CS12192, a novel JAK3/JAK1/TBK1 inhibitor, attenuates autoimmune dermatoses in murine models.

OBJECTIVE: Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models. METHODS: Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly. RESULTS: In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor. CONCLUSION: Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.

Mechanistic insights into poly(C)-binding protein hnRNP K resolving i-motif DNA secondary structures.

I-motifs are four-strand noncanonical secondary structures formed by cytosine (C)-rich sequences in living cells. The structural dynamics of i-motifs play essential roles in many cellular processes, such as telomerase inhibition, DNA replication, and transcriptional regulation. In cells, the structural dynamics of the i-motif can be modulated by the interaction of poly(C)-binding proteins (PCBPs), and the interaction is closely related to human health, through modulating the transcription of oncogenes and telomere stability. Therefore, the mechanisms of how PCBPs interact with i-motif structures are fundamentally important. However, the underlying mechanisms remain elusive. I-motif structures in the promoter of the c-MYC oncogene can be unfolded by heterogeneous nuclear ribonucleoprotein K (hnRNP K), a PCBP, to activate its transcription. Here, we selected this system as an example to comprehensively study the unfolding mechanisms. We found that the promoter sequence containing 5 C-runs preferred folding into type-1245 to type-1234 i-motif structures based on their folding stability, which was further confirmed by single-molecule FRET. In addition, we first revealed that the c-MYC i-motif structure was discretely resolved by hnRNP K through two intermediate states, which were assigned to the opposite hairpin and neighboring hairpin, as further confirmed by site mutations. Furthermore, we found all three KH (hnRNP K homology) domains of hnRNP K could unfold the c-MYC i-motif structure, and KH2 and KH3 were more active than KH1. In conclusion, this study may deepen our understanding of the interactions between i-motifs and PCBPs and may be helpful for drug development.

Insights into the structural dynamics and helicase-catalyzed unfolding of plant RNA G-quadruplexes.

RNA G-quadruplexes (rG4s) are noncanonical RNA secondary structures formed by guanine (G)-rich sequences. These complexes play important regulatory roles in both animals and plants through their structural dynamics and are closely related to human diseases and plant growth, development, and adaption. Thus, studying the structural dynamics of rG4s is fundamentally important; however, their folding pathways and their unfolding by specialized helicases are not well understood. In addition, no plant rG4-specialized helicases have been identified. Here, using single-molecule FRET, we experimentally elucidated for the first time the folding pathway and intermediates, including a G-hairpin and G-triplex. In addition, using proteomics screening and microscale thermophoresis, we identified and validated five rG4-specialized helicases in Arabidopsis thaliana. Furthermore, DExH1, the ortholog of the famous human rG4 helicase RHAU/DHX36, stood out for its robust rG4 unwinding ability. Taken together, these results shed light on the structural dynamics of plant rG4s.

Antitumor and immunomodulatory effects of a novel multitarget inhibitor, CS2164, in mouse hepatocellular carcinoma models.

As a novel orally active multitarget small molecule inhibitor, CS2164 has shown broad antitumor activities against several human tumor xenograft models in immune-compromised mice. However, the ability of CS2164 to modulate antitumor immunity in an immune-competent mouse tumor model remains undefined, although antiangiogenic treatment has been reported to affect immune cell infiltration and remodel the tumor immune microenvironment. In the present study, the subcutaneous and ascites hepatocellular carcinoma (HCC) models in syngeneic Balb/c mice established by inoculation of an H22 hepatoma cell line were utilized to investigate the antitumor and immunomodulatory effects of CS2164. Although the antitumor effects of CS2164 were validated in both subcutaneous and ascites HCC models in syngeneic mice, CS2164 treatment consistently modulated immune cell populations, both in the periphery and in tumor microenvironments, with upregulation of CD4 and CD8 T cells in the spleen, but downregulation of immunosuppressive populations including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages in the spleen and tumor tissues. Furthermore, CS2164 increased the relative gene expression and protein production of several proinflammatory cytokines in tumor-related ascites. These results indicate that CS2164 exerts an antitumor effect associated with its immunomodulatory activities in mouse HCC models, and may also provide evidence for the immunotherapy potentiation of CS2164 in future cancer treatment.

CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.

Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R+ cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer.

CS12192: A novel selective and potent JAK3 inhibitor mitigates acute graft-versus-host disease in bone marrow transplantation.

BACKGROUND: Despite the significant role of JAK3 in various autoimmune diseases, including graft-versus-host disease (GVHD), there has been a lack of potent and selective JAK3 inhibitors specifically studied for GVHD. In our preclinical investigations, we evaluated a novel JAK3 inhibitor called CS12192, which is already undergoing clinical investigation in autoimmune diseases. METHODS: We evaluated the efficacy of CS12192 in GVHD through mixed lymphocyte reaction (MLR) in both mouse and human cells, as well as allogeneic bone marrow transplantation (BMT) in a murine model. RESULTS: CS12192, starting at a concentration of 0.5 µM, dose-dependently reduced the intracellular positivity for cytokines TNF-α and IFN-γ in CD4+ T cells (p < 0.05 to p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001) during mouse allogeneic MLR assays. This effect was observed for both single and double positivity of the cytokines. Moreover, In MLR assays with three different human donors, CS12192 also demonstrated a dose-dependent reduction in the proportion of IFN-γ positive CD4+ T cells (p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001). Additionally, it suppressed T cell proliferation in the mouse MLR (p < 0.05 to p < 0.0001), but this effect was observed in only one human donor (p < 0.001 to p < 0.0001). Furthermore, the administration of CS12192 at 40 and 80 mg/kg BID significantly improved the survival rate in the BMT model, resulting in cumulative 62-day survival rates of 88.89% (p < 0.01) and 100% (p < 0.001), respectively, compared with prednisolone (p < 0.05). CONCLUSIONS: CS12192 is a novel, potent and selective JAK3 inhibitor demonstrating great potential to mitigate acute GVHD.

Comprehensive insights into the structures and dynamics of plant telomeric G-quadruplexes.

Telomeres, which are located at the ends of eukaryotic chromosomes, are crucial for genomic maintenance. Most telomeric DNA is composed of tandemly repeated guanine (G)-rich sequences, which form G-quadruplexes (G4s). The structures and dynamics of telomeric G4s are essential for telomere functioning and helpful for G4-based biosensing. However, they are far from being understood, especially for plants. In this contribution, the folding, environment-induced G4 dynamics, and protein-catalyzed unfolding of plant telomeric G4s were comprehensively studied. It was found that diverse plant telomeric sequences from land plants to green algae could fold into G4 structures. In addition, 5'-proximal ssDNA but not 3'-proximal ssDNA drove conversion of anti-parallel G4 structures to parallel structures, and both 5' and 3' ssDNA decreased the stability of G4s in dilute solution. Furthermore, molecular crowding promoted the formation of parallel structures for three-layer but not for two-layer G4s, and increased the stability of all selected G4s. Finally, AtRecQ2 helicase resolved the stable parallel structure of typical plant telomeric G4 in crowded solution, but ssDNA binding protein AtRPA did not. Furthermore, AtRecQ2 unwound the structure more efficiently in the presence of AtRPA. The results may expand our understanding on the structures and dynamics of plant telomeric G4s.

Characteristics of phytoplankton community and its influencing factors in the Yanhe River Basin, Northwest China.

Yanhe River is one of the important tributaries of the Yellow River, with a vital role in the maintenance of biodiversity and ecological conservation in the middle reaches of the Yellow River. In this study, we conducted a systematic aquatic ecological survey of the Yanhe River Basin in spring (April-May) and autumn (September-October) of 2021, with phytoplankton as indicator organism. A total of 33 sampling sections were selected in the mainstem, five first-class tributaries, and impounded water bodies (reservoir and check dam water bodies) of the Yanhe River Basin. The results showed that a total of 253 phytoplankton species, belonging to 7 phyla and 91 genera, were detected in the two surveys. Diatoms and green algae prevailed in spring (168 species), while diatoms and cyanobacteria dominated in autumn (179 species). The mean phytoplankton density and biomass were 316.07×104 cells·L-1 and 6.41 mg·L-1 in spring, and 69.56×104 cells·L-1 and 1.59 mg·L-1 in autumn, respectively. At the temporal scale, phytoplankton abundance in spring was higher than that in autumn. At the spatial scale, the phytoplankton abundance in the middle and lower reaches of the mainstream was higher than that in the upper reaches. Phytoplankton biomass in the impounded water bodies formed by dam interception was maintained at a high level, which was significantly higher than that in the mainstem and tributary water bodies in autumn. The phytoplankton diversity, as indicated by Shannon diversity index, Margalef richness index, and Pielou evenness index, in spring was greater than that in autumn. Phytoplankton diversity was greater in the trunk and tributary waters than that in impounded waters. The results of redundancy analysis showed that the key factors driving the phytoplankton community structure in spring were flow velocity, dissolved oxygen, nitrite nitrogen, and water depth. In contrast, the key driving factors in autumn were nitrate nitrogen, water depth, and dissolved oxygen.

Application of the kurtosis statistic to the evaluation of the risk of hearing loss in workers exposed to high-level complex noise.

OBJECTIVE: Develop dose-response relations for two groups of industrial workers exposed to Gaussian or non-Gaussian (complex) types of continuous noises and to investigate what role, if any, the kurtosis statistic can play in the evaluation of industrial noise-induced hearing loss (NIHL). DESIGN: Audiometric and noise exposure data were acquired on a population (N = 195) of screened workers from a textile manufacturing plant and a metal fabrication facility located in Henan province of China. Thirty-two of the subjects were exposed to non-Gaussian (non-G) noise and 163 were exposed to a Gaussian (G) continuous noise. Each subject was given a general physical and an otologic examination. Hearing threshold levels (0.5-8.0 kHz) were age adjusted (ISI-1999) and the prevalence of NIHL at 3, 4, or 6 kHz was determined. The kurtosis metric, which is sensitive to the peak and temporal characteristics of a noise, was introduced into the calculation of the cumulative noise exposure metric. Using the prevalence of hearing loss and the cumulative noise exposure metric, a dose-response relation for the G and non-G noise-exposed groups was constructed. RESULTS: An analysis of the noise environments in the two plants showed that the noise exposures in the textile plant were of a Gaussian type with an Leq(A)8hr that varied from 96 to 105 dB whereas the exposures in the metal fabrication facility with an Leq(A)8hr = 95 dB were of a non-G type containing high levels (up to 125 dB peak SPL) of impact noise. The kurtosis statistic was used to quantify the deviation of the non-G noise environment from the Gaussian. The dose-response relation for the non-G noise-exposed subjects showed a higher prevalence of hearing loss for a comparable cumulative noise exposure than did the G noise-exposed subjects. By introducing the kurtosis variable into the temporal component of the cumulative noise exposure calculation, the two dose-response curves could be made to overlap, essentially yielding an equivalent noise-induced effect for the two study groups. CONCLUSIONS: For the same exposure level, the prevalence of NIHL is greater in workers exposed to non-G noise environments than for workers exposed to G noise. The kurtosis metric may be a reasonable candidate for use in modifying exposure level calculations that are used to estimate the risk of NIHL from any type of noise exposure environment. However, studies involving a large number of workers with well-documented exposures are needed before a relation between a metric such as the kurtosis and the risk of hearing loss can be refined.

Utilizing benchmarked dataset and gene regulatory network to investigate hub genes in postmenopausal osteoporosis.

OBJECTIVE: The objective of this paper was to investigate hub genes of postmenopausal osteoporosis (PO) utilizing benchmarked dataset and gene regulatory network (GRN). MATERIALS AND METHODS: To achieve this goal, the first step was to benchmark the dataset downloaded from the ArrayExpress database by adding local noise and global noise. Second, differentially expressed genes (DEGs) between PO and normal controls were identified using the Linear Models for Microarray Data package based on benchmarked dataset. Third, five kinds of GRN inference methods, which comprised Zscore, GeneNet, context likelihood of relatedness (CLR) algorithm, Partial Correlation coefficient with Information Theory (PCIT), and GEne Network Inference with Ensemble of trees (Genie3), were described and evaluated by receiver operating characteristic (ROC) and precision and recall (PR) curves. Finally, GRN constructed according to the method with best performance was implemented to conduct topological centrality (closeness) for the purpose of investigate hub genes of PO. RESULTS: A total of 236 DEGs were obtained based on benchmarked dataset of 20,554 genes. By assessing Zscore, GeneNet, CLR, PCIT, and Genie3 on the basis of ROC and PR curves, Genie3 had a clear advantage than others and was applied to construct the GRN which was composed of 236 nodes and 27,730 edges. Closeness centrality analysis of GRN was carried out, and we identified 14 hub genes (such as TTN, ACTA1, and MYBPC1) for PO. CONCLUSION: In conclusion, we have identified 14 hub genes (such as TN, ACTA1, and MYBPC1) based on benchmarked dataset and GRN. These genes might be potential biomarkers and give insights for diagnose and treatment of PO.

Therapeutic treatment of a novel selective JAK3/JAK1/TBK1 inhibitor, CS12192, in rat and mouse models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic inflammation and joint destruction. Although biological inhibitors such as TNF-α and IL-6 antibodies have achieved success in clinical therapy, small molecule inhibitors against the Janus kinases (JAKs) involved in the signaling pathways of various cytokine receptors have gained more attraction as safe and efficacious options. In this study, we identified CS12192 as a novel selective JAK3/JAK1/TBK1 inhibitor and investigated its pharmacological effects on the experimental arthritis models in rat and mouse. We found that CS12192 showed a more selective inhibitory activity on JAK3, and to a less extent on JAK1 and TBK1, that were verified by decreased activation of p-STATs and p-IRF3 as well as down-regulation of IFN gene expression in the cultured cells with relevant stimuli. Furthermore, oral treatment with CS12192 dose-dependently ameliorated the disease severity, hind paw swelling, body weight loss, and bone destruction in rat models of adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA). In a mouse CIA model, CS12192 also attenuated the disease severity, which was correlated with the suppressed CD4+ T cell activation and Th17 function, as well as the reduced cytokine levels in sera and pro-inflammatory cytokine and chemokine gene expression in joint tissue. Corroboratively, RANKL-induced osteoclast formation was inhibited by CS12192. Thus, these results suggest that CS12192 as a novel selective JAK inhibitor has therapeutic potential for the treatment of RA and may provide a new strategy for the control of autoimmune diseases.

Naringenin and hesperetin, two flavonoids derived from Citrus aurantium up-regulate transcription of adiponectin.

The dried, immature fruit of Citrus aurantium L., 'Zhiqiao' in Chinese, has been used to treat cardiovascular diseases in traditional Chinese medicine for centuries. Naringenin and hesperetin and their glycosides present in considerable amounts (about 10 approximately 15%) in the herb. The aim of this study is to test whether naringenin and hesperetin influence adiponectin expression, which plays an important role in glucose and lipid metabolism with antiatherogenic and anti-inflammatory properties. Treatment with naringenin and hesperetin enhanced adiponectin transcription in differentiated 3T3-L1 cells. Both naringenin and hesperetin induced peroxisome proliferator-activated receptor (PPAR)gamma-controlled luciferase expression in a dose-dependent manner (20-160 microM), whereas only naringenin possessed significant activity to activate PPARalpha. These results suggested the two flavonoids might exert antiatherogenic effects partly through activating PPAR and up-regulating adiponectin expression in adipocytes. Our findings give new insight for the molecular explanations for the therapeutic effects of Zhiqiao.

Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ.

Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.

Peroxisome proliferator-activated receptor-gamma transcriptionally up-regulates hormone-sensitive lipase via the involvement of specificity protein-1.

Both peroxisome proliferator-activated receptor (PPAR)-gamma and hormone-sensitive lipase (HSL) play important roles in lipid metabolism and insulin sensitivity. We demonstrate that expression of the HSL gene is up-regulated by PPARgamma and PPARgamma agonists (rosiglitazone and pioglitazone) in the cultured hepatic cells and differentiating preadipocytes. Rosiglitazone treatment also results in up-regulation of the HSL gene in liver and skeleton muscle from an experimental obese rat model, accompanied by the decreased triglyceride content in these tissues. The proximal promoter (-87 bp of the human HSL gene) was found to be essential for PPARgamma-mediated transactivating activity. This important promoter region contains two GC-boxes and binds the transcription factor specificity protein-1 (Sp1) but not PPARgamma. The Sp1-promoter binding activity can be endogenously enhanced by PPARgamma and rosiglitazone, as demonstrated by analysis of EMSA and chromatin immunoprecipitation assay. Mutations in the GC-box sequences reduce the promoter binding activity of Sp1 and the transactivating activity of PPARgamma. In addition, mithramycin A, the specific inhibitor for Sp1-DNA binding activity, abolishes the PPARgamma-mediated up-regulation of HSL. These results indicate that PPARgamma positively regulates the HSL gene expression, and up-regulation of HSL by PPARgamma requires the involvement of Sp1. Taken together, this study suggests that HSL may be a newly identified PPARgamma target gene, and up-regulation of HSL may be an important mechanism involved in action of PPARgamma agonists in type 2 diabetes.

The PPARalpha/gamma dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats.

1. The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipid-lowering effect is mediated through its activation of PPARalpha. 2. Chiglitazar is a PPARalpha/gamma dual agonist. 3. The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats. 4. Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets. 5. Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARalpha, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats. 6. These data suggest that PPARalpha/gamma coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARgamma agonists.

[Adjustment of dose-response relationship of industrial impulse noise induced high frequency hearing loss with different exchange rate].

OBJECTIVE: To explore a new method to evaluate the dose-response relationship between the noise exposure and prevalence of noise induced high frequency hearing loss. METHODS: Physical examination and questionnaire survey were conducted among 32 mechanical workers, 12 males and 20 females, aged 35.1 +/- 7.2, exposed to industrial impulse noise (impulse noise group), and 163 textile workers, 82 males and 81 females, aged 31.5 +/- 8.7, exposed continuous noise (continuous noise group). SH-126 dosimeter was used to measure the A weighted equal sound level in continuous eight working hours (L(Aeq.8h)) so as to evaluate the individual noise exposure. Cumulative noise exposure (CNE) was calculated with the values of L(Aeq.8h) and noise working year adjusted by different exchange rates (ERs) for each worker. Hearing threshold was measured by audiometer with routine method and adjusted by age and gender according to GBZ49-2002. High frequency hearing loss was diagnosed based on the GBZ49-2002 for each worker. RESULTS: According to the equal energy rule, with the ER = 3 the CNE of the impulse noise group was [103.2 dB (A).year +/- 4.2dB (A).year], significantly lower than that of the continuous noise group [110.6 +/- 6.0 dB (A).year, P < 0.05]. With the ER = 5.5, the CNE of the impulse noise group was 110.3 +/- 6.6 dB (A).year, not significantly different from that of the continuous noise group [110.6 +/- 6.0 dB (A).year]. The high frequency hearing loss prevalence of the impulse noise group was 68.8%, not significantly different that of the continuous noise group (65%, P > 0.05). Trend chi square test showed significant differences in the relationship between CNE and hearing loss prevalence among the impulse noise group with the ER = 3, the impulse noise group with the ER = 5.5, and continuous noise group (all P < 0.01). With the ER = 3, the high frequency hearing loss prevalence of the impulse noise group with the CNE of 100-104 dB (A).year was 76.9%, significant higher than that of the continuous noise group (30.4%, P < 0.05); and the high frequency hearing loss prevalence of the impulse noise group with the CNE of 105-108 dB (A).year was 90.9%, significantly higher than that of the continuous noise group (50.0%, P < 0.05). With the ER = 5.5, there was no difference in the prevalence of high frequency hearing loss between the continuous noise group and impulse noise group. Logistic regression model showed that with the ER = 3, the dose-response curve of the impulse noise group presented a left shift and with a slope sharper than that of the continuous noise group. With the ER increasing the dose-response curve of the impulse noise group showed a right shift and with a gradually lowering slope. When the ER equaled to 6 in the impulse noise group and equaled to 3 in the continuous noise group, the two dose-response curves were almost superposed. CONCLUSION: Impulse noise causes more serious damage in causing high frequency hearing loss than continuous noise according to equal energy rule. Increasing the ER value in the impulse noise group adjusts the dose-response curve to be close to that of the continuous noise group.

[Relationship between sample size and variation of means for personal noise exposure in weaving workers].

OBJECTIVE: To explore the relationship between sample size and variance of means for personal noise exposure in weaving workers as to contributing evidence for establishing personal noise exposure measurement guideline. METHODS: A personal noise exposure measurement database from a group of weaving workers was used in the randomized re-sampling data analysis. The sampling cases were one number selecting from one to fifteen at each randomized re-sampling procedure. The randomized re-sampling was one thousand times from original personal noise exposure measurement database to get one thousands of re-sampling database. One thousands of L(Aeq.8 h) mean were calculated by re-sampling databases. The variation of randomized re-sampling means was analyzed for different re-sampling numbers. RESULTS: The change for narrow trend of maximum, minimum, 95 percent number, 5 percent number of L(Aeq.8 h) mean was faster when randomized re-sampling number was smaller in variation vs randomized re-sampling number curve analysis. After that, the change for narrow trend of L(Aeq.8 h) mean was smooth for increasing the randomized re-sampling numbers. The 95% - 5% of L(Aeq.8 h) mean was about half for randomized re-sampling four cases (3.30 dB) vs one case (7.40 dB), and about one third for seven cases (2.44 dB), and about one fourth for eleven cases (1.85 dB). CONCLUSION: The sample size in personal noise exposure measurement guideline could be selected from four to eleven.

[Relationship between impulse noise and continuous noise inducing hearing loss by dosimeter measurement in working populations].

OBJECTIVE: To compare the dose-response relationship differences between impulse noise exposure workers and continuous noise exposure workers in prevalence of noise inducing hearing loss using dosimeter measurement. METHODS: Thirty-two mechanical workers in a workshop were selected as impulse noise group and 163 textile workers in a textile factory as continuous noise group. SH-126 dosimeter was used to measure A weighted equal sound level of eight hours (L(Aeq.8 h)) during full working duration with equal energy rule for the selected workers. The cumulative noise exposure (CNE) was calculated by L(Aeq.8 h) and noise working years with equal energy rule for each worker. Hearing thresholds were measured by audiometer by routine method and adjusted by age and gender with GBZ49 - 2002. Hearing loss was diagnosed by GBZ49 - 2002 for each worker. RESULTS: CNE of impulse noise group [(103.2 +/- 4.2) dB (A) .year] was found lower than the continuous noise group [(110.6 +/- 6.0) dB (A) .year] by significance, P < 0.05. The hearing loss prevalence of impulse noise group (68.8%) was similar as continuous noise group (65%) without significance, P > 0.05. Strata analysis showed the hearing loss prevalence in 100 - 104 dB (A) .year and 105 - 109 dB (A) .year of impulse noise group was double than that of continuous noise group (76.9%, 90.9% vs 30.4%, 50.0%), P < 0.05. The chi-square test showed a relationship between CNE and hearing loss prevalence that was in high significance (P < 0.01) in both impulse noise group and continuous noise group. Logistic regression model showed the dose-response relationship curve of impulse noise group was left shift and sharp slope. CONCLUSION: The damage of impulse noise on hearing loss was much more than that of continuous noise according to equal energy rule of dosimeter data.

Increased Neutrophil-Lymphocyte Ratio Is a Poor Prognostic Factor in Patients with Esophageal Cancer in a High Incidence Area in China.

BACKGROUND AND AIMS: Neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR) have been assumed to be a marker to predict the survival of patients with different types of cancer. We undertook this study to verify the prognostic value of the NLR and the PLR for predicting the survival rate of patients with esophageal cancer in a high incidence area in China. METHODS: In total, 820 cases from a high incidence area that had pathologically confirmed esophageal cancers initially diagnosed at the Fourth Hospital of Hebei Medical University from 2007-2008 were analyzed. The medical record system was used to collect patient information regarding personal details, cancer type, treatment, and routine blood examinations at the time of admission. Follow-up evaluations were conducted by the established follow-up system at the hospital. We used Kaplan-Meier method to calculate overall survival (OS) rate. We used Cox regression analysis to analyze the factors that may affect the OS rate of the patients. SPSS 13.0 and Excel software packages were used for statistical analysis. RESULTS: In total, 864 cases were consistent with the inclusion criterion. At the end of the study, 820 cases received follow-up evaluation. Follow-up rate was 94.91%. Among the 820 cases, 334 died of esophageal cancer, whereas 486 remain alive as of March 15, 2014. Five-year OS rate of the patients with esophageal cancer was 40.66%. Patients in the NLR ≥3.5 group demonstrated shorter OS than patients in the NLR <3.5 group (53.2 vs. 33.4 months, p = 0.001). Multivariate analysis indicated that age, pathological type, TNM stage, surgery and NLR were all independent risk factors for esophageal cancer. OR of NLR ≥3.5 group was 1.287 (1.049-1.580). CONCLUSIONS: NLR may be an independent prognostic factor for esophageal cancer in high incidence areas.

Sequence analysis of F gene of SF02 isolate of goose paramyxovirus and its identification by multiplex RT-PCR.

The complete F gene of SF02 of goose paramyxovirus (GPV) has been cloned and analyzed. The sequence analysis demonstrated that the F gene of SF02 contains 1 662 nt and encodes 553 amino acids, and its cleavage activation site of F gene has the same deduced amino acid sequence, (112)R-R-Q-K-R-F(117), as the velogenic (highly pathogenic) strain of newcastle disease virus. The latter correlated with the virulence of the isolate in biological assays. The F gene of SF02 isolate with the domestic standard velogenic strain NDV, F48E9, shared 86.5% homology in nucleotide and 90.8% homology in amino acid sequences. The SF02 isolate is closer to some NDV strains prevalent in Taiwan and West-European countries in recent years. Based on the F gene sequence a multiplex RT-PCR method has been developed. It could be used for the discrimination of GPV from NDV.