Predicting bladder cancer survival with high accuracy: insights from MAPK pathway-related genes.

The mitogen-activated protein kinase (MAPK) pathway plays a critical role in tumor development and immunotherapy. Nevertheless, additional research is necessary to comprehend the relationship between the MAPK pathway and the prognosis of bladder cancer (BLCA), as well as its influence on the tumor immune microenvironment. To create prognostic models, we screened ten genes associated with the MAPK pathway using COX and least absolute shrinkage and selection operator (LASSO) regression analysis. These models were validated in the Genomic Data Commons (GEO) cohort and further examined for immune infiltration, somatic mutation, and drug sensitivity characteristics. Finally, the findings were validated using The Human Protein Atlas (HPA) database and through Quantitative Real-time PCR (qRT-PCR). Patients were classified into high-risk and low-risk groups based on the prognosis-related genes of the MAPK pathway. The high-risk group had poorer overall survival than the low-risk group and showed increased immune infiltration compared to the low-risk group. Additionally, the nomograms built using the risk scores and clinical factors exhibited high accuracy in predicting the survival of BLCA patients. The prognostic profiling of MAPK pathway-associated genes represents a potent clinical prediction tool, serving as the foundation for precise clinical treatment of BLCA.

miR-449a disturbs atherosclerotic plaque stability in streptozotocin and high-fat diet-induced diabetic mice by targeting CEACAM1.

BACKGROUND: Emerging evidence indicates carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in the development of atherosclerosis (AS). However, the roles and functions of CEACAM1 in AS remain unknown. Therefore, this study aims to investigate the roles and molecular functions of CEACAM1 in AS. METHODS: We constructed a diabetes mellitus (DM) + high-fat diet (HFD) mouse model based on the streptozotocin (STZ)-induced apolipoprotein E-knockdown (ApopE-/-) mouse to investigate the roles and regulatory mechanism of miR-449a/CEACAM1 axis. The mRNA expression and protein levels in this study were examined using quantity PCR, western blot, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC), respectively. And the lipid deposition and collagen content were detected using Oil Red O and Sirius Red staining. Cell apoptosis, migration, invasion, and tuber formation were detected by Annexin-V FITC/PI, wound healing, transwell, and tuber formation assays, respectively. The relationship between miR-449a and CEACAM1 was determined by a dual-luciferase reporter gene assay. RESULTS: miR-449a and MMP-9 were upregulated, and CEACAM1 was downregulated in the DM + HFD MOUSE model. Upregulation of CEACAM1 promoted atherosclerotic plaque stability and inhibited inflammation in the DM + HFD mouse model. And miR-449a directly targeted CEACAM1. Besides, miR-449a interacted with CEACAM1 to regulate atherosclerotic plaque stability and inflammation in DM-associated AS mice. In vitro, the rescue experiments showed miR-449a interacted with CEACAM1 to affect apoptosis, migration, invasion, and tuber formation ability in high glucose (HG)-induced HUVECs. CONCLUSION: These results demonstrated that miR-449a promoted plaque instability and inflammation in DM and HFD-induced mice by targeting CEACAM1.

A 12-year follow up of principles learned in a pediatric dentistry Master of Public Health dual degree program applied to professional practice.

Introduction: Dental public health professionals play a critical role in preventing and controlling oral diseases. The purpose of this study was to assess the application of public health principles learned in a pediatric dentistry Master of Public Health (MPH) dual degree program to professional practice upon graduation. Methods: Semi-structured interviews were conducted with pediatric dentistry/MPH dual degree alumni who graduated from the program between 2012 and 2023. Interview questions inquired about characteristics of patient population, location of providers' clinic/organization, whether the program was worthwhile to their practice and application of principles learned in the program to their professional practice. Results: Twenty of the 22 program alumni agreed to be interviewed. All alumni thought the program was extremely worthwhile to their practice. They felt the MPH component of the program gave them the public health background and tools they needed to provide comprehensive and holistic care to their patients. Additionally, all alumni reported applying the public health principles they learned in the program to their professional practice through leadership roles, research and teaching that focuses on oral disease prevention and the promotion of dental health. Discussion: Given the importance of a dental public health professionals' role in reducing oral health disparities at the population level, more pediatric dentistry MPH dual degree programs are urgently needed. Additionally, more research is necessary to demonstrate the effectiveness of these programs, which will be critical to helping ensure the value of a dual degree in dentistry and public health is recognized and promoted worldwide.

Clinical prognostic value of different NPM1 mutations in acute myeloid leukemia patients.

BACKGROUND: Acute myeloid leukemia (AML) patients with various nucleophosmin 1 (NPM1) mutations are controversial in the prognosis. This study aimed to investigate the prognosis of patients according to types of NPM1 mutations (NPM1mut). METHODS: Bone marrow samples of 528 patients newly diagnosed with AML, were collected for morphology, immunology, cytogenetics, and molecular biology examinations. Gene mutations were detected by next-generation sequencing (NGS) technology. RESULTS: About 25.2% of cases exhibited NPM1mut. 83.5% of cases were type A, while type B and D were respectively account for 2.3% and 3.0%. Furthermore, 15 cases of rare types were identified, of which 2 cases have not been reported. Clinical characteristics were similar between patients with A-type NPM1 mutations (NPM1A - type mut) and non-A-type NPM1 mutations (NPM1non - A-type mut). Event-free survival (EFS) was significantly different between patients with low NPM1non - A-type mut variant allele frequency (VAF) and low NPM1A - type mut VAF (median EFS = 3.9 vs. 8.5 months, P = 0.020). The median overall survival (OS) of the NPM1non - A-type mutFLT3-ITDmut group, the NPM1A - type mutFLT3-ITDmut group, the NPM1non - A-type mutFLT3-ITDwt group, and the NPM1A - type mutFLT3-ITDwt group were 3.9, 10.7, 17.3 and 18.8 months, while the median EFS of the corresponding groups was 1.4, 5.0, 7.6 and 9.2 months (P < 0.0001 and P = 0.004, respectively). CONCLUSIONS: No significant difference was observed in OS and EFS between patients with NPM1A - type mut and NPM1non - A-type mut. However, types of NPM1 mutations and the status of FLT3-ITD mutations may jointly have an impact on the prognosis of AML patients.

Dimension-Confined Growth of a Crack-Free PbS Microplate Array for Infrared Image Sensing.

Epitaxy of semiconductors is a necessary step toward the development of electronic devices such as lasers, detectors, transistors, and solar cells. However, the lattice ordering of semiconductor functional films is inevitably disrupted by excessive concentrated stress due to the mismatch of the thermal expansion coefficient. Herein, combined with the first-principles calculation, we find that a rigid film/substrate bilayer heterostructure with a large thermal expansion mismatch upon cooling to room temperature from growth is free of surface cracks when the rigid film exhibits a dimension smaller than the critical condition for the breaking energy. The principle has been verified in a PbS/SrTiO3 bilayer system that is crack free on PbS single-crystalline microplate arrays through the designing of a dimension-confined growth (DCG) method. Interestingly, this crack-free, large-scale PbS microplate array exhibits exceptional uniformity in morphology, dimensions, thickness, and photodetection properties, enabling a broad-band infrared image sensing. This work provides a new perspective to design materials and arrays that demand smooth and continuous surfaces, which are not limited only to semiconductor electronics but also include mechanical structures, optical materials, biomedical materials, and others.

Incidence of cardiovascular mortality among head and neck cancer patients.

BACKGROUND: While treatment advancements have prolonged the lives of patients with head and neck cancer, the subgroups of these patients at higher risk for cardiovascular disease (CVD) mortality remain unclear. METHODS: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with head and neck cancer from 2000 to 2019. We compared their CVD mortality against the general US population using standardized mortality ratios (SMRs). RESULTS: Our analysis included 474,366 patients, identifying that 14% of deaths were due to CVD, with an SMR of 1.19. Notably, patients under the age of 39 had a CVD SMR increase of over 100-fold. Those with distant tumor stages showed the highest CVD SMR of 1.52 (95% CI 1.50-1.54). An upward trend in SMR to 2.53 (95% CI 2.51-2.56) was observed from 2011 to 2019. Within the initial 5-year post-diagnosis, the SMR for CVD was 3.17 (95% CI 3.14-3.20), which exceeded the general population's rates but declined in the 5-20-year range after diagnosis. Patients who did not any therapy had the greatest CVD SMR of 2.26 (95% CI 2.24-2.28). Hypopharyngeal cancer patients exhibited the highest CVD SMR of 1.54 (95% CI 1.52-1.56). CONCLUSIONS: The study highlights that head and neck cancer patients, especially younger individuals and those with advanced disease stages, face substantial CVD mortality risks. The CVD SMR peaks within 5 years following diagnosis. Patients abstaining from treatment bear the highest risk of CVD mortality. Cardioprotective measures should be considered critical for this patient population.

Aging in climate change: Unpacking residential mobility and changes of social determinants of health in southern United States.

The southern coastal states of the United States are susceptible to extreme weather and climate events. With growing move-in and -out older populations in the region, health implications of their residential mobility lack sufficient knowledge. Using 126,352 person-level records from 2012 to 2021, we examined geospatial and temporal patterns of older populations' residential mobility, considering the changing social determinants of health and disparities. We found the moves of older populations with socioeconomic or health disadvantages were related to increased exposure to environmental hazards and reduced access to health resources. The findings inform targeted strategies for climate adaptation that address the needs of vulnerable aging populations.

Shikonin and chitosan-silver nanoparticles synergize against triple-negative breast cancer through RIPK3-triggered necroptotic immunogenic cell death.

Necroptotic immunogenic cell death (ICD) can activate the human immune system to treat the metastasis and recurrence of triple-negative breast cancer (TNBC). However, developing the necroptotic inducer and precisely delivering it to the tumor site is the key issue. Herein, we reported that the combination of shikonin (SHK) and chitosan silver nanoparticles (Chi-Ag NPs) effectively induced ICD by triggering necroptosis in 4T1 cells. Moreover, to address the lack of selectivity of drugs for in vivo application, we developed an MUC1 aptamer-targeted nanocomplex (MUC1@Chi-Ag@CPB@SHK, abbreviated as MUC1@ACS) for co-delivering SHK and Chi-Ag NPs. The accumulation of MUC1@ACS NPs at the tumor site showed a 6.02-fold increase compared to the free drug. Subsequently, upon reaching the tumor site, the acid-responsive release of SHK and Chi-Ag NPs from MUC1@ACS NPs cooperatively induced necroptosis in tumor cells by upregulating the expression of RIPK3, p-RIPK3, and tetrameric MLKL, thereby effectively triggering ICD. The sequential maturation of dendritic cells (DCs) subsequently enhanced the infiltration of CD8+ and CD4+ T cells in tumors, while inhibiting regulatory T cells (Treg cells), resulting in the effective treatment of primary and distal tumor growth and the inhibition of TNBC metastasis. This work highlights the importance of nanoparticles in mediating drug interactions during necroptotic ICD.

Corrigendum: Co-treatment of chloroquine and trametinib inhibits melanoma cell proliferation and decreases immune cell infiltration.

[This corrects the article DOI: 10.3389/fonc.2022.782877.].

A New Quinazolinone Alkaloid along with Known Compounds with Seed-Germination-Promoting Activity from Rhodiola tibetica Endophytic Fungus Penicillium sp. HJT-A-6.

A new quinazolinone alkaloid named peniquinazolinone A (1), as well as eleven known compounds, 2-(2-hydroxy-3-phenylpropionamido)-N-methylbenzamide (2), viridicatin (3), viridicatol (4), (±)-cyclopeptin (5a/5b), dehydrocyclopeptin (6), cyclopenin (7), cyclopenol (8), methyl-indole-3-carboxylate (9), 2,5-dihydroxyphenyl acetate (10), methyl m-hydroxyphenylacetate (11), and conidiogenone B (12), were isolated from the endophytic Penicillium sp. HJT-A-6. The chemical structures of all the compounds were elucidated by comprehensive spectroscopic analysis, including 1D and 2D NMR and HRESIMS. The absolute configuration at C-13 of peniquinazolinone A (1) was established by applying the modified Mosher's method. Compounds 2, 3, and 7 exhibited an optimal promoting effect on the seed germination of Rhodiola tibetica at a concentration of 0.01 mg/mL, while the optimal concentration for compounds 4 and 9 to promote Rhodiola tibetica seed germination was 0.001 mg/mL. Compound 12 showed optimal seed-germination-promoting activity at a concentration of 0.1 mg/mL. Compared with the positive drug 6-benzyladenine (6-BA), compounds 2, 3, 4, 7, 9, and 12 could extend the seed germination period of Rhodiola tibetica up to the 11th day.

LINC01002 functions as a ceRNA to regulate FRMD8 by sponging miR-4324 for the development of COVID-19.

BACKGROUND: Syndrome coronavirus-2 (SARS-CoV-2) has developed various strategies to evade the antiviral impact of type I IFN. Non-structural proteins and auxiliary proteins have been extensively researched on their role in immune escape. Nevertheless, the detailed mechanisms of structural protein-induced immune evasion have not been well elucidated. METHODS: Human alveolar basal epithelial carcinoma cell line (A549) was stimulated with polyinosinic-polycytidylic acid (PIC) and independently transfected with four structural proteins expression plasmids, including nucleocapsid (N), spike (S), membrane (M) and envelope (E) proteins. By RT-qPCR and ELISA, the structural protein with the most pronounced inhibitory effects on IFN-ß induction was screened. RNA-sequencing (RNA-Seq) and two differential analysis strategies were used to obtain differentially expressed genes associated with N protein inhibition of IFN-ß induction. Based on DIANA-LncBase and StarBase databases, the interactive competitive endogenous RNA (ceRNA) network for N protein-associated genes was constructed. By combining single-cell sequencing data (GSE158055), lncRNA-miRNA-mRNA axis was further determined. Finally, RT-qPCR was utilized to illustrate the regulatory functions among components of the ceRNA axis. RESULTS: SARS-CoV-2 N protein inhibited IFN-ß induction in human alveolar epithelial cells most significantly compared with other structural proteins. RNA-Seq data analysis revealed genes related to N protein inhibiting IFNs induction. The obtained 858 differentially expressed genes formed the reliable ceRNA network. The function of LINC01002-miR-4324-FRMD8 axis in the IFN-dominated immune evasion was further demonstrated through integrating single-cell sequencing data. Moreover, we validated that N protein could reverse the effect of PIC on LINC01002, FRMD8 and miR-4324 expression, and subsequently on IFN-ß expression level. And LINC01002 could regulate the production of FRMD8 by inhibiting miR-4324. CONCLUSION: SARS-CoV-2 N protein suppressed the induction of IFN-ß by regulating LINC01002 which was as a ceRNA, sponging miR-4324 and participating in the regulation of FRMD8 mRNA. Our discovery provides new insights into early intervention therapy and drug development on SARS-CoV-2 infection.

Screening for metastasis-related genes in mouse melanoma cells through sequential tail vein injection.

Tumor metastasis, responsible for approximately 90% of cancer-associated mortality, remains poorly understood. Here in this study, we employed a melanoma lung metastasis model to screen for metastasis-related genes. By sequential tail vein injection of mouse melanoma B16F10 cells and the subsequently derived cells from lung metastasis into BALB/c mice, we successfully obtained highly metastatic B16F15 cells after five rounds of in vivo screening. RNA-sequencing analysis of B16F15 and B16F10 cells revealed a number of differentially expressed genes, some of these genes have previously been associated with tumor metastasis while others are novel discoveries. The identification of these metastasis-related genes not only improves our understanding of the metastasis mechanisms, but also provides potential diagnostic biomarkers and therapeutic targets for metastatic melanoma.

The Fabrication of a Customized Surgical Template for a Miniscrew Placement Using a Fully Digitized Process.

This report presents a clinical case involving the application of a computer-aided design and manufacturing (CAD-CAM) guide to insert miniscrew anchorage at the zygomatic alveolar ridge. A 24-year-old male adult came in with overcrowded teeth and a protruding facial profile, particularly severe overcrowding in the upper teeth and moderate overcrowding in the lower teeth. The orthodontic treatment plan involved extracting four first premolars and adding a mini-implant in the upper jaw to enhance anchorage. A miniscrew was placed in the patient's left zygomatic alveolar ridge using a guide and in the right zygomatic alveolar ridge based on experience. The use of a mini-implant guide improves the accuracy of mini-implant positioning and angulation in the infrazygomatic crest zone, reduces the risk of tooth root damage, and enhances mini-implant stability.

Impact of exposures to Heated Tobacco Products in the media and through social connections on product perceptions and use.

INTRODUCTION: Little is known about media exposures to heated tobacco products (HTPs). In this study, we examined sources of HTP exposure, including from paid and unpaid media and social connections, in relation to HTP use and use intentions. METHODS: In the fall of 2021, we conducted a cross-sectional survey among adult online panelists (aged 18-45 years) in the US and Israel, oversampling tobacco users. The current study analyzed data from participants who responded to the question about HTP awareness or use (n=2061). Multivariable linear and logistic regression analyses examined the relationship between sources of HTP exposure, HTP use, and use intentions. RESULTS: Among those aware of HTPs, both Israelis and Americans reported past-month HTP media exposure via advertisements (58.2% vs 48.0%), non-advertisement sources (49.7% vs 30.7%), and social connections (51.5% vs 33.6%), respectively. Factors associated with HTP awareness (n=677/2061; 32.9%) included media use frequency (AOR=1.13; 95% CI: 1.01-1.28) and social connections using HTPs (AOR=2.45; 95% CI: 1.92-3.15). Among those aware of HTPs, past-month HTP exposure via digital media advertisements (AOR=2.06; 95% CI: 1.09-3.91) and non-advertising promotion via radio, podcast, movie, television or theatre (AOR=2.30; 95% CI: 1.19-4.44) and websites (AOR=2.36; 95% CI: 1.32-4.21) were associated with current HTP use. Exposure to digital media advertisements (ß=0.35; 95% CI: 0.07-0.62) and non-advertising promotion via social media (ß=0.62; 95% CI: 0.34-0.91) were correlated with higher use intentions. Having social connections using HTPs was correlated with higher use (AOR=2.21; 95% CI: 1.19-4.11) and intentions (ß=0.66; 95% CI: 0.42-0.91). No significant differences were found across countries. CONCLUSIONS: Digital media (e.g. online, social media) were particularly salient correlates of HTP intentions and use. Future studies are needed that further examine media exposures to these products, as well as that examine possible regulations to limit HTP promotion via these channels.

Heated tobacco product marketing: a mixed-methods study examining exposure and perceptions among US and Israeli adults.

The marketing of heated tobacco products (HTPs), like IQOS, influences consumers' perceptions. This mixed-methods study analyzed (i) survey data (2021) of 2222 US and Israeli adults comparing perceptions of 7 IQOS attributes (design, technology, colors, customization, flavors, cost and maintenance) and 10 marketing messages (e.g. 'Go smoke-free…') across tobacco use subgroups and (ii) qualitative interviews (n = 84) regarding IQOS perceptions. In initial bivariate analyses, those never using HTPs (86.2%) reported the least overall appeal; those currently using HTPs (7.7%) reported the greatest appeal. Notably, almost all (94.8%) currently using HTPs also currently used cigarettes (82.0%) and/or e-cigarettes (64.0%). Thus, multivariable linear regression accounted for current cigarette/e-cigarette use subgroup and HTP use separately; compared to neither cigarette/e-cigarette use (62.8%), cigarette/no e-cigarette use (17.1%) and e-cigarette/no cigarette use (6.5%), those with dual use (13.5%) indicated greater overall IQOS appeal (per composite index score); current HTP use was not associated. Qualitative data indicated varied perceptions regarding advantages (e.g. harm, addiction and complexity) of IQOS versus cigarettes and e-cigarettes, and perceived target markets included young people, those looking for cigarette alternatives and females. Given the perceived target markets and particular appeal to dual cigarette/e-cigarette use groups, IQOS marketing and population impact warrant ongoing monitoring to inform regulation.

Risk of Enzyme- and Transporter-Mediated Drug Interactions With Drugs Approved by the US Food and Drug Administration in 2022: A Detailed Analysis of In Vitro and Clinical Data Available in New Drug Application Reviews.

PURPOSE: This analysis aimed to provide mechanistic understanding and clinical relevance of pharmacokinetic drug-drug interactions (DDIs) associated with drugs approved by the Food and Drug Administration in 2022. METHODS: Drug metabolism, transport, and DDI data available in New Drug Applications (NDAs) of small molecular drugs approved (n = 22) was analyzed. The mechanism and clinical magnitude of these interactions were characterized based on in vitro, in silico, and clinical data. FINDINGS: As victims, 10 drugs were identified as clinical substrates. Of these, 7 drugs were substrates of CYP3A, including the sensitive substrates daridorexant and mitapivat. As perpetrators, 3 drugs (adagrasib, lenacapavir, and vonoprazan) were clinical inhibitors of CYP enzymes, and 2 drugs (mavacamten and mitapivat) showed induction. Regarding transporter data, abrocitinib and deucravacitinib were found to be substrates of OAT3 and P-gp/BCRP, respectively, and 4 drugs (abrocitinib, adagrasib, lenacapavir, and oteseconazole) were found to inhibit P-gp and/or BCRP. As expected, all clinical DDIs with AUC changes ≥ 2-fold triggered label recommendations. Over half of DDIs with an AUC change < 2 also had label recommendations, pertaining most often to the concomitant use of drugs with a narrow therapeutic index. Overall, CYP3A played a major role in the drug disposition of the drugs approved in 2022, mediating all strong drug interactions. IMPLICATIONS: The mechanistic information obtained from studying these new therapeutics with marker compounds can be extrapolated to common concomitant medications sharing the same pharmacokinetic properties, enhancing the safe and effective administration of these products in situations of polytherapy.

Comprehensive review on lipid metabolism and RNA methylation: Biological mechanisms, perspectives and challenges.

Adipose tissue plays a crucial role in maintaining energy balance, regulating hormones, and promoting metabolic health. To address disorders related to obesity and develop effective therapies, it is essential to have a deep understanding of adipose tissue biology. In recent years, RNA methylation has emerged as a significant epigenetic modification involved in various cellular functions and metabolic pathways. Particularly in the realm of adipogenesis and lipid metabolism, extensive research is ongoing to uncover the mechanisms and functional importance of RNA methylation. Increasing evidence suggests that RNA methylation plays a regulatory role in adipocyte development, metabolism, and lipid utilization across different organs. This comprehensive review aims to provide an overview of common RNA methylation modifications, their occurrences, and regulatory mechanisms, focusing specifically on their intricate connections to fat metabolism. Additionally, we discuss the research methodologies used in studying RNA methylation and highlight relevant databases that can aid researchers in this rapidly advancing field.