Diagnostic and therapeutic value of progastrin‐releasing peptide on small‐cell lung cancer: A Single‐Center Experience in China

We aimed to compare the diagnostic efficiency of proGRP and NSE on SCLC and to investigate whether the change of proGRP level would predict therapeutic response. Patients who were firstly diagnosed pathologically in Nanjing Chest Hospital and measured proGRP level consecutively were enrolled in the study. ProGRP level was detected using Elecsys ProGRP Assay. Totally 75 SCLC, 234 NSCLC and 264 benign lung diseases (BLD) were enrolled. Both proGRP and NSE levels in SCLC were significantly higher than those in NSCLC and BLD, and proGRP in extensive stage SCLC was higher than which in limited stage (P ≤ .001). The diagnostic efficiency of proGRP on SCLC was higher than that of NSE, but when the two biomarkers were bind together, the diagnostic efficiency was the best. When SCLC was differentiated from NSCLC and BLD, the cut‐off values were 114.35 pg/mL and 162.55 pg/mL respectively. For treatment responsive patients, proGRP level decreased markedly after the first cycle of therapy and kept a continued momentum of decline during treatment. But for unresponsive patients, no obvious decline was observed. ProGRP had higher diagnostic efficiency on SCLC when compared to NSE, and it could better predict therapeutic response of pulmonary target lesions on chemotherapy.     

CEA is an Independent Prognostic Indicator that is Associated with Reduced Survival and Liver Metastases in SCLC

Small-cell lung cancer (SCLC) is classified into two stages, limited-stage small-cell lung cancer (LS-SCLC) and extensive-stage small-cell lung cancer (ES-SCLC), with ES-SCLC being associated with reduced survival. However, disease stage alone is not a very precise predictor of survival time. The aim of this study is to search for a prognostic indicator that can be used in conjunction with the staging system in SCLC. We performed a prospective analysis of 116 patients with SCLC undergoing standard chemotherapy with or without radiotherapy. Expression levels of 12 tumor markers were measured at the time of diagnosis by a commercial protein chip system, and patients were followed up for a maximum of 54 weeks. CEA was the most frequently detected tumor marker in SCLC, with 32.8% of samples scoring positive, and was also the only marker that correlated with overall survival. The average survival time was 16.78 months for patients with CEA below 5 ng/ml and 11.4 months for patients with CEA above 5 ng/ml (P < 0.001). In contrast, no association was found between tumor stage and overall survival. CEA expression was independent of tumor stage (P = 0.930). CEA is an independent prognostic factor that can be used in conjunction with disease stage in SCLC.     

Serum TNFRII: A promising biomarker for predicting the risk of subcentimetre lung adenocarcinoma

Early diagnosis of lung adenocarcinoma requires effective risk predictors. TNFRII was reported to be related to tumorigenesis, but remained unclear in lung cancer. This research set out to investigate the relationship between the sTNFRII (serum TNFRII) level and the risk of lung adenocarcinoma less than 1 cm in diameter. Seventy-one pairs of subcentimetre lung adenocarcinoma patients and healthy controls were analysed through multiplex bead-based Luminex assay and found a significantly lower expression of sTNFRII in patients with subcentimetre lung adenocarcinoma than that in the healthy controls (P < .001), which was further verified through ONCOMINE database analysis. Increased levels of sTNFRII reduced the risk of subcentimetre lung adenocarcinoma by 89% (P < .001). Patients with a higher level of BLC had a 2.70-fold (P < .01) higher risk of subcentimetre adenocarcinoma. Furthermore, a higher BLC/TNFRII ratio was related to a 35-fold higher risk of subcentimetre adenocarcinoma. TNFRII showed good specificity, sensitivity and accuracy (0.72, 0.75 and 0.73, respectively), with an AUC of 0.73 (P < .001). In conclusion, the present study assessed the value of sTNFRII as a potential biomarker to predict the risk of subcentimetre lung adenocarcinoma and provided evidence for the further use of TNFRII as an auxiliary marker in the diagnosis of subcentimetre lung adenocarcinoma.     

Serum tumour M2-pyruvate kinase as a biomarker for diagnosis and prognosis of early-stage non–small cell lung cancer

Tumour M2-pyruvate kinase (TUM2-PK) is up-regulated in many human cancers. This study was to evaluate the clinical value of serum TUM2-PK in early-stage non–small cell lung cancer (NSCLC) patients. A total of 162 consecutive early-stage NSCLC patients were enrolled and followed up after tumour resection. Serum TUM2-PK level was detected by enzyme-linked immunosorbent assay (ELISA) in NSCLC patients, 50 benign pulmonary disease patients and 102 healthy controls. The TUM2-PK level in NSCLC patients was higher than that of healthy controls (P < .001) and benign pulmonary disease patients (P < .001). A threshold of 30 U/mL could be used to diagnose early-stage NSCLC with 71.6% sensitivity and 98.0% specificity. The 5-year overall survival rate in patients with high TUM2-PK level was lower than that of patients with low TUM2-PK level (P = .009). Multivariable Cox regression showed that high TUM2-PK level was an independent risk factor for overall survival (HR = 2.595, 95% CI: 1.231-5.474, P = .012). High serum TUM2-PK level could be a potential biomarker for diagnosis and prognosis of early-stage NSCLC patients.     

Cyclosporin A Treatment and Decreased Fungal Load/Antigenemia in Experimental Murine Paracoccidioidomycosis

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the fungus Paracoccidioides brasiliensis (Pb). The cyclosporin A (CsA) is an immunosuppressant drug that inhibits calcineurin and has been described as a potential antifungal drug. The present study investigated the effect of CsA on the immune response, fungal load/antigenemia in experimental murine PCM. It was used four groups of BALB/c mice: (a) infected with 1 × 10⁵ Pb18 yeast cells (Pb), (b) infected and treated with CsA every other day 10 mg/kg of CsA (s.c.) during 30 days (Pb/CsA), (c) treated with CsA (CsA) and (d) no infected/treated (PBS). The immune response was evaluated by lymphocyte proliferation, DTH assays to exoAgs, ELISA for IgG anti-gp43 (specific immune responses) and cytokine serum levels (IFN-γ, TNF-α, IL-4 and IL-10). Fungal load was determined by lung colony-forming units (CFU) counts, lung and liver histopathology analysis and antigenemia determined by inhibition-ELISA. As expected, CsA was able to inhibit the specific cellular and humoral immune response (P < 0.05), with decrease in serum IFN-γ, TNF-α and IL-4 levels (P < 0.05). Cyclosporin A treatment also resulted in significantly decreased lung Pb CFU (P < 0.05) as well as a lower number of yeasts in the lung and liver (P < 0.05) by histopathology. In concordance, the decreased antigenemia was observed in Pb/CsA group (P < 0.05). In conclusion, even with immunosuppressive action, treatment with CsA results in decreased lung fungal load/antigenemia in experimental PCM in BALB/c mice. Further study is required to determine whether this represents less severe disease or protection by CsA.     

Identification of quantitative trait loci for productive tiller number and its relationship to agronomic traits in spring wheat

Productive tiller number (PTN), defined as the number of tillers that produce spikes and seeds, is a key component of grain yield in wheat. Spring wheat cultivars in the northern Great Plains of North America differ in PTN. The objectives of this study were (1) to determine the relationship of PTN to agronomic traits using recombinant inbred line (RIL) populations derived from crosses Reeder/Conan, McNeal/Thatcher and Reeder/McNeal grown under a range of environments, and (2) to identify and validate quantitative trait loci (QTL) associated with high PTN. Correlation between PTN and plot weight ranged from r = 0.4–0.6 among the populations based on combined means over years, and was positive in every environment for all crosses (P < 0.05). A genetic map generated for the Reeder/Conan RIL allowed identification of a QTL for PTN consistent over environments, located on chromosome 6B. The QTL on chromosome 6B (QTn.mst-6B) explained 9–17% of the variation of PTN and co-segregated with a QTL for yield in the Reeder/Conan RIL. QTn.mst-6B was validated by single marker analysis in the McNeal/Thatcher RIL, McNeal/Reeder RIL, and a set of near isogenic line (NIL) developed for QTn.mst-6B. The allele for high PTN significantly increased PTN by 8.7, 4, and 13% in the McNeal/Reeder RIL, McNeal/Thatcher RIL and Choteau/Reeder NIL, respectively. The allele for high PTN also had a significant positive effect on plot weight in the McNeal/Reeder RIL. Our results suggest that high PTN, controlled to a significant extent by QTn.mst-6B, contributed to increased yield potential over a range of environmental conditions. QTn.mst-6B may be useful for improving spring wheat in the northern Great Plains of North America and similar environments.     

Onconeural antibodies in sera from patients with various types of tumours

Purpose  We assessed the frequency and levels of onconeural antibodies in 974 patients with various types of tumours, but without apparent paraneoplastic neurological syndromes (PNS). Patients and methods  We included patients with the following tumours: 200 small-cell lung cancer (SCLC) patients, 253 breast cancer patients, 182 ovarian cancer patients, 266 uterine cancer patients and 73 thymoma patients, as well as 52 patients with PNS and cancer and 300 healthy blood donors. Sera were screened for amphiphysin, CRMP5, Hu, Ma2, Ri and Yo antibodies using a multi-well immunoprecipitation technique. Results  The most frequently detected antibodies were Hu followed by CRMP5. Ma2, Yo, amphiphysin and Ri antibodies were less common, but each was found at similar frequencies. Onconeural antibodies were present at similar levels in sera from the PNS control group and from cancer patients. Hu antibodies were rare in cancers other than SCLC. CRMP5 was the only antibody found in patients with thymoma and this antibody was more common among patients with thymoma than in other tumour patients. With one exception, coexisting antibodies were only found in patients with SCLC. The presence of onconeural antibodies in SCLC patients was not associated with prolonged survival. Conclusion  Onconeural antibodies are associated with various types of tumours suggesting that all antibodies should be included in the serological screening for possible PNS. The levels of onconeural antibody are not sufficiently sensitive to discriminate between cancer patients with PNS and those without.     

Behaviour of interleukin-2 serum levels in advanced non-small-cell lung cancer patients: relationship with response to therapy and survival

 Interleukin(IL)-2 is a T helper (Th) 1 type cytokine that has been shown to play an important role in antitumour immune responses. In this study, the prognostic significance of serum IL-2 levels was investigated in 60 advanced non-small-cell lung cancer (NSCLC) patients. IL-2 serum levels were determined before chemotherapy, at the end of chemotherapy and during follow-up, using a commercially available enzyme-linked immunoadsorbent assay kit. The results were analysed according to the response to therapy and were used to generate a model predicting overall survival and time to treatment failure. All 60 patients were shown to have higher IL-2 serum levels than controls (P < 0.0001). Stage IV patients had significantly lower IL-2 levels than stage III patients (P < 0.0001), although they were still significantly higher than controls (P < 0.0001). It is interesting that, when patients were divided into responders and non-responders according to the response to therapy, the former were shown to have significantly higher pre-chemotherapy levels than the latter (P < 0.0001). Moreover, a further significant increase in IL-2 serum levels (P=0.004) and a significant decrease (P < 0.0001) were shown in responders and non-responders, respectively at the end of the therapy. Using univariate and multivariate analyses, both overall survival and time to treatment failure were shown to be affected by the mean pathological levels of IL-2. Furthermore, the prognostic significance of the serum level of IL-2 was confirmed by the stepwise regression analysis. In conclusion, determination of pre-treatment IL-2 serum levels was shown to be of independent prognostic utility in patients with advanced NSCLC; therefore, its possible use for prediction of outcome is proposed. Received: 16 March 2000 / Accepted: 27 July 2000     

Significance of tumour cell HLA‐G5/‐G6 isoform expression in discrimination for adenocarcinoma from squamous cell carcinoma in lung cancer patients

Human leucocyte antigen (HLA)‐G has seven isoforms, of which HLA‐G1‐G4 are membrane‐bound and HLA‐G5‐G7 are soluble. Previous studies reinforced HLA‐G expression was strongly related to poor prognosis in different types of cancers. Among these studies, the monoclonal antibody (mAb) 4H84 was used which detects all HLA‐G isoform heavy chain; unfortunately, leaves the specific types of isoforms expressed in lesions undistinguished and its clinical significance needs to be clarified. To explore clinical significance of lesion soluble HLA‐G (sHLA‐G) in non‐small‐cell lung cancer (NSCLC), mAb 5A6G7 recognizing HLA‐G5/‐G6 molecules was used. Tumour cell sHLA‐G expression in 131 primary NSCLC lesions (66 squamous cell carcinoma, 55 adenocarcinoma and 10 adenosquamous carcinoma) were analysed with immunohistochemistry. Data showed that sHLA‐G expression was observed in 34.0% (45/131) of the NSCLC lesions, which was unrelated to patient age, sex, lymph nodal status, tumour–node–metastasis stage and patient survival. However, tumour cell sHLA‐G expression in lesions was predominately observed in adenocarcinoma lesions (73.0%, 40/55) which was significantly higher than that in squamous cell carcinoma (6.0%, 4/66) and adenosquamous carcinoma lesions (10.0%, 1/10, P < 0.001). The area under the receiver operating characteristic curve for lesion sHLA‐G was 0.833 (95% CI: 0.754–0.912, P < 0.001) for adenocarcinoma versus squamous cell carcinoma. Our findings for the first time showed that tumour cell sHLA‐G was predominately expressed in lung adenocarcinoma, which could be a useful biomarker to discriminate adenocarcinoma from squamous cell carcinoma in NSCLC patients.     

Association of glycosylated haemoglobin HbA1c levels with outcome in patients with COVID-19: A Retrospective Study

Patients with hyperglycemia tend to be susceptible to Coronavirus disease 2019 (COVID-19). However, the association of HbA1c level with outcome of COVID-19 patients was unclear. We performed a retrospective study of 2880 cases of COVID-19 admitted in Tongji Hospital, Wuhan, China, among which 922 had detected the HbA1c levels. We found that COVID-19 patients with either lower levels of HbAlc (3%-4.9%) or higher levels of HbAlc (≥6%) were associated with elevated all-cause mortality. Meanwhile, we observed that HbAlc levels were highly correlated with haemoglobin (Hb) and total cholesterol (TC) (P < .0001), moderately correlated with albumin (ALB) and high-sensitive C reaction protein (hs-CRP) (0.0001 < P<.001), and relatively low correlated with low-density lipoprotein cholesterol (LDL-C) (.001 < P<.01). These associated cofactors might together contribute to the clinical outcome of COVID-19 patients. Furthermore, the mortality was higher in COVID-19 patients with newly diagnosed diabetes mellitus (DM) compared with COVID-19 patients with history of DM. Moreover, in patients with history of DM, the mortality was decreased in patients treated with anti-hyperglycaemic drugs. In summary, our data showed that the in-hospital mortality was increased in COVID-19 patients with lower or higher levels of HbAlc. Meanwhile, initiation of appropriate anti-hyperglycaemic treatment might improve the clinical outcome in COVID-19 patients.     

Association of polymorphisms in the human IL-10 and IL-18 genes with rheumatoid arthritis

The decrease of anti-inflammatory cytokine and increase of pro-inflammatory cytokine was observed in rheumatoid arthritis (RA). Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, has been demonstrated to suppress joint swelling and deformation in RA animal model. Interleukin-18 (IL-18), a widely distributed pro-inflammatory cytokine, induces the production of IFN-γ, activate NK cells, and promote inflammation. Recent studies demonstrated that the serum IL-10 and IL-18 levels may be influenced by genetics and related to susceptibility to several autoimmune diseases. In the present study, using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing techniques, we analyzed the genotype and allele distributions of two single nucleotide polymorphisms (SNP) loci in the promoter region of IL-10 and IL-18 genes (IL-10-592 A/C and IL-18-607 A/C loci, respectively). Our results indicated that IL-10-592 allelic and genotypic frequencies were significantly different between the RA patients and normal subjects (P < 0.05). In addition, significant differences of IL-10-592 allelic and genotypic frequencies were also detected between the patients with or without anti-cyclic citrullinated peptide antibody (anti-CCP) (P < 0.05). In contrast, allelic and genotypic frequencies of IL-18-607 did not show significant difference between RA patients and normal subjects (P > 0.05) or between anti-CCP-positive and anti-CCP-negative RA patients (P > 0.05). Furthermore, ELISA detection of IL-10 and IL-18 serum levels revealed that the genotype of IL-10-592 was associated with IL-10 serum level (P < 0.05), but the genotype and allele frequency of IL-18-607 was not associated with IL-18 serum level (P > 0.05). Taken together, our findings provide new insight for the polymorphism of IL-10 gene in the pathogenesis of RA.     

Mannose-Binding Lectin Serum Levels are Low in Persons with Clinically Active Coccidioidomycosis

Background  Mannose-binding lectin (MBL) is a circulating collectin that is part of the innate immune response. We explored the serum levels of MBL in persons with different forms of coccidioidomycosis. Methods  Serum MBL was measured by ELISA from samples obtained from healthy donors with immunity to Coccidioides, and those with various forms of active coccidioidomycosis. Blood cell specimens from a subgroup of subjects with active coccidioidomycosis were examined for single nucleotide polymorphisms of the MBL gene and promoter regions. Results  The control group comprised 29 healthy immune subjects. Patient groups with active coccidioidomycosis consisted of 20 patients with symptomatic primary pulmonary coccidioidomycosis, 26 with non-meningeal disseminated coccidioidomycosis, and nine with coccidioidal meningitis. The group with active coccidioidomycosis was significantly older and more likely to be male than the control group (for both, P < 0.001). The mean ± SEM level of serum MBL in the healthy controls was 169.4 ± 28.6 ng/ml, significantly higher than the 79.2 ± 10.9 ng/ml for all active groups (P < 0.001). Moreover, the active coccidioidomycosis group was significantly more likely to have serum MBL level ≤70 ng/ml compared to the control group (P = 0.001). Genetic analysis in 27 subjects with active coccidioidomycosis revealed marked variation based on race and ethnicity. Among a subgroup of 10 white, non-hispanic men with active coccidioidomycosis, there was a significant association between the H and P haplotypes and MBL levels ≤70 ng/ml (P < 0.036 and P < 0.035, respectively). Conclusions  These data suggest that there is an association between low serum MBL levels and symptomatic coccidioidomycosis.     

Elevated Levels of Oxidized Low-Density Lipoprotein Correlate Positively with C-Reactive Protein in Patients with Acute Coronary Syndrome

The relationship between oxidized low-density lipoprotein (Ox-LDL) and C-reactive protein (CRP) in patients with acute coronary syndrome (ACS) is unknown. We, therefore, measured serum levels of Ox-LDL and high-sensitivity (hs)-CRP in 90 ACS patients, 45 stable angina pectoris (SAP) patients, and 66 healthy controls using sandwich ELISA. ACS patients were subdivided into: (1) acute myocardial infarction (AMI; n = 45); (2) unstable angina pectoris (UAP; n = 45) groups. In AMI patients, Ox-LDL (177.5 mmol/l) and hs-CRP (25.40 mg/l) levels were significantly higher (P < 0.01) than in UAP (Ox-LDL:107.5 mmol/l, hs-CRP:10.7 mg/l) and SAP (Ox-LDL:82.3 mmol/l, hs-CRP:2.10 mg/l) patients as well as controls (Ox-LDL:41.4 mmol/l, hs-CRP:1.76 mg/l). Ox-LDL/hs-CRP levels in UAP patients were significantly higher (P < 0.01) than in SAP patients and controls. Importantly, a positive correlation was found between Ox-LDL and CRP (r = 0.622; P < 0.01) levels. Serum levels of total, HDL, and LDL cholesterol did not differ among these patient groups. In conclusion, our data show that Ox-LDL and hs-CRP levels correlate positively in ACS patients, supporting the hypothesis that Ox-LDL and CRP may play a direct role in promoting the inflammatory component of atherosclerosis in these individuals. We suggest that Ox-LDL/CRP elevated levels may serve as markers of the severity of the disease in evaluation and management of ACS patients.     

Angiotensin converting enzyme I/D,angiotensinogen M235T and AT1-R A/C1166 gene polymorphisms in patients with acromegaly

Acromegaly is associated with increased morbidity and mortality related to cardiovascular disease. Hypertension is one of the most common cardiovascular risk factors in acromegalic patients. The aim of this study was to investigate association between the frequencies of angiotensin converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and the angiotensin II type 1 receptor (AT1-R) A/C1166 gene polymorphisms and some clinical parameters of acromegalic patients. Total of 33 acromegalic patients and 63 controls were enrolled to study. We determined the ACE I/D, AGT M235T and AT1-R A/C1166 gene polymorphisms. Serum insulin, glucose, triglyceride, HDL-cholesterol, LDL-cholesterol, growth hormone and Insulin-like growth factor I (IGF-I) levels of subjects were analyzed. The frequencies of ACE and M235T AGT genotype were not significantly different between control and patients. The distribution of AT1R A/C1166 genotypes was significantly different between patients and control subjects (P = 0.016). None of the three ACE genotypes, DD, ID and II displayed significant difference in acromegalic patients. A significant difference in systolic blood pressure and the serum IGF-I levels among the three AGT genotype, MM, MT and TT genotypes was found in patient group. Individuals with MT genotypes had significantly higher serum IGF-I levels and systolic blood pressure than MM and TT genotype subjects, P < 0.05. In addition, serum triglyceride and HDL levels differed significantly between MM and MT genotypes, P < 0.05. However, systolic blood pressure of patients with CC genotypes was found to be significantly higher than AA genotypes individuals in acromegaly group, P < 0.05. It can be said that the angiotensinojen MT and AT1R CC1166 genotype carriers may have more risk than other genotypes in the development of hypertension in acromegaly.     

Plasma Catechols in Familial Dysautonomia: A Long-term Follow-up Study

This study tested whether familial dysautonomia (FD) involves progressive loss of noradrenergic nerves. Plasma levels of catechols, including dihydroxyphenylglycol (DHPG), norepinephrine (NE), dopamine (DA), and DOPA, were measured in 7 adult patients with FD and 50 healthy control subjects. FD patients were re-tested after a mean follow-up period of 13 years. Compared to controls, FD patients had low plasma levels of DHPG (P < 0.001), high DOPA and DA levels (P = 0.01, P = 0.0002), and high NE:DHPG (P < 0.0001), DA:NE (P = 0.0003), and DOPA:DHPG (P < 0.0001) ratios. At follow-up there were no changes in plasma levels of individual catechols; however, there were further increases in DOPA:DHPG ratios (mean 24 ± 7%, P = 0.01). In FD, plasma catechol profiles are sufficiently stable, at least over a decade, to be used as a biomarker of disease involvement. An increasing DOPA:DHPG ratio suggests slight but consistent, progressive loss of noradrenergic neurons.     

Inhibition of yes‐associated protein suppresses brain metastasis of human lung adenocarcinoma in a murine model

Yes‐associated protein (YAP) is a main mediator of the Hippo pathway and promotes cancer development and progression in human lung cancer. We sought to determine whether inhibition of YAP suppresses metastasis of human lung adenocarcinoma in a murine model. We found that metastatic NSCLC cell lines H2030‐BrM3(K‐ras^G12C mutation) and PC9‐BrM3 (EGFR^Δexon19 mutation) had a significantly decreased p‐YAP(S127)/YAP ratio compared to parental H2030 (K‐ras^G12C mutation) and PC9 (EGFR^Δexon19 mutation) cells (P < .05). H2030‐BrM3 cells had significantly increased YAP mRNA and expression of Hippo downstream genes CTGF and CYR61 compared to parental H2030 cells (P < .05). Inhibition of YAP by short hairpin RNA (shRNA) and small interfering RNA (siRNA) significantly decreased mRNA expression in downstream genes CTGF and CYR61 in H2030‐BrM3 cells (P < .05). In addition, inhibiting YAP by YAP shRNA significantly decreased migration and invasion abilities of H2030‐BrM3 cells (P < .05). We are first to show that mice inoculated with YAP shRNA‐transfected H2030‐BrM3 cells had significantly decreased metastatic tumour burden and survived longer than control mice (P < .05). Collectively, our results suggest that YAP plays an important role in promoting lung adenocarcinoma brain metastasis and that direct inhibition of YAP by shRNA suppresses H2030‐BrM3 cell brain metastasis in a murine model.     

A pilot study of angiogenin in heart failure with preserved ejection fraction: a novel potential biomarker for diagnosis and prognosis?

Characteristics of heart failure with preserved ejection fraction (HFPEF) have not yet been fully understood. The objectives of this pilot study are to detect protein expression profile in the sera of HFPEF patients, and to identify potential biomarkers for the disease. Five hundred and seven proteins were detected in the sera of healthy volunteers and patients with either HFPEF or hypertension using antibody microarrays (three in each group). The results showed that the serum concentrations of 17 proteins (e.g. angiogenin, activin A and artemin) differed considerably between HFPEF and non‐HFPEF patients (hypertensive patients and healthy controls), while a protein expression pattern distinct from that in non‐HFPEF patients was associated with HFPEF patients. The up‐regulation of angiogenin in both HFPEF patients with LVEF ≥50% (P = 0.004) and a subset of HFPEF patients with LVEF = 41–49% (P < 0.001) was further validated in 16 HFPEF patients and 16 healthy controls. Meanwhile, angiogenin distinguished HFPEF patients from controls with a mean area under the receiver operating characteristic curve of 0.88 (P < 0.001) and a diagnostic cut‐off point of 426 ng/ml. Moreover, the angiogenin levels in HFPEF patients were positively correlated with Lg(N‐terminal pro‐B‐type natriuretic peptide, NT‐proBNP) (P < 0.001). In addition, high angiogenin level (≥426 ng/ml) was a predictor of all‐cause death within a short‐term follow‐up duration, but not in the longer term of 36 months. This pilot study indicates that the aforementioned 17 potential biomarkers, such as angiogenin, may hold great promise for both diagnosis and prognosis assessment of HFPEF.     

Simvastatin impairs the induction of pulmonary fibrosis caused by a western style diet: a preliminary study

The role of an atherogenic diet in causing pulmonary fibrosis has received little attention and simvastatin has been shown to reduce pulmonary fibrosis in animal models. To determine if an atherogenic diet can induce pulmonary fibrosis and whether simvastatin treatment is beneficial by up‐regulating heat shock protein 70 and 90. New Zealand white rabbits (n = 15) were divided: Group 1 (control); Group 2 (MC) received a normal rabbit diet with 1% methionine plus 0.5% cholesterol (atherogenic diet). Group 3 received the same diet as the MC group plus 5 mg/kg/day simvastatin orally (MCS). After 4 weeks, the lungs were collected and analysed. Picrosirus red staining of lung interstitial collagen content showed that the atherogenic diet increased fibrosis 2.9‐fold (P < 0.05), bronchiole adventitial collagen was increased 2.3‐fold (P < 0.05) and bronchiole epithelium was increased 34‐fold (P < 0.05), and simvastatin treatment severely reduced this effect (P < 0.05). Western blot analysis showed that the atherogenic diet significantly reduced lung Hsp70 protein by 22% (P < 0.05) and Hsp90 protein by 18% (P < 0.05) and simvastatin treatment did not affect this result. However, aortic hyper‐responsiveness to vasoconstrictors (angiotensin II and phenylephrine) were markedly reduced by simvastatin treatment. We report that an atherogenic diet stimulates pulmonary fibrosis and reduces lung Hsp70/Hsp90 protein concentration. Simvastatin impairs this by mechanisms unrelated to Hsp70/Hsp90, but possibly a reduction in angiotensin II receptor or alpha adrenergic receptor pathways. These results could have implications in idiopathic pulmonary fibrosis.     

High ambient temperature exposure during late gestation disrupts glycolipid metabolism and hepatic mitochondrial function tightly related to gut microbial dysbiosis in pregnant mice

As global warming intensifies, emerging evidence has demonstrated high ambient temperature during pregnancy negatively affects maternal physiology with compromised pregnant outcomes; however, little is known about the roles of gut microbiota and its underlying mechanisms in this process. Here, for the first time, we explored the potential mechanisms of gut microbiota involved in the disrupted glycolipid metabolism via hepatic mitochondrial function. Our results indicate heat stress (HS) reduces fat and protein contents and serum levels of insulin and triglyceride (TG), while increases that of non-esterified fatty acid (NEFA), β-hydroxybutyric acid (B-HBA), creatinine and blood urea nitrogen (BUN) (P < 0.05). Additionally, HS downregulates both mitochondrial genes (mtDNA) and nuclear encoding mitochondrial functional genes with increasing serum levels of malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) (P < 0.05). Regarding microbial response, HS boosts serum levels of lipopolysaccharide (LPS) (P < 0.05) and alters β-diversity (ANOSIM, P < 0.01), increasing the proportions of Escherichia–Shigella, Acinetobacter and Klebsiella (q < 0.05), while reducing that of Ruminiclostridium, Blautia, Lachnospiraceae_NK4A136_group, Clostridium VadinBB60 and Muribaculaceae (q < 0.05). PICRUSt analysis predicts that HS upregulates 11 KEGG pathways, mainly including bile secretion and bacterial invasion of epithelial cells. The collective results suggest that microbial dysbiosis due to late gestational HS has strong associations with damaged hepatic mitochondrial function and disrupted metabolic profiles.