[Serum glycocalyx markers in patients after cardiac arrest: association with outcomes].

Objective: To assess the levels of serum glycocalyx markers in the first 24 hours after cardiac arrest (CA) and investigate their relationship with 30-day outcomes. Methods: A retrospective cohort study was conducted on prospectively collected data from CA patients, who were admitted to the intensive care units of the Affiliated Hospital of Xuzhou Medical University and obtained return of spontaneous circulation for more than 24 hours between September 2021 and October 2022. Serum samples obtained at the 24-hour after CA were utilized to measure the levels of glycocalyx markers, including heparan sulfate (HS), hyaluronic acid (HA), and syndecan-1 (Sdc-1). Patients were allocated into good function (CPC1-2) and poor function (CPC3-5) groups on the basis of cerebral performance category (CPC) at 30 days post-CA. Logistic regression analysis was used to determine the association between serum glycocalyx markers and neurological outcomes. Patients were regrouped in light of 30-d mortality and Cox regression analysis was used to determine the association between serum glycocalyx markers and 30-d mortality. Results: A total of 71 patients were included in the study, including 31 (43.7%) females and 40 (56.3%) males, with an average age of (59.0±17.0) years. The poor function group (n=49) demonstrated significantly elevated levels of HS and HA when compared to the good function group (n=22) [HS: 2 461.0(1 623.0, 5 492.0) µg/L vs 1 492.0 (914.0, 2 550.0) µg/L, P=0.008; HA: 124.0(97.0, 365.0)µg/L vs 337.0(135.0, 1 421.0) µg/L, P=0.033]. Adjusted logistic regression analysis revealed that HS was independently associated with poor neurological outcome [odds ratio (OR)=0.389, 95% confidence interval (CI): 0.182-0.828, P=0.014]. In the 30-day mortality analysis, the death group (n=32) exhibited significantly higher levels of HS and HA when compared to the survival group (n=39) [HS: 1 880.0(1 011.0, 3 554.0) µg/L vs 2 500.0(1 726.0, 6 276.0) µg/L, P=0.027; HA: 162.0(99.0, 537.0) µg/L vs 813.0(148.0, 1 531.0) µg/L, P=0.025]. Adjusted Cox regression analysis indicated that elevated levels of HS and HA were independent risk factors (HS: HR=1.697, 95%CI: 1.126-2.557, P=0.011; HA: HR=1.336, 95%CI: 1.047-1.705, P=0.020) for 30-day mortality. Conclusions: High level of serum HS in 24 hours after CA may serve as a potential predictive marker for both neurological function and 30-day mortality. However, high level of serum HA appears to primarily predict 30-day mortality. Sdc-1 does not seem to contribute to outcome prediction.

[Application of near infrared fluorescence imaging in detection of residual cancer in oral squamous cell carcinoma].

Objective: Local recurrence is the main cause of treatment failure in patients with oral squamous cell carcinoma (OSCC). This study was proposed to investigate the feasibility of near infrared fluorescence (NIF) via indocyanine green (ICG) for monitoring surgical marginal in operation for OSCC patients. Methods: In 35 patients with OSCC treated surgically in the Department of Oral and Maxillofacial Surgery, Nanjing University School of Medicine, from January 2019 to June 2020, ICG (0.75 mg/kg) was administered intravenously via elbow vein at (12±1) hours before surgery, and NIF was performed intraoperatively on the surgical field and the cut edge of the surgically excised specimen, and fluorescence intensity was measured for OSCC tissue and normal oral mucosa, abnormal fluorescence signals were taken and subjected to rapid cryopathological examination. Correlation between NIF tumor boundary grading and pathological tumor boundary grading was analyzed by Spearman correlation analysis. Results: Clear ICG NIF was obtained for tumor lesions in all 35 patients, with a positive rate of 100%. The fluorescence intensity of OSCC tissue was (412.73±146.56) au, which was higher than that of normal oral mucosa tissue [(279.38±82.56) au, P<0.01]. Abnormal fluorescence signals were detected at the tumor bed and the cut edge of the surgical resection specimen in 4 patients, of which 2 cases were pathologically confirmed as cancer cell residue and 2 cases as inflammatory cell infiltration. The rate of positive detection of cut margins using ICG NIF technique in OSCC was 5.7% (2/35). Twenty of the 35 OSCC patients had grade 1, 11 of grade 2, and 4 of grade 3 tumor borders revealed by NIF of surgical resection specimens, which was positively correlated with pathological tumor border (r=0.809, P<0.001). Conclusions: ICG NIF technique can effectively detect the residual cancer cells at the incision margin, which is of great clinical value in reducing local recurrence of OSCC after surgery due to intraoperative cancer residue.

[Investigation on noise exposure level and health status of workers in transportation equipment manufacturing industry].

Objective: To explore the noise exposure level and the health status of workers in transportation equipment manufacturing industry, and provide a scientific basis for guidance and implementation of intervention measures. Methods: From January to December in 2019, a total of 2088 noise workers from a large enterprise were selected by cluster sampling method in railway transportation equipment manufacturing, automobile manufacturing and aerospace aircraft manufacturing enterprises. The worker's noise exposure level was detected. Occupational health checkups were performed on the noise workers including electrical audiometry, blood pressure and electrocardiogram. χ(2) test and trend χ(2) test were used to analyze the data. Results: The noise exposure level of 66.9% (1396/2088) workers exceeded 85 dB (A) , and the median noise level was 87.9 (84.3-90.3) dB (A) . Among them, workers of railway transportation equipment manufacturing enterprises had the highest noise exposure level[89.9 (87.8-91.6) dB (A) ]. The detection rate of high-frequency hearing loss, abnormal blood pressure and abnormal electrocardiogram of noise workers were 15.7% (327/2088) , 18.1% (378/2088) and 6.1% (128/2088) , respectively. The differences in the detection rates of high-frequency hearing loss, abnormal blood pressure, and abnormal electrocardiogram in workers of railway transportation equipment manufacturing enterprises, automobile manufacturing enterprises, and aerospace manufacturing enterprises were statistically significant (P<0.05) . Workers of railway transportation equipment manufacturing enterprises had higher detection rates of high-frequency hearing loss (17.6%, 186/1056) . Workers of aerospace manufacturing enterprises had higher detection rates of abnormal blood pressure and abnormal electrocardiogram (26.3%, 169/642; 10.0%, 64/642) . The differences in the detection rates of high-frequency hearing loss, abnormal blood pressure and abnormal electrocardiogram of noise workers were statistically significant in different age and working age groups, and gradually increased with age and working age (P<0.05) . The difference in the detection rate of high-frequency hearing loss of noise workers was statistically significant in different noise intensity groups, and the overall trend was increasing (P<0.05) . Conclusion: The transportation equipment manufacturing industry has serious noise hazards, especially the railway transportation equipment manufacturing industry. Long-term occupational noise exposure can adversely affect workers' hearing and cardiovascular system. Enterprises should strengthen occupational health inspections, and at the same time, take personal protective measures to protect the health of workers.

[Analysis of hearing surveillance of noise-exposed workers in Zhuzhou city].

Objective: To understand the hearing loss status of workers exposed to noise, and provide a scientific basis for formulating effective prevention and control strategies. Methods: From Januaryl to October 31 , 2018, through the occupational hazard declaration and record management system of the workplace and the health checkup system , the basic information and physical examination information of 7806 noise-exposed workers in 136 companies in Zhuzhou City in 2018 and the related information about the industry, type, and scale of the enterprises were collected. The χ(2) test was used to analyze the occupational health monitoring data of the noise-exposed workers. Results: The average age of 7806 workers in Zhuzhou was(36. 1±9. 3) years, and the working age was 7. 0(3. 0, 11. 0) years. And 1 270 workers with noise induced hearing loss(NIHL) were detected, including 51 suspected occupational noise deafness. The detection rates of NIHL and the suspected occupational noise deafness were 16. 27% , 0. 65% , respectively. The detection rate of noise was 0.01% in 1deaf person. It showed that the male had higher morbidity than the female (P<0. 05) and the workers with longer exposure time had a higher morbidity (P<0. 05) . There was a statistically significant difference in the detection rate of NIHL and suspected occupational noise deafness between workers of different types of work (P<0. 05 ) . It was noted that the morbidity varied in different enterprises, industry types and terms of scales (P<0. 05 ) . Non- metal ore mining and dressing industry workers had higher NIHL detection rate (33. 33%, 14/42) and small companies workers had higher NIHL detection rate(19. 32%, 296/1532) . There was a statistically significant difference in the detection rate of suspected occupational noise deafness between workers of different economic types of enterprises. There was a high detection rate of suspected occupational noise deafness among workers in private enterprises(1. 29%, 36/2782) . Conclusion: The noise operation in Zhuzhou is seriously endangered.Occupational health protection measures for non-metallic mining and dressing industries, small and private enterprises should be strengthened.Occupational health law enforcement efforts should be strengthened to protect workers' health.

Applicability of first-trimester combined screening for fetal trisomy 21 in a resource-limited setting in mainland China.

OBJECTIVE: To assess the feasibility and performance of the first-trimester combined screening test for trisomy 21 in a resource-limited setting in mainland China. DESIGN: Prospective observational cohort study. SETTING: First Affiliated Hospital of Kunming Medical University, China. POPULATION: Ten thousand four hundred and forty-two pregnant women requesting first-trimester screening. METHODS: The combined screening test was performed from May 2012 to December 2014. Women with a high-risk result (≥1:600) were offered further confirmatory tests after counselling. The threshold for high risk was determined by Monte Carlo simulation to achieve a 5% false-positive rate according to the local age distribution. Pregnancy outcome and screening results were recorded for all women and monthly audits were conducted. MAIN OUTCOME MEASURES: Sensitivity, screen positive rate, cost per case of Down syndrome detected. RESULTS: Six hundred and ten women (5.8% of the total screened) had a high-risk screening test, of whom 274 (44.9%) underwent a diagnostic test and 169 (27.7%) opted for a noninvasive prenatal screening test (NIPT); 160 (26.2%) declined further testing after counselling. The pregnancy outcome was available for 10 174 (97.4%) of the women. The observed incidence of Down syndrome was 0.13% (1/750). All 14 women with a trisomy 21 pregnancy had a high-risk screening test result. The cost per Down syndrome detected was RMB596 686 compared with RMB1.79 million if all had been screened by NIPT. CONCLUSIONS: The combined screening test appears to be a more cost-effective strategy in mainland China. Screening performance in China would be improved by adopting Chinese-specific models, external quality control and assurance, and establishing risk thresholds appropriate for the age distribution of the population. TWEETABLE ABSTRACT: Combined first-trimester Downs screening in China was improved by adopting Chinese-specific models and external QC.

[A preliminary evaluation of mental status and an investigation of occupational health knowledge demand in operating and maintenance personnel in wind power plants].

Objective: To investigate the mental status, level of occupational health knowledge, health behaviors, and occupational health knowledge demand in operating and maintenance personnel in wind power plants, and to provide a basis for formulating protective measures of occupational health for operating and maintenance personnel in wind power plants. Methods: A cluster sampling was performed in regionally representative wind power plants in the wind power industry from May 2014 to June 2015, and the Symptom Checklist-90 (SCL-90) and a self-made evaluation questionnaire were used to investigate the general status, mental health, and occupational health knowledge demand in 160 operating and maintenance workers. Results: Of all respondents, 26.9% had mental health issues. The awareness rate of infectious disease knowledge and preventive measures was 11.9%. Of all workers, 96.5% wanted to know the occupational hazard factors in the workplace, and 96.3% wanted to get the knowledge of the prevention of related diseases. Conclusion: Mental health issues in operating and maintenance personnel in wind power plants cannot be neglected and there is a high demand for occupational health services and related knowledge. Comprehensive intervention measures for health promotion in the workplace should be adopted to improve working environment, enhance individual mental health education, increase the level of occupational health management, and protect the health of workers.

[Research advances on severe burn infection and cytokine storm].

Mortality due to severe burns has always been at a high level. A large number of studies have shown that the rapid onset of infectious symptoms and rapid progression of severely burned patients are closely related to the occurrence of cytokine storm. However, in clinical practice, cytokine storm monitoring, early warning, and symptomatic treatment are still in exploratory stage. This article reviews the cytokine storm and its related cytokines, the mechanism, early warning, and treatment of cytokine storm induced by burn infection, aiming to provide clinical references for reducing infection and mortality in severely burned patients.

Influence of light supplement on duck sternal calcification from integrated analysis of metabolome and transcriptome.

Calcification of bones is the critical process of bone development in birds, which is very important for sustaining the normal biological function of bones. Light is one of the vital factors affecting bone development, but whether light intensity affects bone calcification and the underlying mechanism is still unknown. In this study, we used duck sternum as a model to analyze the calcification process under different light regimes. In addition, the underlying mechanism was also illustrated by integrating metabolomics and transcriptome methods. The experiment lasted from 14 to 51 d of duck age. The control group (LP1) kept light intensity 2 lx during the whole experiment. The two light supplement groups (LP2, LP3) were given light with the intensity of 70 lx at different time (14-29 d for LP2, 14-43 d for LP3). Samples were collected at 52 d of duck age. Sternal calcification analysis showed no significant difference in proportion of area of cartilage matrix and trabecular bone in keel tissue among the 3 groups, but the degree of keel calcification in LP3 was higher than in the other 2 groups. Serum metabolomics showed 32 and 28 differentially accumulated metabolites (DAMs) in the 2 comparison groups, LP1 vs. LP3 and LP1 vs. LP2, respectively. Carboxylic acids and derivatives were the most abundant among the DAMs. Sternal transcriptome analysis showed 231 differentially expressed genes (DEGs), including 177 upregulated genes and 54 downregulated genes in group LP1 vs. LP3, and 22 DEGs in group LP1 vs. LP2. Protein-protein interaction (PPI) network analysis on DEGs between LP1 and LP3 showed that genes BTRC, GLI1, BMP4, and FOS were in the core position of the interaction network, and are also involved in bone development. KEGG pathway analysis of DAMs and DEGs showed that differences in Hedgehog signaling pathway, MAPK signaling pathway, apoptosis, energy metabolism, and amino acid metabolism following light treatment seem likely to have contributed to the observed difference in calcification of duck sternum.

Effect of different types of sugar on gut physiology and microbiota in overfed goose.

To explored the difference of goose fatty liver formation induced-by different types of sugar from the intestinal physiology and the gut microflora, an integrated analysis of intestinal physiology and gut microbiota metagenomes was performed using samples collected from the geese including the normal-feeding geese and the overfed geese which were overfed with maize flour or overfeeding dietary supplementation with 10% sugar (glucose, fructose or sucrose, respectively), respectively. The results showed that the foie gras weight of the fructose group and the sucrose group was heavier (P < 0.05) than other groups. Compared with the control group, the ileum weight was significantly higher (P < 0.01), and the cecum weight was significantly lower in the sugar treatment groups (P < 0.001). Compared with the control group, the ratio of villi height to crypt depth in the fructose group was the highest in jejunum (P < 0.05); the trypsin activity of the ileum was higher in the fructose group and the sucrose group (P < 0.05). At the phylum level, Firmicutes, Proteobacteria and Bacteroidetes were the main intestinal flora of geese; and the abundance of Firmicutes in the jejunum was higher in the sugar treatment groups than that of the maize flour group. At the genus level, the abundance of Lactobacillus in the jejunum was higher (P < 0.05) in the sugar treatment groups than that of the maize flour group. In conclusion, forced-feeding diet supplementation with sugar induced stronger digestion and absorption capacity, increased the abundance of Firmicutes and Bacteroidetes and the abundance of Lactobacillus (especially fructose and sucrose) in the gut. So, the fructose and sucrose had higher induction on hepatic steatosis in goose fatty liver formation.

Activation of peripheral Th17 lymphocytes in patients with asthma.

A recently identified interleukin (IL)-17-producing T-helper (Th) lymphocyte subset, which comprises Th17 cells producing hallmark cytokines IL-17A, IL-17F and IL-22, is involved in chronic inflammatory diseases. Elevated gene and protein expressions of IL-17 are manifested in allergic asthma. We further characterized the activation of Th17 cells in asthmatic patients. Peripheral blood mononuclear cells (PBMC) were purified from 31 asthmatic patients and 20 sex- and age-matched control subjects. The number of IL-17A secreting cells in peripheral blood was enumerated by enzyme-linked immunosorbent spot assay. Cell surface expression of Th17-related chemokine receptor CCR6, and plasma level of IL-17A, IL-17F and IL-22, and ex vivo production of IL-17A and IL-22 were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. The number of peripheral Th17 lymphocytes, expression of CCR6 on Th cells, and ex vivo IL-23, anti-CD3 and anti-CD28 induced production of IL-22 by PBMC were significantly elevated in asthmatic patients compared with control subjects (all p < 0.01). This clinical study further confirmed increased number of peripheral Th17 lymphocytes and cell surface expression of CCR6 receptors on Th cells in asthmatic patients. Pro-inflammatory cytokine IL-23 can exacerbate disease severity by activating pathogenic Th17 lymphocytes to release downstream inflammatory cytokine IL-22 in asthma.

[A cohort study on body mass index and risk of all-cause mortality among hypertensive population].

Objective: To investigate the relationship between body mass index (BMI) and all-cause mortality in hypertensive population. Methods: All participants were selected from a prospective cohort study based on a rural population from Henan province, China. Cox proportional hazards regression models were used to estimate the associations of different levels of BMI stratification with all-cause mortality. Restricted cubic spline models were used to detect the dose-response relation. Results: Among the 5 461 hypertensive patients, a total of 31 048.38 person-years follow-up was conducted. The median of follow-up time was 6 years, and 589 deaths occurred during the follow-up period. Compared to normal weight group (18.5 kg/m(2)

Effects of nonglycosylated and glycosylated prolactin on basal and gonadotropin-stimulated steroidogenesis in chicken ovarian follicles.

In galliformes, the circulating isoform of prolactin (PRL) significantly changes during different reproductive states. However, the role of the major isoform (glycosylated PRL [G-PRL]) in ovarian steroidogenesis is unknown. The present study aimed to compare the effects of nonglycosylated (NG-) and G-PRL on basal and gonadotropin-stimulated estradiol (E2) and progesterone (P4) production in granulosa cells or follicular walls of chicken of different size class follicles. In the initial experiment, granulosa cells of preovulatory F3-F1 and prehierarchical 6- to 8-mm follicles were incubated for 24 h with different concentrations of NG- or G-PRL (0, 1, 10, 100, or 1,000 ng/mL). In the subsequent experiments, these categorized granulosa cells and follicular walls of prehierarchical 4-6, 2-4, and <2-mm follicles were incubated for 24 h in the absence and presence of 10-ng/mL FSH or LH, or in combination with different concentrations of NG- or G-PRL (10, 100, or 1,000 ng/mL). We observed that lower levels of NG-PRL induced (P < 0.05) E2 and P4 secretion in granulosa cells of either preovulatory or prehierarchical follicles, but at higher levels, this effect was reduced. In contrast, G-PRL promoted (P < 0.05) basal E2 and P4 secretion in preovulatory granulosa cells but was inhibitory (P < 0.05) in prehierarchical granulosa cells. Results obtained by real-time quantitative PCR (qPCR) demonstrated that these effects were mediated through modulation of the expression of StAR, CYP11A1, CYP19A1, and 3ß-HSD. Furthermore, G-PRL was less potent than NG-PRL in inhibiting FSH- or LH-stimulated E2 and P4 production in granulosa cells of preovulatory follicles, whereas NG-PRL enhanced (P < 0.05) but G-PRL reduced (P < 0.05) FSH-induced P4 production in those of prehierarchical follicles. In follicular walls from each group of prehierarchical 4-6, 2-4, and <2-mm follicles, NG- and G-PRL had both stimulatory and inhibitory influences on the actions of FSH on E2 and P4 secretion, but both suppressed (P < 0.05) LH-induced E2 and P4 secretion except for the synergistic effects of LH and G-PRL on P4 secretion by follicular walls of the follicles of 4-6 mm. Taken together, these results suggest that both NG- and G-PRL are biologically active in regulating basal and gonadotropin-stimulated E2 and P4 production in chicken ovarian follicles. However, their effects are different depending on the concentration, the type of gonadotropin (FSH or LH), and the stage of follicle development.

The renin-angiotensin system blockers as adjunctive therapy for cancer: a meta-analysis of survival outcome.

OBJECTIVE: The renin-angiotensin system blockers (RASBs), including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are widely used to reduce cardiovascular disease (CVD) events. Accumulating pre-clinical and clinical studies suggested that RASBs possesses anti-carcinogenic properties, and their use is associated with favorable outcomes in several type cancers. To conduct a meta-analysis to evaluate the effect of adjunctive therapy of renin-angiotensin system blockers combined with chemotherapeutic agents in cancer patients. MATERIALS AND METHODS: Data from a total of 2436 patients from 7 retrospective studies investigating chemotherapeutic agents in combination with RASBs agents versus chemotherapeutic agents were included in this meta-analysis. Publication bias was assessed by the Begg's Test, Egger's test and funnel plot. Subgroup analysis was conducted when the chemotherapeutic agents were the same. RESULTS: A significant reduction in overall mortality in favor of chemotherapeutic agents in combination with RASBs agents was observed, hazard ratio (HR) 0.80 (95% CI: 0.69-0.92); there was a significant decrease in the risk of disease progression in favor of chemotherapeutic agents in combination with RASBs regimens, HR 0.79 (95% CI: 0.66-0.94), compared with those who only used chemotherapeutic agents. Subgroup analysis indicated that platinum-based agents plus ACEI/ARB could increase significantly the survival outcome (HR = 0.56; 95% CI: 0.38-0.82). CONCLUSIONS: Our results suggest that RASBs combined with chemotherapeutic agents may improve outcomes in multiple types' cancer patients. More research and well-designed, rigorous, large clinical trials are required to address these issues.

[The clinical features of patients with allergic rhinitis of Nantong city in China].

Objective:To comprehensively analyze the clinical features of patients with AR by a retrospective study. Method:A total number of 8 102 patients diagnosed with AR were enrolled in Nantong area, and detailed clinical data were documented in all cases. Skin prick tests with standardized aeroallergens were conducted in these patients; The samples were divided into two groups(children and adults group) and the clinical features between two groups were analysed. Result:Children in schoolage were the majority of AR patients in children group. There were 4 581 cases(56.54%) with ocular symptoms, 3 977 cases(49.09%)with lower respiratory tract symptoms. Nasal congestion (97.37%) was the most common symptoms in patients with AR,while eye itching(32.68%) was the most common ocular symptoms in patients with AR, followed by the dacryorrhea(23.57%);and cough(44.72%) was the most common lower respiratory tract symptoms. Dermatophagoides pteronyssinus and dermatophagoides farinae had the highest positivity among all allergens, and the shrimp was the main food allergen. Conclusion:We analyzed the clinical features of patients with AR, that would provide a more scientific basis for prevention,clinical diagnosis, treatment and epidemiological studies for AR.

Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue.

Functional surfaces of a protein are often mapped by combination of X-ray crystallography and mutagenesis. Such studies of insulin have yielded paradoxical results, suggesting that the native state is inactive and reorganizes on receptor binding. Of particular interest is the N-terminal alpha-helix of the A-chain. Does this segment function as an alpha-helix or reorganize as recently proposed in a prohormone-convertase complex? To correlate structure and function, we describe a mapping strategy based on protein design. The solution structure of an engineered monomer ([AspB10, LysB28, ProB29]-human insulin) is determined at neutral pH as a template for synthesis of a novel A-chain analogue. Designed by analogy to a protein-folding intermediate, the analogue lacks the A6-A11 disulphide bridge; the cysteine residues are replaced by serine. Its solution structure is remarkable for segmental unfolding of the N-terminal A-chain alpha-helix (A1 to A8) in an otherwise native subdomain. The structure demonstrates that the overall orientation of the A and B chains is consistent with reorganization of the A-chain's N-terminal segment. Nevertheless, the analogue's low biological activity suggests that this segment, a site of clinical mutation causing diabetes mellitus, functions as a preformed recognition alpha-helix.

Mini-proinsulin and mini-IGF-I: homologous protein sequences encoding non-homologous structures.

Protein minimization highlights essential determinants of structure and function. Minimal models of proinsulin and insulin-like growth factor I contain homologous A and B domains as single-chain analogues. Such models (designated mini-proinsulin and mini-IGF-I) have attracted wide interest due to their native foldability but complete absence of biological activity. The crystal structure of mini-proinsulin, determined as a T3R3 hexamer, is similar to that of the native insulin hexamer. Here, we describe the solution structure of a monomeric mini-proinsulin under physiologic conditions and compare this structure to that of the corresponding two-chain analogue. The two proteins each contain substitutions in the B-chain (HisB10-->Asp and ProB28-->Asp) designed to destabilize self-association by electrostatic repulsion; the proteins differ by the presence or absence of a peptide bond between LysB29 and GlyA1. The structures are essentially identical, resembling in each case the T-state crystallographic protomer. Differences are observed near the site of cross-linking: the adjoining A1-A8 alpha-helix (variable among crystal structures) is less well-ordered in mini-proinsulin than in the two-chain variant. The single-chain analogue is not completely inactive: its affinity for the insulin receptor is 1500-fold lower than that of the two-chain analogue. Moreover, at saturating concentrations mini-proinsulin retains the ability to stimulate lipogenesis in adipocytes (native biological potency). These results suggest that a change in the conformation of insulin, as tethered by the B29-A1 peptide bond, optimizes affinity but is not integral to the mechanism of transmembrane signaling. Surprisingly, the tertiary structure of mini-proinsulin differs from that of mini-IGF-I (main-chain rms deviation 4.5 A) despite strict conservation of non-polar residues in their respective hydrophobic cores (side-chain rms deviation 4.9 A). Three-dimensional profile scores suggest that the two structures each provide acceptable templates for threading of insulin-like sequences. Mini-proinsulin and mini-IGF-I thus provide examples of homologous protein sequences encoding non-homologous structures.

The cancer-associated fibroblasts and drug resistance.

The present treatment of solid tumors is plagued by drug resistance. Despite continued development of meticulously designed therapeutic scheme, cancer cells remain poorly being completely eliminated. Because therapeutic resistance is a problem with the drug used in cancer therapy, most of the studies about the drugs resistance have focused on the role of epithelial cancer cells themselves. However, it is becoming increasingly apparent that tumor microenvironment could provide a shelter for tumor cells which keep their survival after initial drug exposure. Cancer-associated fibroblasts (CAFs) are the crucial component of the tumor microenvironment; substantial evidence suggests that the CAFs mediate resistance of solid tumor cells to the anticancer drugs. In this review, we describe how the CAFs may be involved in the resistance of tumor cells to the therapeutic agents and present some of the emerging therapeutic targets for modulation this resistant phenotype.

Losartan improves the distribution and efficacy of doxorubicin in CT26 tumor.

OBJECTIVE: The effectiveness of chemotherapeutic agents is impaired by limited delivery of chemotherapeutic agents to the tumor cells. Improving drug penetration in tumor tissues is very important. We tested whether losartan, a selective antagonist against type 1 angiotensin II receptors (AT1R) with noted antifibrotic activity, can enhance the penetration and efficacy of doxorubicin. MATERIALS AND METHODS: BALB/C mice, which implanted with CT26 tumor cells, were divided into four groups: control, doxorubicin alone, losartan alone and doxorubicin + losartan combination groups. At day 0, the losartan alone and doxorubicin + losartan combination groups received losartan; and at day 8, the doxorubicin alone and doxorubicin + losartan combination groups received doxorubicin i.v. Tumor growth and intratumoral distribution of doxorubicin were evaluated. The mechanism underlying the enhanced anti-tumor effect of the combination of doxorubicin and losartan was investigated by immunohistochemical analysis. RESULTS: Treatment with losartan alone did not suppress tumor growth; In contrast, treatment with doxorubicin alone decreased tumor growth; losartan and doxorubicin were administered in combination, had a synergistic effect that the tumor growth was much more inhibited. The decreased proliferation as indicated by down-regulation of Ki67, and increased apoptosis as indicated by TUNEL and caspase-3 staining. The expression of tumor suppressor gene P53 increased in doxorubicin + losartan combination groups. CONCLUSIONS: Losartan can increase the therapeutic effectiveness of doxorubicin, yielding more great antitumor benefit. This study provided a rationale for initiating clinical trials using losartan in combination with chemotherapeutic agents to increase their therapeutic effectiveness.

Early third trimester maternal response to glucose challenge and pregnancy outcome in Chinese women-relationship between upper distribution level and recommended diagnostic criteria.

BACKGROUND/OBJECTIVES: The objective of this study was to examine the relationship between upper distribution levels of glucose values in the 75-g oral glucose tolerance test (OGTT) and recommended diagnostic criteria for gestational diabetes mellitus (GDM) and adverse pregnancy outcomes. SUBJECTS/METHODS: The distribution of the OGTT 2-h values of 13,501 pregnant women, which were below the World Health Organization (WHO) threshold for overt diabetes mellitus (DM), and managed in one teaching hospital in China, was reviewed and related to maternal characteristics and pregnancy outcomes. RESULTS: For the entire group, the 90th and 95th percentile values of the OGTT 2-h glucose level, respectively, were close to the diagnostic cutoff values of the WHO and International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. For adverse maternal outcomes, glucose level above the 90th percentile value was associated with increased hypertensive disorders, whereas no difference was seen with cutoff using the 95th percentile value. For perinatal outcomes, the 90th percentile was associated with increased neonatal intensive care unit admission and hypoglycemia, whereas the 95th percentile showed in addition association with phototherapy for jaundice and 5th-minute Apgar score <7. Although no differences in the incidence of adverse pregnancy outcomes were found using the different cutoffs, the >95th percentile cutoff value would have missed out 33.3-56.7% of the cases of adverse outcomes that would otherwise have been attributed to GDM. CONCLUSIONS: Further studies are warranted to clarify which diagnostic criterion is most appropriate universally to identify adverse pregnancy outcomes attributed to GDM, and which could be mitigated with treatment specific for GDM.