Mex-3 RNA binding family member A (MEX3A)/circMPP6 complex promotes colorectal cancer progression by inhibiting autophagy.

RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.

NEIL1 drives the initiation of colorectal cancer through transcriptional regulation of COL17A1.

Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells. A NEIL1 peptide suppresses intestinal tumorigenesis in ApcMin/+ mice, and targeting NEIL1 demonstrates a synergistic suppressive effect on tumor growth when combined with a nuclear factor κB (NF-κB) inhibitor. These results suggest that combined targeting of NEIL1 and NF-κB may represent a promising strategy for CRC therapy.

Lessons from the stigma of COVID-19 survivors: A Marxist criticism appraisal.

Stigma refers to devalued stereotypes that create barriers for stigmatized individuals. During the COVID-19 pandemic, the stigmatization of survivors worsened existing inequalities and triggered mass hysteria. The paper delves into the stigmatization experienced by COVID-19 survivors and the role of Marxist criticism in analyzing this issue. The main findings from the empiricist tradition approach suggest that the perception of COVID-19 stigma is higher among those who are older, belong to ethnic minorities, lack social support, have manual occupations, and possess lower levels of education. The proposed destigmatization pathways include psychological counseling services, social support, and health education. Employing a Marxist perspective can aid in illuminating how economic practices and material conditions influence prevalent ideologies related to stigma. The stigmatization of COVID-19 survivors may be perceived as a consequence of social power inequality, although the current emphasis on individual characteristics as triggers for stigma may neglect the wider systemic forces in operation. Thus, it's crucial to establish improved social care policies to combat exploitation and oppression due to power imbalances. The ultimate objective of such an examination is to identify effective approaches to tackle and eradicate stigma regarding health-related concerns. An interdisciplinary approach integrating a pluralistic perspective would benefit investigating how social systems and individual attributes contribute to the exacerbation of social inequality and stigmatization.

Association between serum cotinine and volatile organic compounds (VOCs) in adults living with HIV, HBV, or HCV (NHANES 2005-2018).

Although people all know that nicotine in tobacco smoke is the key to cause health damage, they ignore the synergistic effect of a large number of Volatile Organic Compounds (VOCs) produced by incomplete tobacco combustion on nicotine or cotinine metabolism. Our aim is to investigate the association between serum VOCs and cotinine in smokers infected with HIV, HBV or HCV. National Health and Nutrition Examination Survey (NHANES 2005-2018) database, including 13,652 nationally representative subjects' sociodemographic characteristics and serological indicators, was used in this study. Smokers living with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) were compared to non-infected population. The correlation between VOCs and cotinine as well as the effects of VOCs on cotinine metabolism were analyzed by Spearman correlation analysis and multivariable logistic regression analysis, respectively. Among HIV, HBV, or HCV infected smokers with the largest exposure dose to tobacco, the intensity of the association between VOCs and cotinine was the strongest. The results of multivariable binary logistic regression showed that high concentrations of 1,2-Dichlorobenzene (OR:1.036, CI:1.009-1.124), Benzene (OR:1.478, CI:1.036-2.292), Carbon Tetrachloride (OR:1.576, CI:1.275-2.085) and 2,5-Dimethylfuran (OR:1.091, CI:1.030-1.157) in blood might be independent risk factors leading to the increase of serum metabolite cotinine in smokers.

Estimates of prevalence, time-trend, and association of smoking in adults living with HIV, HBV, and HCV (NHANES 1999-2018).

Although the smoking rate of human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infected people was much higher than that of the general population, smoking cessation interventions have long been ineffective. We aimed to examine the estimates of prevalence, time-trend, and association of smoking among people living with HIV, HBV, or HCV. This cohort was composed of 32,115 individuals from the NHANES database (1999-2018) and they were collected in the US. The time trend analysis of smoking and quitting rates was conducted using different years of survey follow-up and different infected groups. Multivariable logistic regression analysis was used to identify the risk factors related to smoking behavior of these infected people. Compared to non-infected smokers, infected smokers were more likely to be older (aged 30-39, OR = 9.92, CI 6.07-16.21; aged 40-49,OR = 3.51, CI 2.49-4.94), males (1.99, 1.54-2.55), lower education and economic level (1.78, 1.39-2.29; 2.05, 1.59-2.65), unemployed (1.63, 1.21-2.20), suffering depression (1.35, 1.05-1.72), and drug users (7.65, 5.04-11.59). Taken together, our study showed that these complex psychosocial characteristics and unhealthy behavioral factors might be major independent risk factors for increasing smoking rate and decreasing smoking cessation rate among these infected people.

CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1.

Abnormal regulation of centrosome components can induce chromosome instability and tumorigenesis. Centrosomal protein 63 (CEP63) is a vital member for assembling centrosome. Yet, the involvement of CEP63 in cancer pathogenesis remains unclear. Here we identify CEP63 as an important mediator for RNA-binding proteins (RBPs) to facilitate regulation on their RNA targets in colorectal cancer (CRC). We demonstrate that CEP63 protein is upregulated in a large cohort of colorectal cancer tissues and predicts poor prognosis, and USP36 is identified for stabilizing CEP63 by enhancing its K48-dependent deubiquitination. CEP63 overexpression promotes the proliferation and tumor growth of CRC cells in vitro and in vivo. Furthermore, we find that CEP63 can promote cancer stem-like cell properties by enhancing YAP1 expression through binding with and inhibiting the K63-ubiquitylation degradation of RBP FXR1 in CRC cells. Importantly, we further verify that the KH domain of FXR1 is necessary for the interaction between CEP63 and FXR1. Moreover, microtube motor proteins can form a complex with CEP63 and FXR1 to mediate the regulation of FXR1 on RNA targets. Additionally, we also confirm that CEP63 can bind and regulate multiple RBPs. In conclusion, our findings unveil an unrecognized CEP63/RBPs/RNA axis that CEP63 may perform as an adapter facilitating the formation of RBPs complex to regulate RNA progression and discover the role of CEP63 involved in signal transduction and RNA regulation, providing potential therapeutic target for CRC patients.

Case Report: Hemodynamic Instability Caused by Splenic Rupture During Video-Assisted Thoracoscopic Lobectomy.

Background: Video-assisted thoracoscopic surgery (VATS) has been widely performed for patients with lung cancer. Splenic rupture after VATS lung procedures is a very rare and serious event. Case Presentation: We reported a case with hemodynamic instability after left lower VATS lobectomy. There was no evidence of diaphragmatic injury during the surgery. Computed tomography (CT) showed spleen injury and large amount of fluid in the abdominal cavity. Emergent laparotomy was performed, and splenic rupture was diagnosed. The patient underwent splenectomy, with two lacerations at the diaphragmatic surface of the spleen. The patient did well postoperatively and was discharged from the hospital on postoperative day 5. Conclusion: There are few similar cases reported in the literature. Persistent hemodynamic instability due to the rupture of spleen is life-threatening. In the situation of unexplained hypotension during VATS procedures (especially left-sided approaches), the possibility of splenic injury and rupture should be considered. Abdominal ultrasonography and/or CT examinations should be carried out for prompt diagnosis and treatment of such rare complication.

KLF16 enhances stress tolerance of colorectal carcinomas by modulating nucleolar homeostasis and translational reprogramming.

Translational reprogramming is part of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, which acts to the advantage of cancer growth and development in different stress conditions, but the mechanism of ER stress-related translational reprogramming in colorectal carcinoma (CRC) progression remains unclear. Here, we identified that Krüppel-like factor 16 (KLF16) can promote CRC progression and stress tolerance through translational reprogramming. The expression of KLF16 was upregulated in CRC tissues and associated with poor prognosis for CRC patients. We found that ER stress inducers can recruit KLF16 to the nucleolus and increase its interaction with two essential proteins for nucleolar homeostasis: nucleophosmin1 (NPM1) and fibrillarin (FBL). Moreover, knockdown of KLF16 can dysregulate nucleolar homeostasis in CRC cells. Translation-reporter system and polysome profiling assays further showed that KLF16 can effectively promote cap-independent translation of ATF4, which can enhance ER-phagy and the proliferation of CRC cells. Overall, our study unveils a previously unrecognized role for KLF16 as an ER stress regulator through mediating translational reprogramming to enhance the stress tolerance of CRC cells and provides a potential therapeutic vulnerability.

TBX20 inhibits colorectal cancer tumorigenesis by impairing NHEJ-mediated DNA repair.

DNA high methylation is one of driving force for colorectal carcinoma (CRC) pathogenesis. Transcription factors (TFs) can determine cell fate and play fundamental roles in multistep process of tumorigenesis. Dysregulation of DNA methylation of TFs should be vital for the progression of CRC. Here, we demonstrated that TBX20, a T-box TF family protein, was downregulated with hypermethylation of promoter in early-stage CRC tissues and correlated with a poor prognosis for CRC patients. Moreover, we identified PDZRN3 as the E3 ubiquitin ligase of TBX20 protein, which mediated the ubiquitination and degradation of TBX20. Furthermore, we revealed that TBX20 suppressed cell proliferation and tumor growth through impairing non-homologous DNA end joining (NHEJ)-mediated double-stranded break repair by binding the middle domain of both Ku70 and Ku80 and therefore inhibiting their recruitment on chromatin in CRC cells. Altogether, our results reveal the tumor-suppressive role of TBX20 by inhibiting NHEJ-mediated DNA repair in CRC cells, and provide a potential biomarker for predicting the prognosis of patients with early-stage CRC and a therapeutic target for combination therapy.

Impact of mature tertiary lymphoid structures on prognosis and therapeutic response of Epstein-Barr virus-associated gastric cancer patients.

Background: Epstein-Barr virus-associated gastric cancer (EBVaGC) exhibits unique histological characteristics within the immune-cell-rich microenvironment, but the role of tertiary lymphoid structure (TLS) in EBVaGC is not yet fully understood. Methods: We retrospectively identified EBVaGC from 8517 consecutive GC cases from the two top cancer centers in China. Furthermore, we evaluated the prognostic value of TLS in 148 EBVaGC patients from our institute and then validated it in an external cohort (76 patients). TLS was quantified and its relationships with overall survival (OS) and therapeutic response were further analyzed. Multiplex immunofluorescence staining and targeted sequencing were used to characterize the composition of TLS and the genomic landscape, respectively. Results: In our study, EBVaGC was observed in 4.3% (190/4436) and 2.6% (109/4081) of GCs in the training and validation cohorts, respectively. TLS was identified in the intratumor (94.6%) and peritumor (77.0%) tissues with lymphoid aggregates, primary and secondary (i.e., mature TLSs) follicles in EBVaGC. Kaplan-Meier analysis showed that mature TLS in intratumoral tissues was associated with a favorable OS in the training and validation cohorts (p < 0.0001; p = 0.0108). Multivariate analyses demonstrated that intratumoral TLS maturation, pTNM, and PD-L1 expression were independent prognostic factors for OS (p < 0.05). Furthermore, the mature TLS was significantly associated with a good response to treatment in EBVaGC patients. Interestingly, the mutation frequency of SMARCA4 was significantly lower in the mature TLS groups. Conclusions: Intratumoral mature TLS was associated with a favorable prognosis and good therapeutic response, suggesting that it is a potential prognostic biomarker and predicts a good therapeutic response in EBVaGC patients.

PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair.

Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.

[Effect of Characteristic Variable Extraction on Accuracy of Cu in Navel Orange Peel by LIBS].

Heavy metals pollution in foodstuffs is more and more serious. It is impossible to satisfy the modern agricultural development by conventional chemical analysis. Laser induced breakdown spectroscopy (LIBS) is an emerging technology with the characteristic of rapid and nondestructive detection. But LIBS' s repeatability, sensitivity and accuracy has much room to improve. In this work, heavy metal Cu in Gannan Navel Orange which is the Jiangxi specialty fruit will be predicted by LIBS. Firstly, the navel orange samples were contaminated in our lab. The spectra of samples were collected by irradiating the peel by optimized LIBS parameters. The laser energy was set as 20 mJ, delay time of Spectral Data Gathering was set as 1.2 micros, the integration time of Spectral data gathering was set as 2 ms. The real concentration in samples was obtained by AAS (atom absorption spectroscopy). The characteristic variables Cu I 324.7 and Cu I 327.4 were extracted. And the calibration model was constructed between LIBS spectra and real concentration about Cu. The results show that relative error of the predicted concentrations of three relational model were 7.01% or less, reached a minimum of 0.02%, 0.01% and 0.02% respectively. The average relative errors were 2.33%, 3.10% and 26.3%. Tests showed that different characteristic variables decided different accuracy. It is very important to choose suitable characteristic variable. At the same time, this work is helpful to explore the distribution of heavy metals between pulp and peel.

[Determination of soluble solids content in navel oranges by Vis/NIR diffuse transmission spectra combined with CARS method].

Soluble solids content (SSC) is one of important internal quality index for navel oranges. In the present study, visible/near infrared (Vis/NIR) diffuse transmission spectra of navel oranges were acquired using a QualitySpec spectrometer in the wavelength range of 350-1 000 nm, and CARS (competitive adaptive reweighted sampling) was used to select important variables related with SSC of navel oranges from spectra data, then was compared with other variable selection methods such as uninformative variables elimination (UVE) and successive projections algorithm (SPA). Finally, partial least squares (PLS) regression was used to develop calibration model for SSC of navel oranges using the 38 selected variables, and the calibration model was used to predict the SSC of 75 samples in the prediction set. The results indicate that CARS method is superior to other variable selection methods such as UVE and SPA, and can select the important variables for SSC efficiently. The calibration model of SSC developed by CARS-PLS is superior to that model developed by full-spectrum PLS, the correlation coefficient (r) and root mean square error (RMSE) in the calibration and prediction sets are 0.948, 0.347% and 0.917, 0.394%, respectively. So, Vis/NIR diffuse transmission spectra combined with CARS method is feasible to assess soluble solids content of navel oranges, and CARS method can simplify the prediction model and improve model prediction precision.

Adherence to quality indicators and survival in patients with breast cancer.

BACKGROUND: International initiatives increasingly advocate physician adherence to clinical protocols that have been shown to improve outcomes, yet the process-outcome relationship for adhering to breast cancer care protocol is unknown. OBJECTIVE: This study explores whether 100% adherence to a set of quality indicators applied to individuals with breast cancer is associated with better survival. RESEARCH DESIGN AND SUBJECTS: Ten quality indicators (4 diagnosis-related and 6 treatment-related indicators) were used to measure the quality of care in 1378 breast cancer patients treated from 1995 to 2001. Adherence to each indicator was based on the number of procedures performed divided by the number of patients eligible for that procedure. The main analysis of adherence was dichotomous (ie, 100% adherence vs. <100% adherence). MEASURES: The outcome measures studied were 5-year overall survival and progression-free survival, calculated using the Kaplan-Meier method. The Cox's proportional hazard regression model was used for univariate and multivariate analyses. RESULTS: Most patients received care that demonstrated good adherence to the quality indicators. Multivariate analysis revealed that 100% adherence to entire set of quality indicators was significantly associated with better overall survival [hazard ratio (HR): 0.46; 95% confidence interval (CI): 0.33-0.63] and progression-free survival (HR 0.51; 95% CI, 0.39-0.67). One hundred percent adherence to treatment indicators alone was also associated with statistically significant improvements in overall and progression-free survivals. CONCLUSIONS: Our study strongly supports that 100% adherence to evidence supported quality-of-care indicators is associated with better survival rates for breast cancer patients and should be a priority for practitioners.