Deciphering extracellular vesicles protein cargo in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) presents a significant therapeutic challenge as it is frequently diagnosed at advanced inoperable stages. Therefore, the development of a reliable screening tool for PDAC is crucial for effective prevention and treatment. Extracellular vesicles (EVs), characterized by their cup-shaped lipid bilayer structure and ubiquitous release from various cell types, offer notable advantages as an emerging liquid biopsy technique that is rapid, minimally invasive, easily sampled, and cost-effective. While EVs play a substantial role in cancer progression, EV proteins serve as direct mediators of diverse cellular behaviors and have immense potential as biomarkers for PDAC diagnosis and prognostication. This review provides an overview of EV proteins regarding PDAC diagnosis and prognostic implications as well as disease progression.

Inhibition of DEF-p65 Interactions as a Potential Avenue to Suppress Tumor Growth in Pancreatic Cancer.

The limited success of current targeted therapies for pancreatic cancer underscores an urgent demand for novel treatment modalities. The challenge in mitigating this malignancy can be attributed to the digestive organ expansion factor (DEF), a pivotal yet underexplored factor in pancreatic tumorigenesis. The study uses a blend of in vitro and in vivo approaches, complemented by the theoretical analyses, to propose DEF as a promising anti-tumor target. Analysis of clinical samples reveals that high expression of DEF is correlated with diminished survival in pancreatic cancer patients. Crucially, the depletion of DEF significantly impedes tumor growth. The study further discovers that DEF binds to p65, shielding it from degradation mediated by the ubiquitin-proteasome pathway in cancer cells. Based on these findings and computational approaches, the study formulates a DEF-mimicking peptide, peptide-031, designed to disrupt the DEF-p65 interaction. The effectiveness of peptide-031 in inhibiting tumor proliferation has been demonstrated both in vitro and in vivo. This study unveils the oncogenic role of DEF while highlighting its prognostic value and therapeutic potential in pancreatic cancer. In addition, peptide-031 is a promising therapeutic agent with potent anti-tumor effects.

Interplay Between Systemic Inflammation, Myocardial Injury, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis: Results From the LiiRA Study.

BACKGROUND: Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk. METHODS AND RESULTS: Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples at baseline and 24 weeks were measured for inflammatory markers (eg, high-sensitivity C-reactive protein [hsCRP], interleukin-1b, and high-sensitivity cardiac troponin T [hs-cTnT]). The primary outcome was mean MFR before and after tumor necrosis factor inhibitor initiation, with Δhs-cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs-cTnT. We studied 66 subjects, 82% of which were women, mean RA duration 7.4 years. The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction and 23% had detectable hs-cTnT. We observed no change in mean MFR before (2.65) and after treatment (2.64, P=0.6) or hs-cTnT. A correlation was observed between a reduction in hsCRP and interleukin-1b with a reduction in hs-cTnT. CONCLUSIONS: In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin-1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02714881.

Nanoparticle-integrated dissolving microneedles for the co-delivery of R848/aPD-1 to synergistically reverse the immunosuppressive microenvironment of triple-negative breast cancer.

Nowadays, effective immunotherapy against triple-negative breast cancer (TNBC) remains challenging due to the immunosuppressive tumor microenvironment. Immune checkpoint inhibitor is mostly employed to restore the activity of tumor-specific immune cells, which however brings little therapeutic outcome owing to the limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue. Aiming to solve these problems, we herein constructed a tailor-made dissolving microneedle co-encapsulating the TLR7/8 agonist R848 and the immune checkpoint inhibitor aPD-1, termed αNP-RNP@DMN, and fabricated it as a transdermal drug delivery system. This well-designed microneedle patch, endowed with efficient tumor drug delivery ability, was able to mature tumor-infiltrating dendritic cells (TIDCs) and further promote the infiltration of CD8+ T cells into the tumor tissue with the aid of R848. Moreover, the introduction of aPD-1 blocked the programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1) immune checkpoints, synergistically reversing the immunosuppressive microenvironment of TNBC. In vivo therapeutic results demonstrated that αNP-RNP@DMN not only significantly prolonged the survival time of 4T1 tumor-bearing mice, but also inhibited tumor recurrence and lung metastasis after surgery, implying the great potential of this effective drug delivery system for enhanced immunotherapy of superficial tumors. STATEMENT OF SIGNIFICANCE: The limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue hinder the effective immunotherapy of triple-negative breast cancer (TNBC). Herein, a dissolving microneedle co-encapsulating TLR7/8 agonist R848 and immune checkpoint inhibitor aPD-1 was developed and fabricated as a transdermal drug delivery system. This tailor-made microneedle patch not only promoted drug accumulation in tumor sites in a safe and painless manner, but also lifted the immune-suppressive state of tumor-infiltrating dendritic cells (TIDCs). The activated TIDCs further enhanced T-cell infiltration into the tumor tissue, thus successfully boosting the therapeutic efficacy of aPD-1. This study demonstrated that this well-designed microneedle patch could be served as an effective drug delivery system for enhanced immunotherapy of TNBC.

Automatic epicardial adipose tissue segmentation in pulmonary computed tomography venography using nnU-Net.

Background: Epicardial adipose tissue (EAT) is a key aspect in the investigation of cardiac pathophysiology. We sought to develop a deep learning (DL) model for fully automatic extraction and quantification of EAT through pulmonary computed tomography venography (PCTV) images. Methods: In this retrospective study, we included 128 patients with atrial fibrillation and PCTV from 2 hospitals. A DL model for automated EAT segmentation was developed from a training set of 51 patients and a validation set of 13 patients from hospital A. The algorithm was further validated using an internal test set of 16 patients from hospital A and an external test set of 48 patients from hospital B. The consistency and measurement agreement of EAT quantification were compared between the DL model and the conventional manual protocol using the Dice score coefficient (DSC), Hausdorff distance (HD95), Pearson correlation coefficient, and Bland-Altman plot. Results: In the internal and external test set, automated segmentation with DL was successful in all cases. The total analysis time was shorter for DL than for manual reconstruction (5.43±2.52 vs. 106.20±15.90 min; P<0.001). The EAT segmented with the DL model had good consistency with manual segmentation (the DSC of the internal and external test sets were 0.92±0.02 and 0.88±0.03, respectively). The quantification of EAT evaluated with the 2 methods showed excellent correlation (all correlation coefficients >0.9; all P values <0.001) and minimal measurement difference. Conclusions: The proposed DL model achieved fully automatic quantification of EAT from PCTV images. The yielded results were highly consistent with those of manual quantification.

Construction of pH-Sensitive Nanovaccines Encapsulating Tumor Cell Lysates and Immune Adjuvants for Breast Cancer Therapy.

The current immunotherapy strategies for triple negative breast cancer (TNBC) are greatly limited due to the immunosuppressive tumor microenvironment (TME). Immunization with cancer vaccines composed of tumor cell lysates (TCL) can induce an effective antitumor immune response. However, this approach also has the disadvantages of inefficient antigen delivery to the tumor tissues and the limited immune response elicited by single-antigen vaccines. To overcome these limitations, a pH-sensitive nanocalcium carbonate (CaCO3 ) carrier loaded with TCL and immune adjuvant CpG (CpG oligodeoxynucleotide 1826) is herein constructed for TNBC immunotherapy. This tailor-made nanovaccine, termed CaCO3 @TCL/CpG, not only neutralizes the acidic TME through the consumption of lactate by CaCO3 , which increases the proportion of the M1/M2 macrophages and promotes infiltration of effector immune cells but also activates the dendritic cells in the tumor tissues and recruits cytotoxic T cells to further kill the tumor cells. In vivo fluorescence imaging study shows that the pegylated nanovaccine could stay longer in the blood circulation and extravasate preferentially into tumor site. Besides, the nanovaccine exhibits high cytotoxicity in 4T1 cells and significantly inhibits tumor growth of tumor-bearing mice. Overall, this pH-sensitive nanovaccine is a promising nanoplatform for enhanced immunotherapy of TNBC.

Identifying shared genetic architecture between rheumatoid arthritis and other conditions: a phenome-wide association study with genetic risk scores.

BACKGROUND: Rheumatoid arthritis (RA) shares genetic variants with other autoimmune conditions, but existing studies test the association between RA variants with a pre-defined set of phenotypes. The objective of this study was to perform a large-scale, systemic screen to determine phenotypes that share genetic architecture with RA to inform our understanding of shared pathways. METHODS: In the UK Biobank (UKB), we constructed RA genetic risk scores (GRS) incorporating human leukocyte antigen (HLA) and non-HLA risk alleles. Phenotypes were defined using groupings of International Classification of Diseases (ICD) codes. Patients with an RA code were excluded to mitigate the possibility of associations being driven by the diagnosis or management of RA. We performed a phenome-wide association study, testing the association between the RA GRS with phenotypes using multivariate generalized estimating equations that adjusted for age, sex, and first five principal components. Statistical significance was defined using Bonferroni correction. Results were replicated in an independent cohort and replicated phenotypes were validated using medical record review of patients. FINDINGS: We studied n = 316,166 subjects from UKB without evidence of RA and screened for association between the RA GRS and n = 1317 phenotypes. In the UKB, 20 phenotypes were significantly associated with the RA GRS, of which 13 (65%) were immune mediated conditions including polymyalgia rheumatica, granulomatosis with polyangiitis (GPA), type 1 diabetes, and multiple sclerosis. We further identified a novel association in Celiac disease where the HLA and non-HLA alleles had strong associations in opposite directions. Strikingly, we observed that the non-HLA GRS was exclusively associated with greater risk of the validated conditions, suggesting shared underlying pathways outside the HLA region. INTERPRETATION: This study replicated and identified novel autoimmune phenotypes verified by medical record review that share immune pathways with RA and may inform opportunities for shared treatment targets, as well as risk assessment for conditions with a paucity of genomic data, such as GPA. FUNDING: This research was funded by the US National Institutes of Health (P30AR072577, R21AR078339, R35GM142879, T32AR007530) and the Harold and DuVal Bowen Fund.

The Zinc Transporter SLC39A10 Plays an Essential Role in Embryonic Hematopoiesis.

The role of zinc in hematopoiesis is currently unclear. Here, SLC39A10 (ZIP10) is identified as a key zinc transporter in hematopoiesis. The results show that in zebrafish, Slc39a10 is a key regulator of the response to zinc deficiency. Surprisingly, both slc39a10 mutant zebrafish and hematopoietic Slc39a10-deficient mice develop a more severe form of impaired hematopoiesis than animals lacking transferrin receptor 1, a well-characterized iron gatekeeper, indicating that zinc plays a larger role than iron in hematopoiesis, at least in early hematopoietic stem cells (HSCs). Furthermore, it is shown that loss of Slc39a10 causes zinc deficiency in fetal HSCs, which in turn leads to DNA damage, apoptosis, and G1 cell cycle arrest. Notably, zinc supplementation largely restores colony formation in HSCs derived from hematopoietic Slc39a10-deficient mice. In addition, inhibiting necroptosis partially restores hematopoiesis in mouse HSCs, providing mechanistic insights into the requirement for zinc in mediating hematopoiesis. Together, these findings indicate that SLC39A10 safeguards hematopoiesis by protecting against zinc deficiency-induced necroptosis, thus providing compelling evidence that SLC39A10 and zinc homeostasis promote the development of fetal HSCs. Moreover, these results suggest that SLC39A10 may serve as a novel therapeutic target for treating anemia and zinc deficiency-related disorders.

Poor Prognostic Biomarker KIAA1522 Is Associated with Immune Infiltrates in Hepatocellular Carcinoma.

Background: The prognosis is poor for hepatocellular carcinoma (HCC), a tumor and cancer associated with inflammation that is common. New data showed that significant levels of KIAA1522 were expressed in HCC tissues and cell lines, suggesting that KIAA1522 may be a highly useful prognostic marker for HCC. However, its biochemical processes and impacts on the immune system go deeper. Objective: To verify the significance of KIAA1522 in HCC and investigate its related carcinogenic mechanisms. Methods: Studies examining the relationship between KIAA1522 expression and clinical-pathologic characteristics in HCC have been checked in the Cancer Genome Atlas (TCGA) database. A receiver operating characteristic (ROC) curve was used to assess the diagnostic efficacy of KIAA1522 in HCC. Western blot analysis was used to find the presence of the KIAA1522 protein in the tumor and paraneoplastic tissues of eight randomly chosen HCC patients. The GSVA program in R language was used to evaluate the relationship between KIAA1522 and immune cell infiltration in HCC. We searched the Search Tool for the Retrieval of Interacting Genes (STRING) database for interacting proteins connected to the expression of KIAA1522. Pathways were involved in the enrichment analysis of KIAA1522 to anticipate potential mechanisms through which KIAA1522 may affect immunological infiltration. Results: Our study found that KIAA1522 was commonly elevated in HCC tumor tissues and that it also signaled a bad outcome. We found an inverse link between KIAA1522 and cytotoxic cells and an inverse relationship between KIAA1522 and Th2 cell infiltration. In STRING analysis, the top 5 coexpressed proteins of KIAA1522 were BAIAP2, NCK2, TSNAXIP1, POGK, and KLHL31. The effect of KIAA1522 on HCC may entail cell cycle alteration, an immunological response, and suppression of the PPAR signaling pathway. Conclusion: High expression of KIAA1522 was linked to HCC immune cell infiltration, disease progression, and a poor prognosis.

Identification of Diagnostic Markers in Infantile Hemangiomas.

Background: Infantile Hemangiomas (IHs) are common benign vascular tumors of infancy that may have serious consequences. The research on diagnostic markers for IHs is scarce. Methods: The "limma" R package was applied to identify differentially expressed genes (DEGs) in developing IHs. Plugin ClueGO in Cytoscape software performed functional enrichment of DEGs. The Search Tool for Retrieving Interacting Genes (STRING) database was utilized to construct the PPI network. The least absolute shrinkage and selection operator (LASSO) regression model and support vector machine recursive feature elimination (SVM-RFE) analysis were used to identify diagnostic genes for IHs. The receiver operating characteristic (ROC) curve evaluated diagnostic genes' discriminatory ability. Single-gene based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was conducted by Gene Set Enrichment Analysis (GSEA). The chemicals related to the diagnostic genes were excavated by the Comparative Toxicogenomics Database (CTD). Finally, the online website Network Analyst was used to predict the transcription factors targeting the diagnostic genes. Results: A total of 205 DEGs were singled out from IHs samples of 6-, 12-, and 24-month-old infants. These genes principally participated in vasculogenesis and development-related, endothelial cell-related biological processes. Then we mined 127 interacting proteins and created a network with 127 nodes and 251 edges. Furthermore, LASSO and SVM-RRF algorithms identified five diagnostic genes, namely, TMEM2, GUCY1A2, ISL1, WARS, and STEAP4. ROC curve analysis results indicated that the diagnostic genes had a powerful ability to distinguish IHs samples from normal samples. Next, the results of GSEA for a single gene illustrated that all five diagnostic genes inhibited the "valine, leucine, and isoleucine degradation" pathway in the development of IHs. WARS, TMEM2, and STEAP4 activated the "blood vessel development" and "vasculature development" in IHs. Subsequently, inhibitors targeting TMEM2, GUCY1A2, ISL1, and STEAP4 were mined. Finally, 14 transcription factors regulating GUCY1A2, 14 transcription factors regulating STEAP4, and 26 transcription factors regulating ISL1 were predicted. Conclusion: This study identified five diagnostic markers for IHs and further explored the mechanisms and targeting drugs, providing a basis for diagnosing and treating IHs.

Downregulation of MCF2L Promoted the Ferroptosis of Hepatocellular Carcinoma Cells through PI3K/mTOR Pathway in a RhoA/Rac1 Dependent Manner.

Methods and Results: The levels of MCF2L were detected by PCR and western blotting assay. The effect of MCF2L on ferroptosis was confirmed by MTT, colony formation assay, Brdu, in vivo animal experiment, and the content of Iron, GSH, ROS, and MDA. The underlying mechanisms were explored by PCR, western blotting, and affinity precipitation assay. Our findings demonstrated that MCF2L is remarkedly upregulated in HCC tissues, and sorafenib can induce the levels of MCF2L, suggesting that MCF2L might function in sorafenib resistance of HCC. Further analysis showed that downregulation of MCF2L enhances HCC cell death induced by sorafenib, and ferroptosis inhibitor can reverse this process. Subsequent experiments showed that downregulation of MCF2L elevates the content of Iron, ROS, and MDA, which are all indicators of ferroptosis. Finally, mechanism analysis showed that MCF2L regulates the PI3K/AKT pathway in a RhoA/Rac1 dependent manner. Conclusions: Our study showed that targeting MCF2L may be a hopeful method to overcome sorafenib-resistance through inducing ferroptosis in HCC.

Nanodrugs Incorporating LDHA siRNA Inhibit M2-like Polarization of TAMs and Amplify Autophagy to Assist Oxaliplatin Chemotherapy against Colorectal Cancer.

Oxaliplatin (OXA) is a first-line chemotherapeutic agent for treating colorectal cancer (CC). However, the chemotherapeutic effect of OXA on CC is limited by the M2-like polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) and protective autophagy of tumor cells. Here, a cationic polymer APEG-PAsp(PEI) (PAPEI) was prepared to deliver small-interfering RNA (siRNA) to silence the lactate dehydrogenase A (LDHA) gene (LDHA-siRNA) to enhance the chemotherapeutic effect of OXA on CC. The PAPEI/LDHA-siRNA nanocomplex effectively silenced the LDHA gene to inhibit the secretion of lactic acid from tumor cells, resulting in inhibition of the M2-like polarization of TAMs. In addition, the nanocomplex also amplified OXA-induced autophagy and transformed protective autophagy into autophagic death. Consequently, the combination treatment of OXA and PAPEI/LDHA-siRNA showed a dramatically increased chemotherapeutic effect on CC compared with the OXA-alone treatment, which also suggested its attractive potential for treating CC-like immune "cold" tumors.

Relationship Between Rheumatoid Arthritis and Pulmonary Function Measures on Spirometry in the UK Biobank.

OBJECTIVE: To investigate the independent relationship of rheumatoid arthritis (RA) to the type and severity of pulmonary patterns on spirometry compared to the pulmonary patterns in general population controls. METHODS: In this cross-sectional study, we investigated the association of RA with pulmonary function measures on spirometry among subjects in the UK Biobank who underwent spirometry for research purposes. RA cases were identified based on self-report and current disease-modifying antirheumatic drug/glucocorticoid use. Controls were subjects without RA from the general population. Outcome measures included continuous forced expiratory volume in 1 second percent predicted (FEV1 %) and forced vital capacity percent predicted (FVC%), type of spirometric pattern (restrictive or obstructive), and severity of the restrictive or obstructive pattern. We used multivariable regression to estimate the effects in RA cases compared to the effects in controls, adjusting for age, sex, body mass index, and smoking status/pack-years. RESULTS: Among 350,776 analyzed subjects who underwent spirometry (mean age 56.3 years; 55.8% female; 45.5% ever smokers), we identified 2,008 cases of treated RA. In multivariable analyses, RA was associated with lower FEV1 % (ß = -2.93 [95% confidence interval (95% CI) -3.63, -2.24]), FVC% (ß = -2.08 [95% CI -2.72, -1.45]), and FEV1 /FVC (ß = -0.008 [95% CI -0.010, -0.005]) compared to controls. RA was additionally associated with restrictive patterns (odds ratio [OR] 1.36 [95% CI 1.21, 1.52]) and obstructive patterns (OR 1.21 [95% CI 1.07, 1.37]) independent of confounders, and was most strongly associated with severe restrictive and obstructive patterns. CONCLUSION: RA is associated with increased odds of restrictive and obstructive patterns, and this relationship is not explained by confounders, including smoking status. In addition to restrictive lung disease, clinicians should also be aware that airway obstruction may be a pulmonary manifestation of RA.

Long noncoding RNA GAS8-AS1: A novel biomarker in human diseases.

Long non-coding RNAs (lncRNAs) represent a group of ncRNAs with more than 200 nucleotides. These RNAs can specifically regulate gene expression at both the transcriptional and the post-transcriptional levels, and increasing evidence indicates that they play vital roles in a variety of disease-related cellular processes. The lncRNA GAS8 antisense RNA 1 (GAS8-AS1, also known as C16orf3) is located in the second intron of GAS8 and has been reported to be both abnormally expressed in several diseases and closely correlated with many clinical characteristics. GAS8-AS1 has been shown to affect many biological functions, including cell proliferation, migration, invasiveness, and autophagy using several signaling pathways. In this review, we have summarized current studies on GAS8-AS1 roles in disease and discuss its potential clinical utility. GAS8-AS1 may be a promising biomarker for both diagnoses and prognoses, and a novel target for many disease therapies.

Admission Homocysteine as a Potential Predictor for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is a primary cause of poor prognosis after aneurysmal subarachnoid hemorrhage (aSAH) and needs close medical attention in clinical practice. Homocysteine (Hcy) has been implicated in cerebrovascular diseases. This study aimed to investigate whether serum Hcy could help to predict the occurrence of DCI in aSAH patients, and compare its diagnostic value with traditional methods. METHODS: We enrolled 241 aSAH patients in this study. Serum Hcy levels were collected from each patient. The baseline information was reviewed and analyzed. The binary logistic regression was used to explore the relation of serum Hcy levels with occurrence of DCI, and diagnostic performance of serum Hcy for predicting DCI was evaluated using a receiver operating characteristic (ROC) curve. RESULTS: The admission serum Hcy levels were found significantly higher in aSAH patients with DCI than those without (P < 0.001). The serum Hcy levels were positively correlated with the World Federation of Neurosurgical Societies (WFNS) scores, modified Fisher scores as well as Hunt and Hess scores at admission. Multivariate analysis revealed that occurrence of DCI was associated with serum Hcy levels (Odds Ratio [OR] = 1.257; 95% Confidence Interval [CI], 1.133-1.396, P < 0.001), modified Fisher scores (OR = 1.871; 95%CI, 1.111-3.150, P = 0.018) and Hunt and Hess scores (OR = 2.581; 95%CI, 1.222-5.452, P = 0.013) after adjusting for the significant variables in univariate analysis. Meanwhile, serum Hcy levels achieved good performance for DCI prediction (area under the curve [AUC], 0.781; 95%CI, 0.723-0.831, P < 0.001). CONCLUSION: Serum homocysteine might have the potential to be a useful and cost-effective biomarker for predicting the occurrence of DCI in aSAH patients.

Lifestyle and Clinical Risk Factors for Incident Rheumatoid Arthritis-associated Interstitial Lung Disease.

OBJECTIVE: To determine the association between novel lifestyle factors on risk of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), define the threshold at which smoking increases RA-ILD risk, and calculate the degree to which known lifestyle and clinical factors predict RA-ILD. METHODS: This nested case-control study matched incident RA-ILD cases to RA non-ILD controls on age, sex, RA duration, rheumatoid factor, and time from exposure assessment to RA-ILD. Exposures included education, BMI, smoking, anticyclic citrullinated peptide antibodies, race, joint erosions, rheumatoid nodules, C-reactive protein (CRP), disease activity score, functional status, disease-modifying antirheumatic drug use, and glucocorticoid use. OR for each exposure on risk of RA-ILD were obtained from logistic regression models. Area under the curve (AUC) was calculated based on all lifestyle and clinical exposures. RESULTS: We identified 84 incident RA-ILD cases and 233 matched controls. After adjustment, obesity, high-positive CRP (≥ 10 mg/L), and poor functional status (multidimensional Health Assessment Questionnaire [MDHAQ] ≥ 1) were associated with increased risk of RA-ILD (OR 2.42, 95% CI 1.11-5.24 vs normal BMI; OR 2.61, 95% CI 1.21-5.64 vs CRP < 3 mg/L; OR 3.10, 95% CI 1.32-7.26 vs MDHAQ < 0.2). Smoking 30 pack-years or more was strongly associated with risk of RA-ILD compared to never smokers (OR 6.06, 95% CI 2.72-13.5). Together, lifestyle and clinical risk factors for RA-ILD had an AUC of 0.79 (95% CI 0.73-0.85). CONCLUSION: Obesity, CRP, functional status, and extensive smoking may be novel risk factors for RA-ILD that may be useful for RA-ILD risk assessment and prevention. The overall ability to predict RA-ILD remains modest.

Identification of Immune Cell Infiltration and Immune-Related Genes in the Tumor Microenvironment of Glioblastomas.

Glioblastoma (GBM) is one of the most prevalent malignant brain tumors with poor prognosis. Increasing evidence has revealed that infiltrating immune cells and other stromal components in the tumor microenvironment (TME) are associated with prognosis of GBM. The aim of the present study was to identify immune cells and immune-related genes extracted from TME in GBM. RNA-sequencing and clinical data of GBM were downloaded from The Cancer Genome Atlas (TCGA). Four survival-related immune cells were identified via Kaplan-Meier survival analysis and immune-related differentially expressed genes (DEGs) screened. Functional enrichment and protein-protein interaction (PPI) networks for the genes were constructed. In addition, we identified 24 hub genes and the expressions of 6 of the genes were significantly associated with prognosis of GBM. Finally, the genes were validated in single-cell sequencing studies of GBM, and the immune cells validated in an independent GBM cohort from the Chinese Glioma Genome Atlas (CGGA). Overall, 24 immune-related genes infiltrating the tumor microenvironment were identified in the present study, which could serve as novel biomarkers and immune therapeutic targets.

Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis.

RATIONALE: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. OBJECTIVE: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. METHODS AND RESULTS: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. CONCLUSIONS: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.

Dysregulated NF-κB signal promotes the hub gene PCLAF expression to facilitate nasopharyngeal carcinoma proliferation and metastasis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is common in Southern China. The molecular mechanism underlying NPC genesis and progression has been comprehensively investigated, but the key gene (s) or pathway (s) pertaining to NPC are unidentified. METHODS: We explored some key genes and pathways involved in NPC through using meta-analysis of deposited expression of microarray data of NPC. The expression of proliferating cell nuclear antigen clamp associated factor (PCLAF) was determined by real-time PCR and western blots. CCK-8 assay, colony formation assay, transwell migration assay, cell wound healing assay, cell cycle analysis and cell apoptosis were carried out to assess biological behaviors caused by downregulation and overexpression of PCLAF in vitro. CHIP was utilized to determine the direct upstream regulatory transcription factors of PCLAF. RESULTS: PCLAF was the key gene of NPC, which was significantly up-regulated in NPC cell line compared to the normal nasopharyngeal cell line. Additionally, in vitro assay has demonstrated the down-regulation and overexpression of PCLAF, resulted in significantly suppressed and enhanced NPC proliferation, metastasis and invasion respectively. Furthermore, the up-regulation of PCLAF in NPC is induced by direct binding of dysregulated NF-κB p50/RelB complex to the promoter of PCLAF. CONCLUSION: Our results offer a strategy for re-using the deposited data to find the key genes and pathways involved in pathogenesis of cancer. Our study has provided evidence of supporting the role of PCLAF in NPC genesis and progression.

Is high tibial osteotomy better than proximal fibula osteotomy for treating knee osteoarthritis? A protocol for a systematic review and meta-analysis of clinical controlled trials.

BACKGROUND: Knee osteoarthritis (KOA) is a common disease in the elderly, which seriously reduces the quality of life of patients and increases the social burden. proximal fibula osteotomy (PFO) and high tibial osteotomy (HTO) are effective methods to treat KOA. However, it is not entirely clear which method has the advantage. Therefore, we evaluated the efficacy and safety of HTO and PFO in the treatment of KOA. METHODS: Randomized controlled trials from online databases including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Data and Chinese Biomedical Literature Database that compared the efficacy of HTO and PFO in the treatment of KOA were retrieved. The main outcomes included hospital for special surgery (HSS) knee scores, knee society knee scoring system (KSS) score, visual analog scale (VAS) knee pain scores, western ontario and McMaster universities osteoarthritis index score, operation time, intraoperative bleeding volume, hospitalization time, complications. The Cochrane risk of bias tool was used to assess methodological quality. RESULTS: The literature will provide a high-quality analysis of the current evidence supporting HTO for KOA based on various comprehensive assessments including HSS scores, KSS score, VAS scores, western Ontario and McMaster universities osteoarthritis index score, operation time, intraoperative bleeding volume, hospitalization time, and complications. CONCLUSION: This proposed systematic review will provide up-to-date evidence to assess the effect of HTO in the treatment for patients with KOA.