The association between neuropsychological impairment, self-perceived cognitive deficit, symptoms, and health related quality of life in newly diagnosed ovarian cancer patients.

Objective: To assess cognitive function in patients newly diagnosed with ovarian cancer (OC) before treatment and explore the relationship between neuropsychological impairment, self-perceived cognitive deficit, symptoms, and health-related quality of life in them. Methods: From May 2021 to February 2022, 105 women newly diagnosed with OC were enrolled in the Cancer Center of Fudan University, Shanghai, China. Objective and subjective cognitive functions were assessed using the Montreal Cognitive Assessment (MoCA) scale and Perceptual Deficits Questionnaire (PDQ). Symptoms and quality of life were evaluated using the Memorial Symptom Assessment Scale (MSAS) and Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O), respectively. Results: This study included 105 newly diagnosed OC patients, with an average age of 49.73 (±8.48) years. Of these, 72.38% had impaired neuropsychological test scores, especially in delayed recall, abstraction, and visuospatial/executive function. Retrospective, and prospective memory were the most serious perceived deficits. The results of the MoCA test were not associated with PDQ (Rs = -0.180, P = 0.067) and significantly correlated with the distress index, physiological and total scores of the MSAS, and emotional well- being of the FACT-O. The PDQ positively correlated with all MSAS dimensions but not with the FACT-O. Conclusion: The incidence of neuropsychological impairment in patients newly diagnosed with OC was high, with no association with self-perceived cognitive deficits. It is recommended that healthcare providers include cognitive impairment in symptom management in this population, who may benefit from early assessment, prevention, and intervention.

5-HT7R enhances neuroimmune resilience and alleviates meningitis by promoting CCR5 ubiquitination.

INTRODUCTION: Excessive immune activation induces tissue damage during infection. Compared to external strategies to reconstruct immune homeostasis, host balancing ways remain largely unclear. OBJECTIVES: Here we found a neuroimmune way that prevents infection-induced tissue damage. METHODS: By FACS and histopathology analysis of brain Streptococcus pneumonia meningitis infection model and behavioral testing. Western blot, co-immunoprecipitation, and ubiquitination analyze the Fluoxetine initiate 5-HT7R-STUB1-CCR5 K48-linked ubiquitination degradation. RESULTS: Fluoxetine, a selective serotonin reuptake inhibitor, or the agonist of serotonin receptor 5-HT7R, protects mice from meningitis by inhibiting CCR5-mediated excessive immune response and tissue damage. Mechanistically, the Fluoxetine-5-HT7R axis induces proteasome-dependent degradation of CCR5 via mTOR signaling, and then recruits STUB1, an E3 ubiquitin ligase, to initiate K48-linked polyubiquitination of CCR5 at K138 and K322, promotes its proteasomal degradation. STUB1 deficiency blocks 5-HT7R-mediated CCR5 degradation. CONCLUSION: Our results reveal a neuroimmune pathway that balances anti-infection immunity via happiness neurotransmitter receptor and suggest the 5-HT7R-CCR5 axis as a potential target to promote neuroimmune resilience.

An AgPd NP-based lateral flow immunoassay for simultaneous detection of glycocholic acid and alpha-fetoprotein.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, ranking third in cancer deaths. Early diagnosis of HCC markers is imperative for effective prognosis and treatment. This study explores the utility of glycocholic acid (GCA) and alpha-fetoprotein (AFP) as biomarkers for liver diseases, with a specific focus on their simultaneous detection for enhanced diagnostic and prognostic capabilities. Harnessing the benefits of lateral flow immunoassay (LFIA), such as operational simplicity, speed, and accuracy, we engineered AgPd nanocomposites with antibodies targeting GCA and AFP. Under the optimized conditions, the visual detection limit for GCA was established at 50 ng mL-1 and the cut-off value at 104 ng mL-1. And for AFP, the visual detection limit was 0.1 ng mL-1 and the cut-off value was 500 ng mL-1. The accuracy and feasibility of the strips were validated through the detection of 39 actual serum samples. The results highlight the potential of LFIA as a rapid and effective tool for clinical diagnosis. The developed LFIA method not only demonstrates accuracy and feasibility but also presents a promising avenue for the early diagnosis of hepatocellular carcinoma.

TCR ß chain repertoire characteristic between healthy human CD4+ and CD8+ T cells.

T cell is vital in the adaptive immune system, which relays on T-cell receptor (TCR) to recognize and defend against infection and tumors. T cells are mainly divided into well-known CD4+ and CD8+ T cells, which can recognize short peptide antigens presented by major histocompatibility complex (MHC) class II and MHC class I respectively in humoral and cell-mediated immunity. Due to the Human Leukocyte Antigen (HLA) diversity and restriction with peptides complexation, TCRs are quite diverse and complicated. To better elucidate the TCR in humans, the present study shows the difference between the TCR repertoire in CD4+ and CD8+ T cells from 30 healthy donors. The result showed count, clonality, diversity, frequency, and VDJ usage in CD4+ and CD8+ TCR-ß repertoire is different, but CDR3 length is not. The Common Clone Cluster result showed that CD4+ and CD8+ TCR repertoires are connected separately between the bodies, which is odd considering the HLA diversity. More knowledge about TCR makes more opportunities for immunotherapy. The TCR repertoire is still a myth for discovery.

Artepillin C Time-Dependently Alleviates Metabolic Syndrome in Obese Mice by Regulating CREB/CRTC2-BMAL1 Signaling.

Artepillin C (APC), a cAMP-response element-binding (CREB)/CREB regulated transcription coactivator 2 (CRTC2) inhibitor isolated from Brazilian green propolis, can ameliorate metabolic syndrome in obese mice. Because the sensitivity and responsiveness of the body to the drug depend on the time of day and the circadian clock alignment, the optimal administration time of APC for desired efficacy in treating metabolic syndrome remains unclear. In this study, APC (20 mg/kg) or the vehicle was intraperitoneally injected into obese mice once daily for one or three weeks. The results of the insulin tolerance test, pyruvate tolerance test, and histological and biochemical assays showed that APC could improve whole-body glucose homeostasis and decrease hepatic lipid synthesis following a circadian rhythm. Further exploration of the underlying mechanism revealed that APC may disturb the diurnal oscillations of the expression of brain and muscle ARNT-like protein (BMAL1) in primary hepatocytes and the livers of the study subjects. Moreover, APC could inhibit hepatic BMAL1 expression by blocking the CREB/CRTC2 transcription complex. BMAL1 overexpression in primary hepatocytes or the livers of db/db mice antagonized the inhibitory effect of APC on hepatic lipid metabolism. In conclusion, the chronotherapy of APC may relieve metabolic syndrome in obese mice, and the mechanism behind APC-mediated time-of-day effects on metabolic syndrome were unveiled, thereby providing a foundation for optimized APC treatment from a mechanistic perspective.

Parathyroid hormone receptor-1 signaling aggravates hepatic fibrosis through upregulating cAMP response element-binding protein-like 2.

BACKGROUND AND AIMS: Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of HSCs and hepatic fibrosis was examined. APPROACH AND RESULTS: PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl 4 )-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl 4 , MCD, or western diet, plus low-dose CCl 4 -induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl 4 -treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of TGFß in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl 4 -treated mice. CONCLUSIONS: In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs through Crebl2/SMAD3/TGFß regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.

Imidazo[1,2-a]Pyridine Derivatives as Novel Dual-Target Inhibitors of ABCB1 and ABCG2 for Reversing Multidrug Resistance.

ABCB1 and ABCG2 are the important ATP-binding cassette (ABC) transporters associated with multidrug resistance (MDR). Herein, we designed a series of imidazo[1,2-a]pyridine derivatives as dual-target inhibitors of ABCB1 and ABCG2 through the scaffold hopping strategy. Compound Y22 displayed potential efflux function inhibitory toward both ABCB1 and ABCG2 (reversal fold: ABCB1 = 8.35 and ABCG2 = 2.71) without obvious cytotoxicity. Y22 also enhanced the potency of antiproliferative drugs in vitro. Mechanistic studies demonstrated that Y22 slightly suppressed ATPase activity but did not affect the protein expression of ABCB1 or ABCG2. Notably, Y22 exhibited negligible CYP3A4 inhibition and enhanced the antiproliferative activity of adriamycin in vivo by restoring the sensitivity of resistant cells. Thus, Y22 may be effective clinically in combination with common chemotherapy agents. In summary, Y22 is a potential dual-target inhibitor that reverses MDR by blocking the efflux function of ABCB1 and ABCG2.

Classification and survival prediction in early-stage cirrhosis by gene expression profiling.

Liver cirrhosis has been increasingly diagnosed at an early stage owing to the non-invasive diagnostic techniques. However, it is difficult to identify patients at high risk of disease progression. Screening cirrhotic patients with poor prognosis who are most in need of surveillance is still challenging. Gene expression data GSE15654 and GSE14520 were downloaded for performing unsupervised clustering analysis. The prognostic differences between the different clusters were explored by Cox regression. Integrative analysis of gene expression signature, immune cell enrichments and clinical characterization was performed for different clusters. Two distinctive subclasses were identified in HCV-related GSE15654, and Kaplan-Meier analysis indicated that subtype 2 had lower survival rates than subtype 1 (p = 0.0399). Further analysis revealed subtype 2 had a higher density of follicular T helper cells, resting natural killer cells and M0, M2 macrophages while subtype 1 with a higher fraction of naive B cells, memory B cells, resting memory CD 4 T cells, activated natural killer cells and monocytes. 226 differentially expressed genes were identified between the two subtypes, and Reactome analysis showed the mainly enriched pathways were biological oxidations and fatty acid metabolism. Five hub genes (AKT1, RPS16, CDC42, CCND1 and PCBP2) and three significant modules were extracted from the PPI network. The results were validated in HBV-related GSE14520 cohort. We identified two subtypes of patients with different prognosis for hepatitis C-related early-stage liver cirrhosis. Bioinformatics analysis of the gene expression and immune cell profile may provide fresh insight into understanding the prognosis difference.

Prevention of polycystic ovary syndrome and postmenopausal osteoporosis by inhibiting apoptosis with Shenling Baizhu powder compound.

Objective: Shenling Baizhu powder (SBP) has been shown to reverse the abnormal expression of the aromatic hydrocarbon receptor (AHR) mediated by air pollution. Our study aimed to understand the main ingredient of SBP and investigate its action mechanism in preventing polycystic ovary syndrome (POCS) and postmenopausal osteoporosis (PMO). Methods: The active ingredients of SBP with the highest binding affinity to AHR were screened using a Chinese medicine database, and their binding mechanism was simulated using molecular dynamics simulation (MDS). Rutin was utilized to treat ovarian granulosa cell lines and osteoblast cell lines. The cell lines were treated with a gradient of rutin concentration (0.01 mmol/L, 0.05 mmol/L and 0.1 mmol/L) to find the optimal drug dose. PCR was used to detect AHR and apoptosis-related proteins, and WB to detect the expression of AHR, caspase-3 and cleaved-caspase-3. Finally, the CCK-8 cell proliferation assay detected the proliferation of cells. Results: We obtained Rutin through the Chinese medicine database, and dynamics simulation determined its binding sites. Ovarian granulosa cell lines and osteoblast cell lines were treated with Rutin. RT-PCR and western blotting revealed that the expression of apoptosis-associated protein Bcl-2 was elevated, and the expression of AHR, Bax, caspase-3 and PARP were decreased. CCK-8 results showed accelerated proliferation in both cell types. Conclusion: Rutin, the main ingredient of SBP compound, works by binding to AHR, which can improve POCS and PMO by inhibiting cell apoptosis and by promoting cell proliferation.

An early novel prognostic model for predicting 80-day survival of patients with COVID-19.

The outbreak of the novel coronavirus disease 2019 (COVID-19) has had an unprecedented impact worldwide, and it is of great significance to predict the prognosis of patients for guiding clinical management. This study aimed to construct a nomogram to predict the prognosis of COVID-19 patients. Clinical records and laboratory results were retrospectively reviewed for 331 patients with laboratory-confirmed COVID-19 from Huangshi Hospital of Traditional Chinese Medicine (TCM) (Infectious Disease Hospital) and Third Affiliated Hospital of Sun Yat-sen University. All COVID-19 patients were followed up for 80 days, and the primary outcome was defined as patient death. Cases were randomly divided into training (n=199) and validation (n=132) groups. Based on baseline data, we used statistically significant prognostic factors to construct a nomogram and assessed its performance. The patients were divided into Death (n=23) and Survival (n=308) groups. Analysis of clinical characteristics showed that these patients presented with fever (n=271, 81.9%), diarrhea (n=20, 6.0%) and had comorbidities (n=89, 26.9.0%). Multivariate Cox regression analysis showed that age, UREA and LDH were independent risk factors for predicting 80-day survival of COVID-19 patients. We constructed a qualitative nomogram with high C-indexes (0.933 and 0.894 in the training and validation groups, respectively). The calibration curve for 80-day survival showed optimal agreement between the predicted and actual outcomes. Decision curve analysis revealed the high clinical net benefit of the nomogram. Overall, our nomogram could effectively predict the 80-day survival of COVID-19 patients and hence assist in providing optimal treatment and decreasing mortality rates.

Biomarkers of interstitial lung disease associated with primary Sjögren's syndrome.

OBJECTIVES: The aim of this study was to investigate serum biomarkers linked to primary Sjögren's syndrome (pSS)-associated interstitial lung disease (ILD). METHODS: 69 pSS patients were consecutively enrolled and evaluated via quantitative ILD scoring based on high-resolution computed tomography (HRCT). Biomarkers of interest were assessed by multiplex enzyme-linked immunosorbent assays (ELISAs). RESULTS: Among consecutively enrolled patients with pSS, the presence of pSS-ILD was 50% based on the presence of radiographically defined interstitial lung abnormalities (ILA) meeting specified criteria for mild/moderate (ILA 2) or severe (ILA 3) disease. Age, immunoglobulin M (IgM), C-reactive protein (CRP), and serum levels of eotaxin/CCL11, Krebs von den Lungen-6 (KL-6), TNFα, and TGFα were significantly higher in the combined pSS-ILD group (ILA 2 + ILA 3) than in the pSS-no-ILD and pSS-indeterminate ILD groups (ILA 0 and ILA 1, respectively) in unadjusted analyses (p < 0.05 for all variables). A binary logistic regression model revealed that disease duration and KL-6 levels were associated with the presence of pSS-ILD (p < 0.05). Complementary least absolute shrinkage and selection operator (LASSO) modeling showed that age, KL-6, and TNF-α effectively differentiated pSS-ILD (ILA 2 + ILA3) from pSS without ILD (ILA 0 + ILA 1), with an area under the curve (AUC) of 0.883 (p value < 0.0001). CONCLUSIONS: Patient age, disease duration, and serum levels of both KL-6 and TNFα were the most discriminating factors associated with the presence of ILD in our pSS patients. Higher levels of CRP, IgM, eotaxin, TGFα, and TNFα should also prompt the search for occult as well as clinically evident lung involvement based on statistically significant univariate associations with pSS-ILD. CLINICAL TRIAL REGISTRATION: None.

Serum MUC5AC protein levels are correlated with the development and severity of connective tissue disease-associated pulmonary interstitial lesions.

Background: Mucin 5AC (MUC5AC) and mucin 5B (MUC5B) are the major components of airway mucins. The expression levels of MUC5AC and MUC5B are related to connective tissue disease-associated interstitial lung disease (CTD-ILD) in the promoter region of MUC5AC and MUC5B and the relevant bronchoalveolar lavage fluid. However, the serum protein levels of MUC5AC and MUC5B have not been tested in CTD-ILD patients. In this study, we tested the serum levels of MUC5AC and MUC5B proteins in CTD-ILD patients and assessed their relationship with the occurrence and development of ILD. Methods: Serum samples were obtained from 168 CTD and 80 healthy participants from the First Affiliated Hospital of Xiamen University. The serum levels of MUC5AC and MUC5B proteins were measured by enzyme-linked immunosorbent assay. Results: Of the 168 individuals with CTD, 70 had primary Sjögren's syndrome (pSS), 64 had systemic sclerosis (SSc), and 34 had polymyositis/dermatomyositis (PM/DM). There were 116 cases with concurrent ILD; ILD scores were 1 (n=23), 2 (n=41), and 3 (n=52). Serum MUC5AC and MUC5B protein levels were considerably higher in CTD-ILD than CTD-only individuals or healthy controls (both p<0.005). Among the CTD subgroups, MUC5AC was higher in individuals with concurrent ILD than in those without ILD (all p<0.05). MUC5AC was positively correlated with ILD severity in all three CTD subgroups (all R>0.47 and all p<0.05). The MUC5B levels varied substantially between SSc and SSc patients with concurrent ILD (p=0.032) and were related to ILD severity only in PM/DM patients (R=0.346 and p=0.045). Conclusion: MUC5AC is correlated with the occurrence and development of ILD, while MUC5B is associated with ILD diagnosis and severity in CTD subgroups. Serum MUC5AC levels present a definite diagnostic utility for CTD-ILD and as proxies for its severity.

Psychometric properties of the Chinese version of female self-advocacy in cancer survivorship scale.

Objective: To translate Female Self-Advocacy in Cancer Survivorship (FSACS) scale and evaluate the psychometric properties of Chinese version of FSACS scale among female cancer survivors in China. Methods: This study employed a cross-sectional design. FSACS scale was forward-backward translated and cognitive interviews were conducted for cultural adaptation. The newly translated tool was distributed to female cancer survivors to test psychometric properties, including item analysis, content validity, construct validity, criterion validity, internal consistency, and test-retest reliability. Results: A total of 436 female cancer survivors were recruited in a Chinese tertiary cancer center from May to August in 2021. Item analysis showed statistical significance (P < 0.05) for each one and no ceiling or floor effect. The item-level content validity index ranged from 0.86 to 1.00 and the scale-level content validity index was 0.98. Three factors were extracted based on parallel analysis, and confirmatory factor analysis proved a good model fit with the original 3-factor structure. Pearson's correlation coefficient showed acceptable criterion validity. The Cronbach's α of 0.880 demonstrated the scale's internal consistency reliability, and the Alpha coefficients were 0.826, 0.763, and 0.859 for its three dimensions, respectively. The interclass correlation coefficients for test-retest reliability was 0.904 (0.870-0.891, P < 0.01) which confirmed the external reliability of the scale. Conclusions: The Chinese version of FSACS scale proved to be a valid and reliable instrument that can be applied among Chinese female cancer survivors. Further research could be conducted in larger populations or people in different cancer stages.

Systematic Review, Meta-Analysis and Bioinformatic Analysis of Biomarkers for Prognosis of Malignant Pleural Mesothelioma.

In previous studies, non-invasive diagnostic biomarkers showed great benefit in the early-stage diagnosis of malignant pleural mesothelioma (MPM). However, the accuracy of different biomarkers was controversial. In this study, meta-analysis and bioinformatics analysis were conducted to compare the accuracy of the following three biomarkers and explore the relationship between the gene expression levels and MPM. A systematic search of meta-analysis was conducted using PubMed, EMBASE and Cochrane Library to identify relevant studies from the inception to March 2021. QUADAS-2 for Quality Assessment of Diagnostic Accuracy Studies was used to evaluate the quality of eligible studies. The meta-analysis was performed utilizing Stata 15.0 and Review Manager 5.4 software. The meta-analysis results showed that 31 studies that involved 8750 participants were included. The pooled sensitivity and specificity (SPE) were 0.90 (95% CI: 0.74, 0.97) and 0.91 (95% CI: 0.84, 0.95) for Fibulin-3, 0.66 (95% CI, 0.51-0.78) and 0.91 (95% CI, 0.82-0.96) for mesothelin (MSLN), 0.68 (95% CI: 0.63,0.73) and 0.86 (95% CI: 0.82,0.90) for soluble mesothelin-related peptides (SMRP), and 0.74 (95% CI, 0.66-0.80) and 0.89 (95% CI, 0.85-0.91) for MSLN + SMRP + Fibulin-3. Compared with the other two biomarkers, Fibulin-3 may be more appropriate to be one of the indicators for combined diagnosis. Bioinformatics analysis showed that the low expression level of the MSLN gene was significantly related to longer survival time and better prognosis of MPM patients. However, considering the limitation in the quality and sample size of the included research, further studies are required.

Comparison between laparoscopic uncut Roux-en-Y and Billroth II with Braun anastomosis after distal gastrectomy: A meta-analysis.

BACKGROUND: Conventional Billroth II (BII) anastomosis after laparoscopic distal gastrectomy (LDG) for gastric cancer (GC) is associated with bile reflux gastritis, and Roux-en-Y anastomosis is associated with Roux-Y stasis syndrome (RSS). The uncut Roux-en-Y (URY) gastrojejunostomy reduces these complications by blocking the entry of bile and pancreatic juice into the residual stomach and preserving the impulse originating from the duodenum, while BII with Braun (BB) anastomosis reduces the postoperative biliary reflux without RSS. Therefore, the purpose of this study was to compare the efficacy and safety of laparoscopic URY with BB anastomosis in patients with GC who underwent radical distal gastrectomy. AIM: To evaluate the value of URY in patients with GC. METHODS: PubMed, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, Chinese Biomedical Database, and VIP Database for Chinese Technical Periodicals (VIP) were used to search relevant studies published from January 1994 to August 18, 2021. The following databases were also used in our search: Clinicaltrials.gov, Data Archiving and Networked Services, the World Health Organization International Clinical Trials Registry Platform Search Portal (https://www.who.int/clinical-trials-registry-platform/the-ictrp-search-portal), the reference lists of articles and relevant conference proceedings in August 2021. In addition, we conducted a relevant search by Reference Citation Analysis (RCA) (https://www.referencecitationanalysis.com). We cited high-quality references using its results analysis functionality. The methodological quality of the eligible randomized clinical trials (RCTs) was evaluated using the Cochrane Risk of Bias Tool, and the non-RCTs were evaluated using the Newcastle-Ottawa scale. Statistical analyses were performed using Review Manager (Version 5.4). RESULTS: Eight studies involving 704 patients were included in this meta-analysis. The incidence of reflux gastritis [odds ratio = 0.07, 95% confidence interval (CI): 0.03-0.19, P < 0.00001] was significantly lower in the URY group than in the BB group. The pH of the postoperative gastric fluid was lower in the URY group than in the BB group at 1 d [mean difference (MD) = -2.03, 95%CI: (-2.73)-(-1.32), P < 0.00001] and 3 d [MD = -2.03, 95%CI: (-2.57)-(-2.03), P < 0.00001] after the operation. However, no significant difference in all the intraoperative outcomes was found between the two groups. CONCLUSION: This work suggests that URY is superior to BB in gastrointestinal reconstruction after LDG when considering postoperative outcomes.

Predictors of long-term prognosis in rheumatoid arthritis-related interstitial lung disease.

The aim of the study was to identify specific clinical and serum protein biomarkers that are associated with longitudinal outcome of RA-associated interstitial lung disease (RA-ILD). 60 RA patients with clinical and serological profiles were assessed by HRCT and pulmonary function tests (PFTs) at baseline (Year 0) and 5 years post enrollment (Year 5). Progression versus non-progression was defined based on changes in Quantitative Modified HRCT scores and PFTs over time. Specific serum protein biomarkers were assessed in serum samples at baseline and Year 5 by Multiplex enzyme-linked immunosorbent assays (ELISAs). At Year 5, 32% of patients demonstrated progressive RA-ILD, 35% were stable, and 33% improved. Baseline age and rheumatoid factor (RF) were significantly different between RA-ILD outcomes of progression vs. no-progression (p < 0.05). Changes in levels of CXCL11/I-TAC and MMP13 over 5 years also distinguished pulmonary outcomes (p < 0.05). A final binary logistic regression model revealed that baseline age and changes in serum MMP13 as well as CXCL11/I-TAC were associated with RA-ILD progression at Year 5 (p < 0.01), with an AUC of 0.7772. Collectively, these analyses demonstrated that baseline clinical variables (age, RF) and shifts in levels of selected serum proteins (CXCL11/I-TAC, MMP13) were strongly linked to RA-ILD outcome over time.

Nematicidal Activity of Burkholderia arboris J211 Against Meloidogyne incognita on Tobacco.

Root-knot nematode (Meloidogyne incognita) is the most widespread nematode affecting Solanaceae crops. Due to the lack of effective measures to control this nematode, its management can be achieved, using biocontrol agents. This study investigated in vitro efficacy of the antagonistic bacterial strain J211 isolated from tobacco rhizosphere soil against M. incognita, and further assessed its role in controlling nematodes, both in pot and field trials. Phylogenetic analysis of the 16S rRNA gene sequence of strain J211 assigned to Burkholderia arboris. Culture filtrates B. arboris J211 exhibited anematicidal activity against the second-stage juveniles (J2s) of M. incognita, with a 96.6% mortality after 24 h exposure. Inoculation of J211 in tobacco roots significantly reduced the root galling caused by M. incognita, both in pot and field trials. Meanwhile, plant growth-promoting (PGP) traits results showed that J211 had outstanding IAA-producing activity, and the IAA production reached 66.60 mg L-1. In the field study, B. arboris J211 also promoted tobacco growth and increase flue-cured tobacco yield by 8.7-24.3%. Overall, B. arboris J211 as a high-yielding IAA nematicidal strain effectively controlled M. incognita and improved tobacco yield making it a promising alternative bionematocide.

GM-CSF-miRNA-Jak2/Stat3 Signaling Mediates Chemotherapy-Induced Cancer Cell Stemness in Gastric Cancer.

Chemotherapy serves as the first choice in clinic to treat advanced gastric cancer. However, emerging evidence indicated the induction of drug resistance and cancer stem cells occasionally by chemotherapy, which seriously limit the therapeutic effects, but the regulatory mechanism remains unclear. Here we treated two human gastric cancer cell lines SGC7901 and BGC823 with 5-Fluorouracil (5-Fu) or Cisplatin (DDP) in vitro. The survived cells showed significant increase of drug resistance, cell stemness and cytokine GM-CSF expression and secretion. As such, GM-CSF was applied to stimulate gastric cancer cells, followed by the subpopulation of CD133 + CSC analysis, sphere formation assay and stemness genes expression analysis. As a result, CSCs showed induction by GM-CSF treatment. A gastric cancer animal model further indicated that the gastric cancer cells significantly promoted tumor growth after GM-CSF treatment in vivo. High-throughput miRNA and mRNA sequencing analyses identified a subset of miRNAs and mRNAs under regulation of both 5-Fu and GM-CSF in gastric cancer cells, including upregulation of miR-877-3p and downregulation of SOCS2. Targeted overexpression or knockdown of miR-877-3p in gastric cancer cells revealed the oncogenic function of miR-877-3p in regulating gastric cancer by suppressing target gene SOCS2. Jak2/Stat3 signaling pathway, as a downstream target of SOCS2, showed activation in vitro and in vivo after treatment with miR-877-3p or GM-CSF. Our findings not only revealed a novel mechanism through which chemotherapy induced CSCs in gastric cancer via GM-CSF-miRNA-Jak2/Stat3 signaling, but also provided an experimental evidence for appropriate dose reduction of adjuvant chemotherapy in treatment of cancer patients.

Identification of IMPA2 as the hub gene associated with colorectal cancer and liver metastasis by integrated bioinformatics analysis.

BACKGROUND AND OBJECTIVES: Colorectal cancer (CRC) is one of the most common malignant tumors worldwide with high incidence and mortality rate, while colorectal liver metastasis (CRLM) is one of the major causes of cancer-related deaths. Therefore, the present study aims to identify the hub gene associated with CRC carcinogenesis and liver metastasis, and then explore its diagnostic and prognostic value as well as the potential regulation mechanism. METHODS: The overlapping differential co-expression genes among CRC, CRLM, and normal tissues were explored on the GSE49355 and GSE81582 datasets from the Gene Expression Omnibus (GEO) database by integrated bioinformatics analysis. Then, the hub prognostic genes were selected from the overlapping genes by univariate Cox proportional hazard analysis and online database Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Subsequently, the clinical value of the hub genes was evaluated in the TCGA and GSE39582 cohorts. Finally, the underlying mechanisms of the hub gene regulating CRC carcinogenesis and metastasis were explored by Gene function annotation and DNA methylation analysis. RESULTS: Inositol mono-phosphatase 2 (IMPA2) was identified as the hub gene associated with CRC carcinogenesis and liver metastasis. IMPA2 had an excellent diagnostic efficiency, and its expression was significantly decreased in CRC and liver metastasis samples, being positively correlated with poor prognosis. Moreover, its low expression was associated with AJCC stage III+IV, T4, N1+2, and M1. In addition, our results revealed that the potential mechanisms used by IMPA2 to mediate CRC carcinogenesis and metastasis could be associated with lipid metabolism and epithelial mesenchymal transition (EMT). Finally, IMPA2 expression could be regulated by DNA methylation. CONCLUSIONS: IMPA2 was identified and reported for the first time as a hub gene biomarker in the diagnosis and prognosis of CRC, which could regulate CRC carcinogenesis and liver metastasis through the regulation of lipid metabolism, EMT, and DNA methylation.

Characterization of Monoclonal Antibodies Recognizing Citrulline-Modified Residues.

Background: Citrullination is a post-translational protein modification linked to the occurrence and development of a variety of diseases. The detection of citrullinated proteins is predominately based on antibody detection although currently available reagents demonstrate detection bias according to the environmental context of the citrullinated residues. This study aimed to develop improved antibody reagents capable of detecting citrullinated residues in proteins in an unbiased manner. Methods: BALB/c mice were sequentially immunized using citrulline conjugates with different carrier proteins, and specific monoclonal antibodies (mAbs) identified by primary screening using citrulline-conjugated proteins unrelated to the immunogen. Secondary screening was performed to identify mAbs whose reactivity could be specifically blocked by free citrulline, followed by identification and performance assessment. Results: Two mAbs, 22F1 and 30G2, specifically recognizing a single citrulline residue were screened from 22 mAbs reacting with citrulline conjugates. Compared with commercially available anti-citrulline antibodies (AB6464, AB100932 and MABN328), 22F1 and 30G2 demonstrated significantly higher reactivity as well as a broader detection spectrum against different citrullinated proteins. 22F1 and 30G2 also had higher specificity than commercial antibodies and overall better applicability to a range of different immunoassays. Conclusion: Two mAbs specifically recognizing a single citrulline residue were successfully produced, each possessing good specificity against different citrullinated proteins. The improved utility of these reagents is expected to make a strong contribution to protein citrullination-related research.