Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis).

ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is frequently mutated in various cancer types and has emerged as a potential therapeutic target. In this study, we observed that ARID1A-deficient colorectal cancer (CRC) cells showed synthetic lethal effects with a p53 activator, RITA (reactivating p53 and inducing tumor apoptosis). RITA, an inhibitor of the p53-MDM2 interaction, exhibits increased sensitivity in ARID1A-deficient cells compared to ARID1A wild-type cells. Mechanistically, the observed synthetic lethality is dependent on both p53 activation and DNA damage accumulation, which are regulated by the interplay between ARID1A and RITA. ARID1A loss exhibits an opposing effect on p53 targets, leading to decreased p21 expression and increased levels of proapoptotic genes, PUMA and NOXA, which is further potentiated by RITA treatment, ultimately inducing cell apoptosis. Meanwhile, ARID1A loss aggravates RITA-induced DNA damage accumulation by downregulating Chk2 phosphorylation. Taken together, ARID1A loss significantly heightens sensitivity to RITA in CRC, revealing a novel synthetic lethal interaction between ARID1A and RITA. These findings present a promising therapeutic approach for colorectal cancer characterized by ARID1A loss-of-function mutations.

Effects of parenting style on depressive symptoms, anxiety symptoms, and their comorbidity during the COVID-19 pandemic lockdown among 3117 Chinese junior high school students.

INTRODUCTION: Depressive symptoms, anxiety symptoms, and comorbidity increased in junior high school students due to the outbreak of COVID-19. The objective of this study was to measure the impacts of parenting style on depressive symptoms, anxiety symptoms, and their comorbidity in Chinese junior high school students during the COVID-19 pandemic lockdown period. METHODS: An online survey was conducted in June 2020 among 3117 junior high school students from Shandong Province, China. The Egna Minnen av Barndoms Uppfostran scale was used to measure parenting styles. The 9-item Patient Health Questionnaire scale and the 7-item Generalized Anxiety Disorder scale were used to measure depressive symptoms and anxiety symptoms, respectively. Multinomial logistic regression was conducted with SPSS 25.0 Version. RESULTS: 3117 junior school students enrolled in this study. The prevalence of depressive symptoms only, anxiety symptoms only, and comorbidity among junior high school students was 11.55 %, 5.29 %, and 22.97 %. Paternal over-protection was a risk factor not only for depressive symptoms only (OR = 1.075, 95 % CI = 1.020-1.134) but for anxiety symptoms only (OR = 1.090, 95 % CI = 1.016-1.170) and comorbidity (OR = 1.098, 95 % CI = 1.050-1.148). Paternal over-interference was a protective factor for depressive symptoms only (OR = 0.947, 95 % CI = 0.908-0.987) and comorbidity (OR = 0.953, 95 % CI = 0.921-0.986). However, maternal over-interference and over-protection were risk factors for depressive symptoms only (OR = 1.039, 95 % CI = 1.011-1.068). LIMITATIONS: This was a cross-sectional study and the causal inferences could not be conducted. CONCLUSIONS: Junior high school students with poorer family environmental factors were more likely to suffer from the comorbidity of anxiety symptoms and depressive symptoms during the COVID-19 pandemic lockdown. Decision-makers from the government, educational, and healthcare institutions should pay more attention to junior high school students at higher risk of mental disorders due to poor parenting styles. We should discuss family interventions in the future to prevent mental disorders in junior high school students.

Fully 3D-printed soft robots with integrated fluidic circuitry.

The emergence of soft robots has presented new challenges associated with controlling the underlying fluidics of such systems. Here, we introduce a strategy for additively manufacturing unified soft robots comprising fully integrated fluidic circuitry in a single print run via PolyJet three-dimensional (3D) printing. We explore the efficacy of this approach for soft robots designed to leverage novel 3D fluidic circuit elements-e.g., fluidic diodes, "normally closed" transistors, and "normally open" transistors with geometrically tunable pressure-gain functionalities-to operate in response to fluidic analogs of conventional electronic signals, including constant-flow ["direct current (DC)"], "alternating current (AC)"-inspired, and preprogrammed aperiodic ("variable current") input conditions. By enabling fully integrated soft robotic entities (composed of soft actuators, fluidic circuitry, and body features) to be rapidly disseminated, modified on demand, and 3D-printed in a single run, the presented design and additive manufacturing strategy offers unique promise to catalyze new classes of soft robots.

Effect of layer-distributed carbon nanotube (CNT) on mechanical and piezoresistive performance of intelligent cement-based sensor.

Agglomerated carbon nanotube (CNT) powder was scattered into a cement paste layer-by-layer to form layer-distributed CNT composite (LDCC) as intelligent cement-based sensor. The characteristic of the CNT agglomerations and its effect on the mechanical and piezoresistive properties of cement paste were investigated in this study, and the results were compared with those of uniformly-dispersed CNT composites (UDCC). Based on the statistics of CNT agglomerations, it was found that the sizes of agglomerations varied from several to dozens of micrometres. The larger sized agglomerations with poorer roundness exhibited a higher possibility to cause the pores or voids accompanied with stress concentration when subjected to external forces. Hence, it is necessary to control the agglomeration sizes to reduce the porosity with edges and corners. The UDCC reached the highest compressive strength, followed by the plain cement paste and then LDCC. The mechanical strength of LDCC decreased with the increase of CNT layers. The piezoresistivity occurred in both the UDCC and LDCC, with the former possessing stable and repeatable performance. In addition, the strain-sensing ability of LDCC with moderate CNT layers presented similar sensing efficiency and repeatability to that of UDCC. The related results provide insight into the intelligent cement-based sensors with layer-distributed CNT and agglomerations, which can improve the efficiency and effectively reduce the cost for practical application.

Progression of Thyroid Carcinoma Is Promoted by the m6A Methyltransferase METTL3 Through Regulating m6A Methylation on TCF1.

OBJECTIVE: This study aims to uncover the progression of thyroid carcinoma influenced by the m6A methyltransferase METTL3 through regulating m6A methylation on TCF1 mRNA and the activated Wnt pathway. METHODS: Thyroid carcinoma tissues and paracancerous ones were collected for detecting levels of METTL3 and TCF1. Potential correlation between levels of METTL3 and TCF1 was analyzed by Pearson analysis. Survival of thyroid carcinoma patients influenced by METTL3 level was assessed by Kaplan-Meier method. Regulatory effect of METTL3 on migratory ability in TPC-1 cells was examined by wound healing assay. The interaction between METTL3 with TCF1 and IGF2BP2 was verified by RNA-Binding Protein Immunoprecipitation (RIP) assay. Meanwhile, the activity of the Wnt pathway was reflected by TOP/FOP-Flash. At last, rescue experiments were conducted to clarify the involvement of TCF1 in phenotype changes of thyroid carcinoma cells that were regulated by METTL3. RESULTS: METTL3 and TCF1 were upregulated in thyroid carcinoma. Similarly, METTL3 was highly expressed in thyroid carcinoma cells as well. Kaplan-Meier method uncovered poor prognosis in thyroid carcinoma patients expressing a high level of METTL3. Silence of METTL3 inhibited migratory ability and Wnt activity in TPC-1 cells. RIP assay confirmed the interaction between TCF1 and METTL3 or IGF2BP2. Moreover, METTL3 positively regulated the enrichment abundance of TCF1 in anti-IGF2BP2. Rescue experiments demonstrated that TCF1 was responsible for METTL3-regulated thyroid carcinoma progression via the m6A methylation. CONCLUSION: Upregulated m6A methyltransferase METTL3 promotes the progression of thyroid carcinoma through m6A methylation on TCF1.

Degradation of Axial Ultimate Load-Bearing Capacity of Circular Thin-Walled Concrete-Filled Steel Tubular Stub Columns after Corrosion.

This work aimed to investigate the effects of steel tube corrosion on the axial ultimate load-bearing capacity (AULC) of circular thin-walled concrete-filled steel tubular (CFST) members. Circular thin-walled CFST stub column specimens were made of steel tubes with various wall-thicknesses. These CFST column specimens were subjected to an accelerated corrosion test, where the steel tubes were corroded to different degrees of corrosion. Then, these CFST specimens with corroded steel tubes experienced an axial static loading test. Results show that the failure patterns of circular thin-walled CFST stub columns with corroded steel tubes are different from those of the counterpart CFST columns with ordinary wall-thickness steel tubes, which is a typical failure mode of shear bulging with slight local outward buckling. The ultimate strength and plastic deformation capacity of the CFST specimens decreased with the increasing degree of steel corrosion. The failure modes of the specimens still belonged to ductile failure because of the confinement of outer steel tube. The degree of steel tube corrosion, diameter-to-thickness ratio, and confinement coefficient had substantial influences on the AULC and the ultimate compressive strength of circular thin-walled CFST stub columns. A simple AULC prediction model for corroded circular thin-walled CFST stub columns was presented through the regression of the experimental data and parameter analysis.

Therapeutic inhibition of SGK1 suppresses colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of death worldwide. Thus, the development of new therapeutic targets for CRC treatment is urgently needed. SGK1 is involved in various cellular activities, and its dysregulation can result in multiple cancers. However, little is known about its roles and associated molecular mechanisms in CRC. In present study, we found that SGK1 was highly expressed in tumor tissues compared with peri-tumor samples from CRC patients. In vitro experiments revealed that SGK1 overexpression promoted colonic tumor cell proliferation and migration and inhibited cell apoptosis induced by 5-fluorouracil (5-FU), while SGK1 shRNA and inhibitors showed the inverse effects. Using CRC xenograft mice models, we demonstrated that knockdown or therapeutic inhibition of SGK1 repressed tumor cell proliferation and tumor growth. Moreover, SGK1 inhibitors increased p27 expression and promoted p27 nuclear accumulation in colorectal cancer cells, and p27 siRNAs could attenuate the repression of CRC cell proliferation induced by SGK1 inhibitors. Collectively, SGK1 promotes colorectal cancer development via regulation of CRC cell proliferation, migration and survival. Inhibition of SGK1 represents a novel strategy for the treatment of CRC.

Development of a new analog of SGK1 inhibitor and its evaluation as a therapeutic molecule of colorectal cancer.

Colorectal cancer (CRC) is one of the most leading causes of cancer-related death worldwide. The serum and glucocorticoid inducible kinase SGK1 is highly expressed and involved in several tumors. GSK650394, a SGK1 inhibitor, has been proved to be effective in impeding tumor growth in vitro. In this study, we developed a novel analog of GSK650394, and evaluated its effects on CRC cells and tumor growth both in vitro and in vivo. HCT116 cells were treated with a concentration gradient of new developed compounds and cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 value of every analog. Cell proliferation analysis was estimated from EdU staining and flow cytometry in vitro, and immunohistochemistry of Ki67 and PCNA in vivo. Cell migration analysis was examined using the transwell assay. In vivo tumor growth was determined in athymic nude mice by injecting the HCT116 cells in the subcutaneous tissue, followed by the injection of QGY-5-114-A. We found that new developed GSK650394 analog QGY-5-114-A has lower IC50 value, and treatment with QGY-5-114-A significantly inhibited CRC cell proliferation and migration in vitro. Besides that, colonic tumor growth was also dramatically restricted by QGY-5-114-A in vivo. In conclusion, pharmacological treatment with QGY-5-114-A impedes CRC tumor cell proliferation, migration and tumor growth.

Chemoradiotherapy is superior to radiotherapy alone after surgery in advanced squamous cell carcinoma of the head and neck: a systematic review and meta-analysis.

BACKGROUND: To conduct a comprehensive review whether chemotherapy to radiotherapy after surgical resection could improve the loco regional control and survival compared with postoperative radiotherapy alone. METHODS: A comprehensive search of PubMed for relevant studies comparing patients with advanced squamous cell carcinoma of the head and neck undergoing chemoradiotherapy or radiotherapy alone after resection was conducted. RESULTS: The meta-analysis demonstrated significant benefits from adding chemotherapy to radiotherapy in local-regional control, disease-free survival and overall survival (p < 0.00001). The adverse effects include hematological and non-hematological toxicities. Although the acute and late toxicities occurred more frequently and severely in chemoradiation combined treatment, there was no significant difference compared with radiotherapy alone, but the estimated pooled RR of mucositis or dysphagia was 1.69 (p < 0.00001) in favor of radiotherapy regimens. CONCLUSIONS: Postoperative chemotherapy adding to radiotherapy is superior to radiotherapy alone. Patients with chemoradiotherapy after surgical resection can achieve the higher LRC, longer DFS and OS.