Identification and biological evaluation of fused tetrahydroisoquinoline derivatives as Wnt/ß-catenin signaling inhibitors to suppress colorectal cancer.

Colorectal cancer (CRC) has been becoming one of the most common causes of cancer mortality worldwide. Accumulating studies suggest that the progressive up-regulation of Wnt/ß-catenin signaling is a crucial hallmark of CRC, and suppressing it is a promising strategy to treat CRC. Herein, we reported our latest efforts in the discovery of novel fused tetrahydroisoquinoline derivatives with good anti-CRC activities by screening our in-house berberine-like library and further structure-activity relationship (SAR) studies, in which we identified compound 10 is a potent lead compound with significant antiproliferation potencies. By the biotinylated probe and LC-MS/MS study, Hsp90 was identified as its molecular target, which is a fully different mechanism of action from what we reported before. Further studies showed compound 10 directly engaged the N-terminal site of Hsp90 and promoted the degradation of ß-catenin, thereby suppressing the Wnt/ß-catenin signaling. More importantly, compound 10 exhibits favorable pharmacokinetic parameters and significant anti-tumor efficacies in the HCT116 xenograft model. Taken together, this study furnished the discovery of candidate drug compound 10 possessing a novel fused tetrahydroisoquinoline scaffold with excellent in vitro and in vivo anti-CRC activities by targeting Hsp90 to disturb Wnt/ß-catenin signaling pathway, which lay a foundation for discovering more effective CRC-targeted therapies.

Correlation of Maternal Vitamin D Status in Early Pregnancy and Vitamin D Supplementation during Pregnancy with Atopic Dermatitis in Infants: A Prospective Birth Cohort Study.

OBJECTIVE: This study aimed to investigate the association of maternal first-trimester vitamin D levels and vitamin D supplementation during pregnancy with infant atopic dermatitis (AD) and to determine the effect of variables such as mode of conception on the association. METHODS: This study was based on the Shanghai sub-cohort of the International Birth Cohort of China. A total of 4051 woman-infant pairs with singleton pregnancies were recruited. Vitamin D deficiency and insufficiency were defined as serum 25-hydroxyvitamin D concentrations of 25 and 50 nmol/L, respectively. AD in infants was assessed during the first six months using a standardized questionnaire based on the British Working Party criteria. Modified Poisson regression estimated the association between maternal vitamin D status and infant AD. RESULTS: The risk of AD in infants was higher in women with deficient 25-hydroxyvitamin D levels in the first trimester (RR: 1.77, 95% CI: 1.41-2.23). This increased risk was seen in naturally conceived pregnancies, but not in those conceived using assisted reproductive technology (ART). The incidence of AD decreased in infants of mothers who took multi-vitamin (RR: 0.79, 95% CI: 0.67-1.98) and vitamin D supplements (RR: 0.51, 95% CI: 0.37-0.71) compared to those whose mothers did not take any supplements. Maternal vitamin D deficiency had varying effects on AD risk based on passive smoking exposure and breastfeeding patterns. CONCLUSIONS: Our findings highlight the importance of monitoring and supplementing vitamin D during pregnancy, especially in specific maternal populations, to reduce the risk of AD in offspring.

Relationship Between Birth Weight and Asthma Diagnosis: A Cross-Sectional Survey Study Based on the National Survey of Children's Health in the U.S.

OBJECTIVE: To assess the association between birth weight and childhood asthma risk using data from the 2019-2020 National Survey of Children's Health database. DESIGN: Cross-sectional study. SETTING: The USA. PATIENTS: A representative cohort of American children. EXPOSURE: The exposure of this study was birth weight regardless of gestational age. Birth weight was divided into three groups: <1500 g, 1500-2500 g and >2500 g. MAIN OUTCOME MEASURES: Primary outcomes were parent-reported diagnosis of asthma. METHOD: The Rao-Scott χ2 test was used to compare the groups. The main analyses examined the association between birth weight and parent-report asthma in children using univariable and multivariable logistic models adjusting for preterm birth, age, sex, race, family poverty, health insurance, smoking, maternal age. Subgroup analysis was performed based on interaction test. RESULTS: A total of 60 172 children aged 3-17 years were enrolled in this study; of these, 5202 (~8.6%) had asthma. Children with asthma were more likely to be born preterm, with low birth weight (LBW) or very LBW (VLBW). The incidence of asthma was the highest in VLBW children at 20.9% and showed a downward trend with an increase in birth weight class, with rates of 10.7% and 8.1% in the LBW and normal birthweight groups, respectively. Children with VLBW (OR 1.97; 95% CI 1.29 to 3.01) had higher odds of developing asthma in the adjusted analysis model. However, VLBW was only shown to be a risk factor for asthma among Hispanics, black/African-Americans and children between the ages of 6 and 12 years, demonstrating racial and age disparities. CONCLUSIONS: VLBW increases the risk of childhood asthma; however, racial and age disparities are evident.

Regulating electron transportation by tungsten oxide nanocapacitors for enhanced radiation therapy.

In the process of radiation therapy (RT), the cytotoxic effects of excited electrons generated from water radiolysis tend to be underestimated due to multiple biochemical factors, particularly the recombination between electrons and hydroxyl radicals (·OH). To take better advantage of radiolytic electrons, we constructed WO3 nanocapacitors that reversibly charge and discharge electrons to regulate electron transportation and utilization. During radiolysis, WO3 nanocapacitors could contain the generated electrons that block electron-·OH recombination and contribute to the yield of ·OH at a high level. These contained electrons could be discharged from WO3 nanocapacitors after radiolysis, resulting in the consumption of cytosolic NAD+ and impairment of NAD+-dependent DNA repair. Overall, this strategy of nanocapacitor-based radiosensitization improves the radiotherapeutic effects by increasing the utilization of radiolytic electrons and ·OH, warranting further validation in multiple tumour models and preclinical experiments.

Identification of m6A-associated LncRNAs as predict factors for the immune infiltration and prognosis of thyroid cancer.

OBJECTIVE: This study aims to evaluate the prognostic value of m6A-associated long noncoding RNAs (lncRNAs) and their interaction with tumour microenvironment in thyroid cancer (THCA). METHODS: The clinical and gene expression data of tumours from 502 patients with THCA and 58 adjacent normal tissues were retrieved from The Cancer Genome Atlas (TCGA)-THCA dataset. The Pearson test was utilized to identify potential m6A-associated lncRNAs (p < 0.001 and Pearson correlation coefficient > 0.4). Quantitative real-time polymerase chain reaction was performed to verify the expression levels of lncRNAs in tissues. MTT, EdU, colony formation and wound-healing assays were performed to determine the functions of m6A-associated lncRNAs in THCA cell proliferation and metastasis. RESULTS: M6A-associated lncRNAs were identified in three cluster groups. A significant survival difference was found among them, with cluster 1 patients showing worse survival. Moreover, lower immune and estimate scores were correlated to poorer prognosis, and CD8+ T cell and memory CD4+ T cell levels were increased in cluster 1. Cluster 2, with better overall survival, had high expression of PD-L1 and CTLA-4. Eleven of the m6A-associated lncRNAs were screened to establish the risk model, including AC007365.1, AC008555.1, AC040160.1, AC064807.1, AC126773.4, AL023583.1, AL512306.2, EIF2AK3-DT, LINC00667, LYPLAL1-DT and MIR181A2HG. Based on the median risk score, THCA patients were stratified into low-risk and high-risk groups. Overall survival analysis showed a dramatic difference between the two groups. qRCR was performed to verify the expression levels of lncRNA (LYPLAL1-DT, EIF2AK3-DT and MIR181A2HG) in THCA and adjacent normal tissues. Furthermore, functional experiments showed that knockdown of MIR181A2HG obviously inhibited the proliferation and migration of papillary thyroid cancer (PTC) cells in vitro, whereas LYPLAL1-DT overexpression promoted PTC cell proliferation and migration. CONCLUSIONS: Eleven of the m6A-associated lncRNAs were identified as a risk model to predict clinical outcomes and provide a novel and efficient immunotherapeutic strategy for THCA patients.Key messagesm6A-associated lncRNAs can be used to predict the clinical outcomes of thyroid cancer patients.An m6A-associated lncRNAs risk model, which can accurately evaluate the immune status and risk stratification in individual thyroid cancer patients, was established.Knockdown/overexpression of representative lncRNAs in the risk model significantly affected the proliferation and migration of papillary thyroid cancer cells.

LIMK2 Is a Novel Prognostic Biomarker and Correlates With Tumor Immune Cell Infiltration in Lung Squamous Cell Carcinoma.

Previous research found that LIM domain kinase 2 (LIMK2) expression correlated with a poor prognosis in many cancers. However, its role in lung squamous cell carcinoma (LUSC) has not yet been clarified. Our study aimed to clarify the role of LIMK2 in LUSC prognosis prediction and explore the relationship between LIMK2 and immune infiltration in LUSC. In this study, we first analyzed the expression level and prognostic value of LIMK2 across cancers. Subsequently, we explored the association of LIMK2 expression with immune infiltrating cells and immune checkpoints. our study found that LIMK2 was highly expressed and positively associated with the overall survival of LUSC. Moreover, our study further indicated that LIMK2 expression was significantly negatively correlated with immune cell infiltration and immune checkpoints in LUSC. Finally, we confirmed upstream regulatory noncoding RNAs (ncRNAs) of LIMK2, and the PVT1 and DHRS4-AS1/miR-423-5p/LIMK2 regulatory axes were successfully constructed in LUSC. Put together, LIMK2 is a novel prognostic biomarker and correlates with tumor immune cell infiltration in LUSC, and the expression of LIMK2 is regulated by the PVT1 and DHRS4-AS1/miR-423-5p axes.

miR-1301-3p promotes the proliferation and migration of lung cancer cells via direct repression of polymerase I and transcript release factor.

Aberrant expression of microRNAs (miRNAs or miRs) is associated with a number of human diseases, including lung cancer. Although numerous differentially expressed miRNAs have been identified in lung cancer via microarray and sequencing methods, to the best of our knowledge, only a small portion of these miRNAs have been experimentally verified. In the present study, miR-1301-3p expression levels in lung tumor tissues and lung cancer cells were measured by reverse transcription-quantitative PCR (RT-qPCR) and by analyzing previously published data. Cell Counting Kit-8 and Transwell assays were used to analyze the function of miR-1301-3p in lung cancer tissues and cells. Bioinformatics analysis, RT-qPCR, western blotting and a dual-luciferase reporter assay were performed to investigate the mechanism of miR-1301-3p in lung cancer cells. It was identified that miR-1301-3p is an upregulated miRNA in lung cancer via analyzing previously published microarray and The Cancer Genome Atlas-lung squamous cell carcinoma project data, and the upregulation of miR-1301-3p was confirmed in collected clinical samples and cells. Inhibition of miR-1301-3p suppressed lung cancer cell proliferation and migration. In addition, miR-1301-3p inhibition upregulated E-cadherin, an epithelial cell maker, and downregulated vimentin, a mesenchymal cell marker. Using bioinformatics analysis, it was revealed that polymerase I and transcript release factor (PTRF) is a target of miR-1301-3p. RT-qPCR, western blotting and dual-luciferase reporter assays demonstrated that PTRF is targeted by miR-1301-3p in lung cancer cells. The rescue experiments indicated that silencing PTRF could attenuate the inhibition of cell proliferation and migration induced by miR-1301-3p inhibitor in lung cancer cells. Furthermore, a strong negative correlation between miR-1301-3p and PTRF mRNA was identified in clinical samples. In summary, the present data highlight the involvement of miR-1301-3p in the proliferation and migration of lung cancer cells, indicating that miR-1301-3p may be a promising biomarker for lung cancer.

Clinical characteristics, treatment patterns and outcomes of patients older than 80 years diagnosed with DLBCL in China over a 10-year period.

PURPOSE: The treatment strategy for elderly patients older than 80 years with DLBCL has not been defined yet because of poor treatment tolerability and lack of data. The aim of this trial was to retrospectively investigate clinical characteristics, treatment patterns and outcomes of patients older than 80 years diagnosed with DLBCL in China over a 10-year period. METHODS: This trial comprised 57 patients, aged ≥ 80 years, who were initial diagnosed as diffuse large B-cell lymphoma from 2007 to 2017. They received at least four cycles of reduced-dose R-CHOP21 (Rituximab 375 mg/m2 day 0, Cyclophosphamide 400 mg/m2 day1, Epirubicin 35 mg/m2 day 1, Vincristine 1 mg day 1, and Prednisone 50 mg/m2 days 1-5). An observational population-based, cohort study was performed. RESULTS: The median age was 82.5 years (range 80-90 years ) and the overall response rate was 73.7%. With a median 36.4-month follow-up, 2-year overall survival (OS) and 2-year progression-free survival were 74.3% and 70.9%, respectively. Using rigorous multivariate analysis, we concluded that NCCN-IPI ≥ 5 was the only predictive poor prognostic factor. CONCLUSIONS: High response rate was concluded on very elderly DLBCL patients (≥ 80 years old) with reduced-dose R-CHOP. However, the very elderly patients with NCCN-IPI score ≥ 5 would lead to poor outcome.

Rituximab plus reduced-dose cyclophosphamide, doxorubicin, vincristine and prednisone (RD R-CHOP) chemotherapy is feasible for very elderly patients (≥80 years) with B-cell lymphoma: analysis of treatment outcome.

OBJECTIVE: The aim of this trial was to evaluate the treatment outcome of reduced-dose (RD)R-CHOP treatment in very elderly patients with B-cell lymphoma. METHODS: This trial comprised 40 patients, aged ≥80 years, who were diagnosed with B-cell lymphoma and recruited at a single centre from 2007 to 2013. They received four to eight cycles of reduced-dose R-CHOP (rituximab 375 mg/m2 Day 0, cyclophosphamide 400 mg/m2 Day 1, epirubicin 35 mg/m2 Day 1, vincristine 1 mg Day 1 and prednisone 50 mg/m2 Days 1-5). The data of treatment responses and survival were collected and analysed comprehensively. RESULTS: The median age was 83 years old (range, 80-93 years old) and the median follow-up duration was 40.86 months. The overall response rate (ORR) was 87.5%. With a 40.9-month follow-up, 3-year overall survival (OS), 3-year progression free survival (PFS) and 3-year event-free survival (EFS) were 17.2, 46.5 and 39.1%, respectively. Using multivariate analysis, we concluded that age ≥85 years; LVEF ≤70%; M-CIRS score ≥6 and ECOG-PS ≥2 were predictive poor prognostic factors. CONCLUSIONS: High response rate was concluded on very elderly B-cell lymphoma patients (≥80 years old) with reduced-dose R-CHOP. However, the very elderly patients with poor performance status and more complications benefit less from treatment.

Intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for stage I-II natural killer/T-cell lymphoma nasal type: dosimetric and clinical results.

BACKGROUND: This study was to compare radiotherapy treatment planning and treatment outcomes following three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) in stage I-II natural killer (NK)/T-cell lymphoma. METHODS: The cases of 94 patients with stage I-II NK/T-cell lymphoma, nasal type in the upper aerodigestive tract who treated between May 2005 and Dec 2008 were reviewed. These patients received radiotherapy with or without induction chemotherapy. Definitive radiotherapy was conducted using 3DCRT in 47 patients and IMRT in the other 47 patients with a regional field and a total dose of 50 Gy. Dosimetric pmeters of radiation treatment plans, local control probability (LCP), overall survival (OS), and toxicities were analyzed and compared between 3DCRT and IMRT. RESULTS: From the dosimetric analysis, IMRT demonstrated significantly better dose coverage and homogeneity than 3DCRT. However, after a median follow-up of 46 months, IMRT was not associated with improvements in 4y-OS (80.9% for 3DCRT vs. 82.7% for IMRT, p=0.87) or 4y-LCP (86.3% for 3DCRT vs. 88.9% for IMR p=0.85). Of the 18 patients who received cervical lymph node irradiation, those in the IMRT group received a lower mean parotid dose. Furthermore, at-risk organs were strictly kept within the safe dose range in both groups, and no severe late toxicity was observed. CONCLUSIONS: IMRT provided better dose coverage than 3DCRT, although it failed to provide LCP and OS benefits. Definitive radiotherapy with a regional field and a total dose of 50 Gy is efficient and safe for NK/T-cell lymphoma using either IMRT or 3DCRT. However, IMRT may have the potential to reduce parotid gland hypofunction following cervical irradiation.