Interplay between lncRNA RP11-367G18.1 variant 2 and YY1 plays a vital role in hypoxia-mediated gene expression and tumorigenesis.

BACKGROUND: The hypoxia-responsive long non-coding RNA, RP11-367G18.1, has recently been reported to induce histone 4 lysine 16 acetylation (H4K16Ac) through its variant 2; however, the underlying molecular mechanism remains poorly understood. METHODS: RNA pull-down assay and liquid chromatography-tandem mass spectrometry were performed to identify RP11-367G18.1 variant 2-binding partner. The molecular events were examined utilizing western blot analysis, real-time PCR, luciferase reporter assay, chromatin immunoprecipitation, and chromatin isolation by RNA purification assays. The migration, invasion, soft agar colony formation, and in vivo xenograft experiments were conducted to evaluate the impact of RP11-367G18.1 variant 2-YY1 complex on tumor progression. RESULTS: In this study, RNA sequencing data revealed that hypoxia and RP11-367G18.1 variant 2 co-regulated genes were enriched in tumor-related pathways. YY1 was identified as an RP11-367G18.1 variant 2-binding partner that activates the H4K16Ac mark. YY1 was upregulated under hypoxic conditions and served as a target gene for hypoxia-inducible factor-1α. RP11-367G18.1 variant 2 colocalized with YY1 and H4K16Ac in the nucleus under hypoxic conditions. Head and neck cancer tissues had higher levels of RP11-367G18.1 and YY1 which were associated with poor patient outcomes. RP11-367G18.1 variant 2-YY1 complex contributes to hypoxia-induced epithelial-mesenchymal transition, cell migration, invasion, and tumorigenicity. YY1 regulated hypoxia-induced genes dependent on RP11-367G18.1 variant 2. CONCLUSIONS: RP11-367G18.1 variant 2-YY1 complex mediates the tumor-promoting effects of hypoxia, suggesting that this complex can be targeted as a novel therapeutic strategy for cancer treatment.

Immunogenic cell death in cancer immunotherapy.

Cancer immunotherapy has been acknowledged as a new paradigm for cancer treatment, with notable therapeutic effects on certain cancer types. Despite their significant potential, clinical studies over the past decade have revealed that cancer immunotherapy has low response rates in the majority of solid tumors. One of the key causes for poor responses is known to be the relatively low immunogenicity of solid tumors. Because most solid tumors are immune desert 'cold tumors' with antitumor immunity blocked from the onset of innate immunity, combination therapies that combine validated T-based therapies with approaches that can increase tumor-immunogenicity are being considered as relevant therapeutic options. This review paper focuses on immunogenic cell death (ICD) as a way of enhancing immunogenicity in tumor tissues. We will thoroughly review how ICDs such as necroptosis, pyroptosis, and ferroptosis can improve anti-tumor immunity and outline clinical trials targeting ICD. Finally, we will discuss the potential of ICD inducers. as an adjuvant for cancer immunotherapy.[BMB Reports 2023; 56(5): 275-286].

T-cell exhaustion and stemness in antitumor immunity: Characteristics, mechanisms, and implications.

T cells play a crucial role in the regulation of immune response and are integral to the efficacy of cancer immunotherapy. Because immunotherapy has emerged as a promising treatment for cancer, increasing attention has been focused on the differentiation and function of T cells in immune response. In this review, we describe the research progress on T-cell exhaustion and stemness in the field of cancer immunotherapy and summarize advances in potential strategies to intervene and treat chronic infection and cancer by reversing T-cell exhaustion and maintaining and increasing T-cell stemness. Moreover, we discuss therapeutic strategies to overcome T-cell immunodeficiency in the tumor microenvironment and promote continuous breakthroughs in the anticancer activity of T cells.

An undefined cystatin CsCPI1 from tea plant Camellia sinensis harbors antithrombotic activity.

Tea consumption has been linked to a decreased risk of cardiovascular disease (CVD) mortality, which imposes a heavy burden on the healthcare system; however, which components in tea cause this beneficial effect is not fully understood. Here we uncovered a cystatin (namely CsCPI1), which is a cysteine proteinase inhibitor (CPI) of the tea plant (Camellia sinensis) that promotes antithrombotic activity. Since thrombosis is a common pathogenesis of fatal CVDs, we investigated the effects of CsCPI1, which showed good therapeutic effects in mouse models of thrombotic disease and ischemic stroke. CsCPI1 significantly increases endothelial cell production of nitric oxide (NO) and inhibits platelet aggregation. Notably, CsCPI1 exhibited no cytotoxicity or resistance to pH and temperature changes, which indicates that CsCPI1 might be a potent antithrombotic agent that contributes to the therapeutic effects of tea consumption against CVD. Specifically, the antithrombotic effects of CsCPI1 are distinct from the classical function of plant cystatins against herbivorous insects. Therefore, our study proposes a new potential role of cystatins in CVD prevention and treatment, which requires further study.

Molecular actions of exosomes and their theragnostics in colorectal cancer: current findings and limitations.

Extracellular vesicles (EVs) are cell-released, membranous structures essential for intercellular communication. The biochemical compositions and physiological impacts of exosomes, lipid-bound, endosomal origin EVs, have been focused on, especially on the tumor-host interactions in a defined tumor microenvironment (TME). Despite recent progress in targeted therapy and cancer immunotherapy in colorectal cancer (CRC), cancer patients still suffer from distal metastasis and tumor relapse, suggesting unmet needs for biomarkers directing therapeutic interventions and predicting treatment responsiveness. As exosomes are indispensable for intercellular communication and high exosome abundance makes them feasible biomarker molecules, this review discusses exosome heterogeneity and how exosomes orchestrate the interplay among tumor cells, cancer stem cells (CSCs) and host cells, including stromal cells, endothelial cells and immunocytes, in the CRC TME. This review also discusses mechanisms for loading exosomal contents and potential exosomal DNA, RNA and protein biomarkers for early CRC detection. Finally, we summarize the diagnostic and therapeutic exosomes in clinical trials. We envision that detecting and targeting cancer-specific exosomes could provide therapeutic advances in developing personalized cancer medicine.

Macrophages Are a Double-Edged Sword: Molecular Crosstalk between Tumor-Associated Macrophages and Cancer Stem Cells.

Cancer stem cells (CSCs) are a subset of highly tumorigenic cells in tumors. They have enhanced self-renewal properties, are usually chemo-radioresistant, and can promote tumor recurrence and metastasis. They can recruit macrophages into the tumor microenvironment and differentiate them into tumor-associated macrophages (TAMs). TAMs maintain CSC stemness and construct niches that are favorable for CSC survival. However, how CSCs and TAMs interact is not completely understood. An understanding on these mechanisms can provide additional targeting strategies for eliminating CSCs. In this review, we comprehensively summarize the reported mechanisms of crosstalk between CSCs and TAMs and update the related signaling pathways involved in tumor progression. In addition, we discuss potential therapies targeting CSC-TAM interaction, including targeting macrophage recruitment and polarization by CSCs and inhibiting the TAM-induced promotion of CSC stemness. This review also provides the perspective on the major challenge for developing potential therapeutic strategies to overcome CSC-TAM crosstalk.

Alanine-Glyoxylate Aminotransferase Sustains Cancer Stemness Properties through the Upregulation of SOX2 and OCT4 in Hepatocellular Carcinoma Cells.

Liver cancer stem cells (LCSCs) are a small subset of oncogenic cells with a self-renewal ability and drug resistance, and they promote the recurrence and metastasis of hepatocellular carcinoma (HCC). However, the mechanisms regulating LCSCs have not been fully explored. By enriching LCSCs from spheroid cultures and performing transcriptomic analysis, we determined that alanine-glyoxylate aminotransferase (AGXT), which participates in the metabolism of serine and glycine, was significantly upregulated in spheroid cultures, and its function in LCSCs remains unknown. Through the exogenous overexpression or short hairpin RNA knockdown of AGXT in HCC cells, we observed that changes in the AGXT level did not affect the spheroid ability and population of LCSCs. The knockdown of AGXT in LCSCs reduced the number of spheroids and the population of LCSCs; this implies that AGXT is required for the maintenance of cancer stemness rather than as a driver of LCSCs. Mechanistically, AGXT may sustain the self-renewal potential of LCSCs by upregulating the expression of SRY-box transcription factor 2 (SOX2) and octamer-binding transcription factor 4 (OCT4), two well-known master regulators of cancer stemness. Taken together, our study demonstrates the role of AGXT in supporting LCSCs; thus, AGXT merits further exploration.

Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer.

Expression of the receptor tyrosine kinase ephrin receptor A10 (EphA10), which is undetectable in most normal tissues except for the male testis, has been shown to correlate with tumor progression and poor prognosis in several malignancies, including triple-negative breast cancer (TNBC). Therefore, EphA10 could be a potential therapeutic target, likely with minimal adverse effects. However, no effective clinical drugs against EphA10 are currently available. Here, we report high expression levels of EphA10 in tumor regions of breast, lung, and ovarian cancers as well as in immunosuppressive myeloid cells in the tumor microenvironment. Furthermore, we developed anti-EphA10 monoclonal antibodies (mAbs) that specifically recognize cell surface EphA10, but not other EphA family isoforms, and target tumor regions precisely in vivo with no apparent accumulation in other organs. In syngeneic TNBC mouse models, we found that anti-EphA10 mAb clone #4 enhanced tumor regression, therapeutic response rate, and T cell-mediated antitumor immunity. Notably, the chimeric antigen receptor T cells derived from clone #4 significantly inhibited TNBC cell viability in vitro and tumor growth in vivo. Together, our findings suggest that targeting EphA10 via EphA10 mAbs and EphA10-specific chimeric antigen receptor-T cell therapy may represent a promising strategy for patients with EphA10-positive tumors.

Nomogram to predict 3-month unfavorable outcome after thrombectomy for stroke.

BACKGROUND: Mechanical thrombectomy (MT) is an effective treatment for large-vessel occlusion in acute ischemic stroke, however, only some revascularized patients have a good prognosis. For stroke patients undergoing MT, predicting the risk of unfavorable outcomes and adjusting the treatment strategies accordingly can greatly improve prognosis. Therefore, we aimed to develop and validate a nomogram that can predict 3-month unfavorable outcomes for individual stroke patient treated with MT. METHODS: We analyzed 258 patients with acute ischemic stroke who underwent MT from January 2018 to February 2021. The primary outcome was a 3-month unfavorable outcome, assessed using the modified Rankin Scale (mRS), 3-6. A nomogram was generated based on a multivariable logistic model. We used the area under the receiver-operating characteristic curve to evaluate the discriminative performance and used the calibration curve and Spiegelhalter's Z-test to assess the calibration performance of the risk prediction model. RESULTS: In our visual nomogram, gender (odds ratio [OR], 3.40; 95%CI, 1.54-7.54), collateral circulation (OR, 0.46; 95%CI, 0.28-0.76), postoperative mTICI (OR, 0.06; 95%CI, 0.01-0.50), stroke-associated pneumonia (OR, 5.76; 95%CI, 2.79-11.87), preoperative Na (OR, 0.82; 95%CI, 0.72-0.92) and creatinine (OR, 1.02; 95%CI, 1.01-1.03) remained independent predictors of 3-month unfavorable outcomes in stroke patients treated with MT. The area under the nomogram curve was 0.8791 with good calibration performance (P = 0.873 for the Spiegelhalter's Z-test). CONCLUSIONS: A novel nomogram consisting of gender, collateral circulation, postoperative mTICI, stroke-associated pneumonia, preoperative Na and creatinine can predict the 3-month unfavorable outcomes in stroke patients treated with MT.

Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (Mpro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 Mpro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.

Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics.

Antagonistic antibodies targeting the inhibitory immune-checkpoint receptor PD-1 or its ligand PD-L1 are used to treat a wide range of cancer types and can substantially improve patient survival. Nevertheless, strategies to overcome intrinsic and acquired resistance are required to respectively increase response rates and durations. PD-L1 is often upregulated in various malignancies, and emerging evidence suggests numerous underlying mechanisms involving distinct oncogenic signalling pathways. Thus, specific small-molecule inhibitors have the potential to simultaneously suppress not only a key oncogenic signalling pathway but also PD-L1 expression and/or activity in particular cancers, thereby presenting attractive candidate drugs for combination with existing immune-checkpoint inhibitors and/or other targeted agents. Herein, we summarize advances in understanding the mechanisms regulating PD-L1 expression at the transcriptional, post-transcriptional, translational and post-translational levels in cancers. We describe the roles of the diverse post-translational modifications of PD-L1, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination. Moreover, we discuss the potential use of small-molecule agents to modulate these mechanisms as well as of predictive biomarkers to stratify patients for optimal treatment, and provide our perspective on potential therapeutic strategies to circumvent resistance to conventional anti-PD-1/PD-L1 antibodies.

Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges.

Cancer immunotherapies, including immune checkpoint inhibitors and immune pathway-targeted therapies, are promising clinical strategies for treating cancer. However, drug resistance and adverse reactions remain the main challenges for immunotherapy management. The future direction of immunotherapy is mainly to reduce side effects and improve the treatment response rate by finding new targets and new methods of combination therapy. Ubiquitination plays a crucial role in regulating the degradation of immune checkpoints and the activation of immune-related pathways. Some drugs that target E3 ubiquitin ligases have exhibited beneficial effects in preclinical and clinical antitumor treatments. In this review, we discuss mechanisms through which E3 ligases regulate tumor immune checkpoints and immune-related pathways as well as the opportunities and challenges for integrating E3 ligases targeting drugs into cancer immunotherapy.

ATXN7L3B promotes hepatocellular carcinoma stemness and is downregulated by metformin.

Hepatocellular carcinoma (HCC) is the major cause of liver cancer-associated morality. Metformin, used for treating type 2 diabetes, has antitumor activity and reduces the risk of some diabetes-related tumors, such as liver and breast cancer. However, the mechanisms underlying metformin's effects in HCC remain unclear. To identify genes associated with metformin treatment in HCC, we conducted transcriptomic and proteomic analyses in HCC cells treated with or without metformin. We identified 41 differentially expressed genes upon metformin treatment. Among them, Ataxin 7 Like 3B (ATXN7L3B), which is a negative regulator of the Spt-Ada-Gcn5 acetyltransferase (SAGA) deubiquitinase (DUB) module and has relatively unknown functions in cancer, attracted our attention. We observed that metformin reduced ATXN7L3B level in HCC cells. ATXN7L3B expression was significantly negatively correlated with survival in liver cancer patients. We also demonstrated that ATXN7L3B promoted HCC stemness. Metformin treatment decreased ATXN7L3B-induced tumor-initiating ability in a HCC mouse model, implying that metformin may inhibit cancer stemness by downregulating ATXN7L3B. Our study supports the antitumor activity of metformin and its potential as an anticancer drug for HCC treatment.

Using esophagus organoid to explore the role of c-Myc in esophageal cancer initiation.

C-Myc gene is aberrantly highly expressed and participates in cancer initiation and development in various malignant tumors including esophageal cancer, while the underlying mechanism(s) still remains unclear. In order to explore the role of c-Myc in the occurrence of esophageal cancer, we successfully established the esophageal organoids (EOs) as the research model. By constructing a lentivirus overexpressing c-Myc and developing more effective infection method, EOs with stable overexpression of c-Myc were efficiently obtained. The morphologies of EOs with or without overexpressing c-Myc were first analyzed with ImageJ, which showed no difference between two groups during continuous subculture. Subsequently, we applied immunofluorescence and CCK8 assays to evaluate the cell proliferation, and the results showed no change in the c-Myc-overexpressed group as compared to control EOs. Furthermore, qPCR was used to detect the expression of genes that are related to cell cycle, cell metabolism as well as esophageal cancer. The results indicated the expression of these genes was not significantly increased in the c-Myc overexpressing EOs. In conclude, we discovered that overexpression of c-Myc gene alone in the esophagus organoid is not sufficient to induce carcinogenesis in esophageal carcinoma. In this study, we successfully established an esophagus organoid culture system and together with efficient lentivirus-infection method for investigation on the effects of overexpressing c-Myc in esophageal cancer. Our work demonstrated a promising research model for the study of esophagus development and esophageal cancer.

miR­29b suppresses proliferation and induces apoptosis of hepatocellular carcinoma ascites H22 cells via regulating TGF­ß1 and p53 signaling pathway.

MicroRNA (miR)­29b is a key tumor regulator. It can inhibit tumor cell proliferation, induce apoptosis, suppress tumor invasion and migration, thus delaying tumor progression. Our previous studies revealed an increased level of miR­29b in hepatoma 22 (H22) cells in ascites tumor­bearing mice. The present study investigated the effect of miR­29b on proliferation and apoptosis of hepatocellular carcinoma ascites H22 cells and its association with the transforming growth factor­ß1 (TGF­ß1) signaling pathway and p53­mediated apoptotic pathway. Briefly, H22 cells were transfected with miR­29b­3p (hereinafter referred to as miR­29b) mimic or miR­29b inhibitor. MTS cell proliferation assay and flow cytometry were used to analyze cell viability and apoptosis. The expression change of the TGF­ß1 signaling pathway and p53­mediated apoptotic pathway were detected by reverse transcription­quantitative PCR, western blotting and immunofluorescence. Furthermore, cells were treated with exogenous TGF­ß1 and TGF­ß1 small interfering RNA to evaluate the crosstalk between TGF­ß1 and p53 under miR­29b regulation. The overexpression of miR­29b decreased cell viability, increased cell apoptosis, activated the TGF­ß1 signaling pathway and p53­mediated apoptotic pathway. Conversely, these effects were reversed by the miR­29b inhibitor. Moreover, the effect of miR­29b mimic was further increased after treating cells with exogenous TGF­ß1. The activation of the TGF­ß1 signaling pathway and p53­mediated apoptotic pathway induced by miR­29b overexpression were reversed by TGF­ß1 inhibition. In summary, these data indicated that miR­29b has an important role in proliferation and apoptosis of H22 cells by regulating the TGF­ß1 signaling pathway, the p53­dependent apoptotic pathway, and the crosstalk between TGF­ß1 and p53.

Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation.

Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis.

Adherence to the Dietary Approaches to Stop Hypertension Diet and Hyperuricemia: A Cross-Sectional Study.

OBJECTIVE: Although several individual nutrients/foods are associated with uric acid status, the association of overall diet quality with hyperuricemia remains unclear. The current study was undertaken to examine the association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and the odds of having hyperuricemia in a Chinese adult population. METHODS: Included were 71,893 Chinese participants in the Kailuan I study and the Kailuan II study (mean age 51.4 years) who were free of gout prior to or in 2014. Dietary intakes were assessed using a validated food frequency questionnaire, and the DASH diet score was calculated based on consumptions of vegetables, fruit, dairy, beans, whole grains, meat, fat, sodium, and sugar-sweetened beverages. Fasting blood samples were collected in 2014, and hyperuricemia was defined as serum uric acid concentrations of ≥7 mg/dl for men, and of ≥6 mg/dl for women. The association between DASH diet score and hyperuricemia was assessed using multiple logistic regression models, adjusting for age, sex, total energy, obesity, physical activity, education, smoking, alcohol drinking, blood pressure, fasting glucose, lipid profiles, renal function, and presence of cardiovascular disease. RESULTS: A High DASH diet score was associated with low odds of having hyperuricemia (adjusted odds ratio for quartile 4 versus quartile 1 0.70 [95% confidence interval 0.66, 0.75], P for trend < 0.001) after adjusting for potential confounders. The association between the DASH diet and hyperuricemia was more pronounced among older individuals (age ≥50 years), women, and physically inactive participants compared with their counterparts (P for interaction < 0.01 for all). CONCLUSION: The DASH diet was associated with a low likelihood of having hyperuricemia in Chinese adults.

Ideal physical activity in association with incident ankylosing spondylitis: a community-based, prospective cohort study.

OBJECTIVES: Only limited risk factors for ankylosing spondylitis (AS) have been identified to date. Therefore, we aimed to explore whether cardiovascular health (CVH) behaviours and factors are associated with the risk of developing AS. METHODS: Patients with incident AS were identified in cohorts from two ongoing prospective studies. Assessments were made of the association of AS with individual baseline cardiovascular health lifestyle behaviours (including smoking status, body mass index, physical activity and diet) and cardiovascular health factors (including total cholesterol levels, blood pressure levels and fasting plasma glucose levels), and with a cardiovascular health metric determined by the number of ideal behaviours and factors. Cox regression analysis was used for the estimation of hazard ratios (HRs) for AS. RESULTS: Among 124,303 participants, incident AS was identified in 53 individuals within the 8 years of follow-up. For participants with ideal physical activity (>80 min/week) the HR was 0.21 (95% CI 0.05-0.89) compared with participants without ideal physical activity after adjusting for potential confounders. No signi cant risk of developing AS was associated with baseline smoking, diet, body mass index, blood pressure, fasting blood glucose or total cholesterol status, nor did cardiovascular health metrics. CONCLUSIONS: Adherence to ideal physical activity may reduce the risk of developing AS.

In Utero and Early Life Exposure to the Great Chinese Famine and Risk of Rheumatoid Arthritis in Adulthood.

OBJECTIVE: To investigate whether early life exposure to the Great Chinese Famine of 1959-1961 is associated with the risk of RA development in adulthood. METHODS: This study included 101,510 participants who were enrolled in the Kailuan Study in 2006. RA cases were confirmed by medical record review. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) for RA according to famine exposure status (exposed in utero or between ages 0 and 3 years, between ages 3 and 6 years, or at age 6 years or older), in comparison to participants born after 1961 who were not exposed to famine. RESULTS: During 12 years of follow-up (2006-2018), we identified 187 RA cases. Individuals exposed to famine in utero or between ages 0 and 3 years had a higher prevalence of RA relative to other groups (0.2-0.35% versus 0.08-0.20%). After adjustment for potential confounders, the OR for RA was 2.95 (95% CI 1.55-5.59) for individuals exposed in utero, 4.53 (95% CI 2.72-7.54) for those exposed between ages 0 and 3 years, 2.55 (95% CI 1.43-4.57) for those exposed between ages 3 and 6 years, and 2.72 (95% CI 1.70-4.36) for those exposed at age 6 years or older versus individuals born after 1961. Similar associations with the risk of RA were observed for men and women when subjects were stratified by sex (P for interaction = 0.89). CONCLUSION: Individuals exposed to famine in utero or in early childhood (between ages 0 and 3 years) were more likely to develop RA in adulthood, highlighting the importance of early life as a vulnerable developmental period.

Inflammatory markers as independent predictors for stroke outcomes.

BACKGROUND: Inflammation plays an important role in the pathophysiology of stroke. The aim of the present study was to investigate the association between various inflammatory risk markers and ischemic stroke outcome and subtype. METHODS: A total of 3,013 ischemic stroke patients who were admitted to our hospital from 01/01/2016 to 12/30/2018 were retrospectively studied. Stroke subtypes were defined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Levels of five common inflammatory markers including white blood cell (WBC) count, neutrophil, lymphocyte, serum C-reactive protein (CRP), and interleukin-6 (IL-6) were measured, and eleven conventional risk factors were further evaluated in the prediction of overall mortality as well as three functional outcomes defined by the National Institute of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the Barthel Index (BI). Independent predictors of outcome were identified by multivariate logistic regression, and an importance score measured by the area under the receiver operating characteristics curve for each predictor using a Naive Bayes model was reported. RESULTS: Neutrophil and WBC were significantly higher in large-artery atherosclerosis (LAA) and cardioembolism (CE) subtype. In contrast, lymphocyte was significantly higher in small-artery occlusion (SAO). Neutrophil-lymphocyte ratio and CRP level were the best independent predictors, after adjustment for traditional risk factors and TOAST subtype for all four types of outcomes. CONCLUSION: Inflammatory risk markers including neutrophil, lymphocyte, and CRP may have strong independent prediction values for stroke outcome.