation, molecule packing, and orientation observed from atomic force microscopy (AFM) and grazing-incidence wide-angle X-ray scattering (GIWAXS) measurements, PM6:BTP-PHD-4F-based devices demonstrate a PCE of 15.91% with a VOC of 0.87 V, a JSC of 25.64 mA/cm2, and an FF of 71.34%. Moreover, PM6:BTP-EHBO-4F-based devices exhibit an impressive PCE of 16.82% with a VOC of 0.85 V, a JSC of 26.12 mA/cm2, and an FF of 75.78%, which is outstanding for OPVs using o-xylene as a solvent.

Drug-like property optimization: Discovery of orally bioavailable quinazoline-based multi-targeted kinase inhibitors.

In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potentanticancercompound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.

Design and synthesis of BPR1K653 derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition.

Twenty five novel chemical analogs of the previously reported Aurora kinase inhibitor BPR1K653 (1-(4-(2-((5-chloro-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino)ethyl)phenyl)-3-(2-((dimethylamino)methyl)phenyl)urea) have been designed, synthesized, and evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays. Similar to BPR1K653, analogs 3b-3h bear alkyl or tertiary amino group at the ortho position of the phenylurea, and showed equal or better inhibition activity for Aurora-B over Aurora-A. Conversely, preferential Aurora-A inhibition activity was observed when the same functional group was moved to the meta position of the phenylurea. Compounds 3m and 3n, both of which harbor a tertiary amino group at the meta position of the phenylurea, showed 10-16 fold inhibition selectivity for Aurora-A over Aurora-B. The in vitro kinase inhibition results were verified by Western blot analysis, and indicated that compounds 3m and 3n were more than 75-fold superior in inhibiting T-loop autophosphorylation of Aurora-A (Thr288), compared to Aurora-B (Thr232) in HCT116 colon carcinoma cells. The computational docking analysis suggested that the tertiary amine at the meta position of the phenylurea formed a more stable interaction with residues in the back pocket of Aurora-A than in Aurora-B, a possible explanation for the observed discrepancy in the selectivity. These results support an alternative small molecule design strategy targeting the back pocket of Aurora kinases for selective isoform inhibition.

The Effects of Quality of Life and Ability to Perform Activities of Daily Living on Mild Cognitive Impairment in Older People Living in Publicly Managed Congregate Housing.

BACKGROUND: Mild cognitive impairment (MCI) is characterized by a decrease in cognitive abilities that does not affect the ability to perform activities of daily living (ADLs). Therefore, this condition is easily overlooked. The prevalence and factors of influence for MCI in older people living in publicly managed congregate housing are currently unknown. PURPOSE: This study investigated the prevalence and distribution of MCI in older people living in publicly managed congregate housing and assessed the correlations among quality of life (QoL), ADL, and MCI. METHODS: This study applied a correlational study design. The participants were older people who met the study criteria and who lived in public housing in Wanhua District, Taipei City, Taiwan. One-on-one interviews were conducted to measure the cognitive abilities of the participants, and 299 valid samples were collected. RESULTS: The prevalence of MCI in older people living in publicly managed congregate housing was 16.1%. The χ test was employed to evaluate the distribution of MCI prevalence and indicated that the group with higher MCI prevalence exhibited the following characteristics: older than 81 years; married; lived in public housing for more than 20 years; cohabiting; had a history of drinking; and exhibited severe memory regression, physical disabilities, psychological distress, and low QoL. The difference between the groups achieved statistical significance (p < .05). After performing logistical regression analysis to control demographic variables, we found that QoL and ADL were critical for predicting MCI. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This study confirmed that QoL and ADL correlate significantly with MCI in older people. Maintaining an open and supportive community enables older people to maintain sufficient mental activity, which has been shown to reduce MCI. These findings may provide an important reference for policy makers, educators, researchers, and community practitioners in their development of service strategies for older people.

Discovery of novel inhibitors of Aurora kinases with indazole scaffold: In silico fragment-based and knowledge-based drug design.

Aurora kinases have emerged as important anticancer targets so that there are several inhibitors have advanced into clinical study. Herein, we identified novel indazole derivatives as potent Aurora kinases inhibitors by utilizing in silico fragment-based approach and knowledge-based drug design. After intensive hit-to-lead optimization, compounds 17 (dual Aurora A and B), 21 (Aurora B selective) and 30 (Aurora A selective) possessed indazole privileged scaffold with different substituents, which provide sub-type kinase selectivity. Computational modeling helps in understanding that the isoform selectivity could be targeted specific residue in the Aurora kinase binding pocket in particular targeting residues Arg220, Thr217 or Glu177.

The Functional Haplotypes of CHRM3 Modulate mRNA Expression and Associate with Bladder Cancer among a Chinese Han Population in Kaohsiung City.

Bladder cancer is one of the major cancer types and both environmental factors and genetic background play important roles in its pathology. Kaohsiung is a high industrialized city in Taiwan, and here we focused on this region to evaluate the genetic effects on bladder cancer. Muscarinic acetylcholine receptor M3 (CHRM3) was reported as a key receptor in different cancer types. CHRM3 is located at 1q42-43 which was reported to associate with bladder cancer. Our study attempted to delineate whether genetic variants of CHRM3 contribute to bladder cancer in Chinese Han population in south Taiwan. Five selected SNPs (rs2165870, rs10802789, rs685550, rs7520974, and rs3738435) were genotyped for 30 bladder cancer patients and 60 control individuals and genetic association studies were performed. Five haplotypes (GTTAT, ATTGT, GCTAC, ACTAC, and ACCAC) were found significantly associated with low CHRM3 mRNA level and contributed to increased susceptibility of bladder cancer in Kaohsiung city after rigid 10000 consecutive permutation tests. To our knowledge, this is the first genetic association study that reveals the genetic contribution of CHRM3 gene in bladder cancer etiology.

Urethral Metastasis from Rectal Adenocarcinoma: A Case Report and Review of the Literature.

CASE: A 73-year-old man with Dukes' C adenocarcinoma of the rectum, pT3N2bM0, stage IIIB, presented with voiding difficulties including poor stream and terminal dribbling for one month. The patient was under careful surveillance and had no postoperative recurrence. Physical examination revealed a palpable irregular nodular lesion (0.5 × 0.5 cm(2)) at the penile-scrotal junction. He underwent urethroscopy, which showed a cauliflower lesion in the pendulous urethra. Transurethral resection was performed and histopathologic and immunochemical staining demonstrated a metastatic moderately differentiated urethral adenocarcinoma from the colorectal primary. OUTCOME: His voiding disorder improved significantly post-operation and he commenced second-line chemotherapy combined with regional radiotherapy. Follow-up urethrocystoscopy and abdominal computed tomography demonstrated no recurrence or metastatic disease. His tumor marker remained within the normal range for 12 months. CONCLUSION: Urethral metastasis from primary colon cancer is extremely rare. This disease, with its various atypical presentations, presents a diagnostic challenge to the clinician. In patients with recurrent or persistent lower urinary tract symptoms, further urologic workup including thorough history taking, physical examination, and imaging surveys is warranted.

Kimura's disease associated necrotizing eosinophilic vasculitis presenting with recurrent peripheral arterial occlusive disease: a case report and review of the literature.

A 33-year-old Chinese man with 9-year history of Kimura's disease (KD) was admitted with a 1-month history of recurrent claudication. He did not have any clinical discomfort and had not taken any preventive medication in the past. He accepted percutaneous transluminal angioplasty and the pathologic diagnosis was reportedly consistent with necrotizing eosinophilic vasculitis. This is the rare reported case of KD associated necrotizing eosinophilic vasculitis presenting with recurrent peripheral arterial occlusive disease and the difficulties encountered in establishing an accurate diagnosis with unusual presentations. This case also highlights the possibility of recurrent complications without aggressive medical treatment in such unusual eosinophilic disorders.