Predictors of postoperative biochemical remission in acromegaly.

PURPOSE: Acromegaly is a rare neuroendocrine condition that can lead to significant morbidity. Despite China's vast population size, studies on acromegaly remain sparse. This study aimed to investigate the clinical characteristics and predictors of biochemical remission after surgery for acromegaly using the China Acromegaly Patient Association (CAPA) database. METHODS: A retrospective nationwide study was conducted using patient-reported data from CAPA database between 1998 and 2018. The principal component analysis (PCA) and logistic regression analysis were employed to determine independent predictors of biochemical remission at 3 months in patients after surgery. RESULTS: Of the 546 surgical cases (mean age: 36.8 years; 59.5% females), macroadenomas and invasive tumors (Knosp score 3-4) were 83.9% and 64.1%, respectively. Ninety-five percent of patients were treated with endonasal surgery and 36.8% exhibited biochemical remission at 3-months postoperatively. The following independent predictors of biochemical remission were identified: preoperative growth hormone (GH) levels between 12 and 28 µg/L [odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.37-0.92; p = 0.021], preoperative GH levels > 28 µg/L (OR = 0.55; 95% CI, 0.34-0.88; p = 0.013), macroadenoma (OR = 0.56; 95% CI, 0.32-0.96; p = 0.034), giant adenomas (OR = 0.14; 95% CI, 0.05-0.38; p < 0.001), Knosp score 3-4 (OR = 0.37; 95% CI, 0.24-0.57; p < 0.001), and preoperative medication usage (OR = 2.32; 95% CI, 1.46-3.70; p < 0.001). CONCLUSIONS: In this nationwide study spanning over two decades, we highlight that higher preoperative GH levels, large tumor size, and greater extent of tumor invasiveness are associated with a lower likelihood of biochemical remission at 3-months after surgery, while preoperative medical therapy increases the chance of remission.

Tissue concentrations, trophic transfer and human risks of antibiotics in freshwater food web in Lake Taihu, China.

The objective of this study was to evaluate the tissue distributions of antibiotics in the fish, the bioaccumulation and trophic transfer in freshwater food web in Taihu Lake, a large shallow freshwater lake. Twenty four out of 41 antibiotics were detected in the biotas of the food web; and antibiotic concentrations followed the orders: fish plasma ~ fish muscle < fish liver ~ fish bile and fish < invertebrates ~ plankton. Antibiotic concentrations in the liver of piscivores were higher than those in omnivores and planktivores. Most bioaccumulation factors (BAFs) of sulfonamides (SAs), macrolides (MLs), ionophores (IPs) and lincomycin (LIN) were less than 2000 L/kg, indicating low bioaccumulation ability of these compounds in fish. Fluoroquinolones (FQs) were frequently detected in fish liver, invertebrates and plankton with much of BAFs great than 5000 L/kg, indicating that FQs have the potential of bioaccumulation in fish. Relationship analysis between BAFs and physicochemical properties of antibiotics showed that the bioaccumulation of antibiotics in the biota was related with their adsorption ability. Generally, the antibiotics in the food web of Lake Taihu including plankton, invertebrates and fish showed trophic dilution. The normalized estimated daily intake (EDI) values are less than the acceptable daily intake (ADI) values, and then hazard quotients were much less than 1. This result suggests the consumption of fish, crab and shrimp in Lake Taihu would probably not pose direct detrimental effects on humans.

MicroRNAs and Target Genes in Pituitary Adenomas.

Pituitary adenomas account for the top three primary intracranial tumors in terms of total incidence rates. The clinical symptoms presented by the disease are often characterized by a series of systemic endocrine disorders, severe occupational lesions, and even some malignant features, and therefore early diagnosis and predicting recurrence would be instructive for clinical treatment of pituitary adenomas. An increasing number of specific microRNA (miRNA) expression signatures have been identified in pituitary, and miRNAs are related with the pituitary tumorigenesis, dysfunction, neurodegeneration, and metastatic non-functioning pituitary carcinoma. Here, this paper reviews the effects of aberrant miRNA expression in human pituitary adenomas and summarizes some corresponding target genes and biological significance over the last 7 years (2010-2017).

SUBCLINICAL IMPAIRMENT OF LEFT VENTRICULAR LONGITUDINAL FUNCTION IN PATIENTS WITH PROLACTINOMAS.

OBJECTIVE: Hyperprolactinemia has been associated with endothelial dysfunction and a wide range of cardiovascular risk factors, thus it can potentially lead to cardiac dysfunction. The present study was designed to interrogate our hypothesis that hyperprolactinemia can contribute to preclinical impaired left ventricular function. METHODS: Thirty-one prolactinoma patients and 60 healthy volunteers were prospectively recruited. Left ventricular function was evaluated using conventional two dimensions and M-mode echocardiography, as well as Doppler tissue imaging (DTI). RESULTS: The Tei index (0.45 ± 0.06 vs. 0.41 ± 0.03, P = .005) and ratio of transmitral and myocardial early diastolic velocities (E/Em; 6.30 ± 1.45 vs. 5.64 ± 0.69, P = .045) were significantly higher, and septal systolic velocity (Sm; 9.88 ± 1.45 vs. 11.58 ± 1.28 cm/s, P<.001) was significantly lower in prolactinoma patients. Furthermore, significant motional abnormalities were detected in regional segments of prolactinoma patients. Pearson's correlation analysis revealed that prolactin level was inversely associated with Sm (r = -0.373, P = .009) and late diastolic phase (Am; r = -0.293, P = .043). Moreover, inverse correlations between prolactin and partial left ventricular segment wall motion were found, including the basal (r = -0.363, P = .014), middle (r = -0.418, P = .004), and apical segment (r = -0.574, P<.001) of the posterior ventricular septum. Multivariate linear regression analysis revealed that prolactin (ß = -0.28, 95% confidence interval -0.011 to 0, P = .035), as a single factor, can significantly predict decreased Sm, independent of traditional vascular risk factors. CONCLUSION: Our results suggest that subclinical cardiac dysfunction occurs in untreated prolactinoma patients and is characterized by impaired systolic and diastolic function of the left ventricle, as well as regional segment motional abnormality. ABBREVIATIONS: A = transmitral late diastolic velocity Am = late diastolic phase Apo = apolipoprotein DTI = Doppler tissue imaging E = transmitral early diastolic velocity Em = myocardial early diastolic velocity FMD = flow-mediated dilation HOMA-IR = homeostasis model assessment of insulin resistance hsCRP = high-sensitivity C-reactive protein IMT = intima media thickness LDL-C = low-density lipoprotein cholesterol LV = left ventricular PPCM = postpartum cardiomyopathy Sm = septal systolic velocity.

Expression profiling of O(6) methylguanine-DNA-methyl transferase in prolactinomas: a correlative study of promoter methylation and pathological features in 136 cases.

BACKGROUND: Low-level expression of O(6) methylguanine-DNA-methyl transferase (MGMT) prolactinomas has been noted previously in case reports, although what modulates MGMT expression remains unclear. This study therefore aimed to delineate the factors regulating MGMT expression in prolactinomas. METHODS: We retrospectively reviewed 136 prolactinoma patients who were treated in our center between January 2000 and September 2013. Expression of MGMT, Ki-67, and p53 protein were examined by immunohistochemical staining, and MGMT promoter methylation evaluated with methylation-specific PCR. RESULTS: MGMT immunopositivity was <25 % in 106/136 tumor specimens (77.94 %). MGMT immunoexpression was positively correlated with age (r = 0.251, p = 0.003), but inversely correlated with p53 staining (r = -0.153, p = 0.021). Moreover, reduced MGMT expression was more frequent in atypical prolactinomas (p = 0.044). Methylated MGMT promoter was confirmed in 10/46 specimens (21.7 %), all of which had low level or absent MGMT staining. Both p53 protein (r = -0.33, p = 0.025) and promoter methylation (r = -0.331, p = 0.025) were negatively associated with MGMT expression. Multivariate logistic analysis indicated that age (odds ratio [OR] = 1.127. 95 % confidence interval [CI] 1.027-1.236, p = 0.012) and p53 (OR = 0.116. 95 % CI 0.018-0.761, p = 0.025) staining were independent determents of MGMT expression. CONCLUSIONS: The majority of prolactinomas, especially atypical prolactinomas, showed low-level or no MGMT immunoexpression, providing a rationale for the utility of temozolomide as an alternative to managing prolactinomas. In summary, epigenetic and transcriptional regulation are involved in silencing MGMT expression.

The marine metabolite SZ-685C induces apoptosis in primary human nonfunctioning pituitary adenoma cells by inhibition of the Akt pathway in vitro.

Nonfunctioning pituitary adenoma (NFPA) is one of the most common types of pituitary adenoma. The marine anthraquinone derivative SZ-685C has been isolated from the secondary metabolites of the mangrove endophytic fungus Halorosellinia sp. (No. 1403) which is found in the South China Sea. Recent research has shown that SZ-685C possesses anticancer and tumor suppressive effects. The tetrazolium-based colorimetric assay (MTT assay) to investigate the different effect of the marine compound SZ-685C on the proliferation of primary human NFPA cells, rat normal pituitary cells (RPCs) and rat prolactinoma MMQ cell lines. Hoechst 33342 dye/propidium iodide (PI) double staining and fluorescein isothiocyanate-conjugated Annexin V/PI (Annexin V-FITC/PI) apoptosis assays detected an enhanced rate of apoptosis in cells treated with SZ-685C. Enhanced expression levels of caspase 3 and phosphate and tensin homolog (PTEN) were determined by Western blotting. Notably, the protein expression levels of Akt were decreased when the primary human NFPA cells were treated with SZ-685C. Here, we show that SZ-685C induces apoptosis of human NFPA cells through inhibition of the Akt pathway in vitro. The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy.

[Genetic Polymorphisms in Wnt Signaling Pathway and Acute Leukemia].

OBJECTIVE: To determine the impacts of Wnt signaling pathway products-polymorphisms of rs4135385, rs11079571 and rs7832767 located in ß-catenin gene (CTNNB1), Axin gene (AXIN2), and secreted frizzled-related protein gene (SFRP1) on the risk and treatment outcomes of acute leukemia. METHODS: Bone marrows (volume 1-1. 5 mL) were collected from 372 untreated patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), and peripheral blood samples (2. 0 mL) were obtained from 401 healthy controls for the purpose of total DNA extraction. Polymorphisms of rs4135385, rs11079571 and rs7832767 located in CTNNB1, AXIN2 and SFRP1 were genotyped with high-resolution melting method (HRM). Chi-square analyses were performed to compare the genotype and allele distributions of the three single nucleotides (SNPs) between the leukemia patients and healthy controls. Single factor variance tests were performed to compare the differences in clinical features among different genotype groups. Complete remission (CR) rates after induction chemotherapy were also compared between different genotype groups using Chi-square tests. RESULTS: No significant differences were found beiween the leukemia patients and healthy controls in the frequencies of alleles and genotypes of CTNNB1 rs4135385, SFRP1 rs7832767 polymorphisms. Those with A allele in AXIN2 rs11079571 polymorphism was less likely to have acute myelomonocytic/monocytic leukemia than those with G allele (P = 0. 016, OR=0. 677, 95%CI:0. 439-0. 930). Acute bead monocyte/mononuclear cell leukemia (AML-M4/5)patients with AA genotype presented higher platelet count (P = 0. 040), and higher complete remission rate after chemotherapy (P = 0. 040), compared with the patients with AG and GG genotypes. CONCLUSION: AML-M4/5 patients have less frequency of A allele in AXIN2 rs11079571 polymorphism than healthy controls. Patients carrying A allele have higher platelet counts and higher sensitivity to chemotherapy.

Increased carotid intima media thickness is associated with prolactin levels in subjects with untreated prolactinoma: a pilot study.

Hyperprolactinemia is associated with endothelial dysfunction and atherogenic risk factors, but carotid intima media thickness (IMT) has not been studied in hyperprolactinemic patients. To determine whether untreated hyperprolactinemia contributes to increased carotid IMT. Thirty-one prolactinoma patients and 60 healthy controls were respectively studied. Participants underwent hormone evaluation. Anthropometric parameters (body mass index and blood pressure), inflammatory markers (high-sensitivity C-reactive protein and fibrinogen), serum glucose, insulin, lipid and apolipoprotein profiles were also determined. Endothelial function measured as the flow-mediated dilation (FMD) of a brachial artery and carotid IMT were evaluated using high-resolution ultrasonography. Multivariate linear regression analysis was applied to identify independent determinants of FMD and carotid IMT. Triglycerides, homeostasis model assessment of insulin resistance, apolipoprotein (apo)B/apoA-I ratio, high-sensitivity C-reactive protein (hsCRP) and fibrinogen were significantly higher, while apoA-I was significantly lower in patients with prolactinomas than in the controls. Meanwhile, decreased FMD and increased carotid IMT were observed in hyperprolactinemic group. Serum prolactin was positively correlated with triglycerides, apoB/apoA-I ratio, hypogonadal, hsCRP and fibrinogen (P < 0.05), but inversely associated with apoA-I and HDL-C (P ≤ 0.001). Moreover, prolactin was found negatively correlated with FMD (r = -0.576, P < 0.0001), and positively correlated with mean carotid IMT (r = 0.652, P < 0.0001). Multivariate regression analysis revealed that prolactin determined, independent of traditional risk factors, FMD (B = -0.589, 95% confidence interval (CI) -2.525 to -0.804, P = 0.001) and mean carotid IMT (B = 0.527, 95% CI 0.027-0.069, P < 0.0001). Hyperprolactinemia may be involved in the preclinical increase in carotid IMT, directly or by promoting atherogenic factors, including insulin resistance, low-grade inflammation and endothelial dysfunction. Additional studies are warranted to confirm our findings and explore the mechanisms underlying prolactin-associated early atherosclerosis.

BMI, apolipoprotein B/apolipoprotein A-I ratio, and insulin resistance in patients with prolactinomas: a pilot study in a Chinese cohort.

Deranged metabolic profiles and insulin resistance (IR) have been documented in patients with prolactinomas. Few data are yet available on the apolipoprotein (apo) B/apoA-I ratio and its relationship with IR in patients with prolactinomas. This study was aimed to evaluate the level of apoB/apoA-I ratio and its association with IR in a Chinese subgroup with prolactinomas. Twenty-three prolactinoma patients and 20 healthy controls were enrolled in this study. The clinical anthropometric parameters and laboratory evaluation were collected. Insulin sensitivity was estimated using homeostatic model assessment [homeostasis model assessment of insulin resistance (HOMA-IR)]. Waist circumference and body weight index (BMI) were significantly higher in patients with prolactinomas than those in the controls (p < 0.05). Meanwhile, the prevalence of general and abdominal obesity seemed more pronounced in male patients compared to that in healthy subjects (57.14 vs. 0 % and 71.43 vs. 16.7 %, respectively). Furthermore, fasting glucose, insulin, HOMA-IR, triglyceride, and apoB/apoA-I ratio were also significantly higher in prolactinoma patients, but with lower level of apoA-I (p < 0.05). Univariate regression analysis revealed that prolactin, waist circumference, BMI, and presence of hypogonadism were significantly associated with IR (p < 0.05). However, only BMI [odds ratio (OR) = 1.937, 95 % confidence interval (CI) 1.112-3.375, p = 0.02] and prolactin (OR = 5.173, 95 % CI 1.073-24.94, p = 0.041) were shown to be independent predictors for the presence of IR in multivariate logistic analysis. This study confirmed the altered metabolic profile, including body weight gain, IR, disordered lipids, and apolipoproteins in prolactinoma patients. Prolactin and BMI were independently associated with IR. The effect of apoB/apoA-I ratio on IR is warranted to be determined in further studies.

Advances in the study of the structures and bioactivities of metabolites isolated from mangrove-derived fungi in the South China Sea.

Many metabolites with novel structures and biological activities have been isolated from the mangrove fungi in the South China Sea, such as anthracenediones, xyloketals, sesquiterpenoids, chromones, lactones, coumarins and isocoumarin derivatives, xanthones, and peroxides. Some compounds have anticancer, antibacterial, antifungal and antiviral properties, but the biosynthesis of these compounds is still limited. This review summarizes the advances in the study of secondary metabolites from the mangrove-derived fungi in the South China Sea, and their biological activities reported between 2008 and mid-2013.

[The expression of MGMT in pituitary adenomas and its association with tumour aggressiveness].

OBJECTIVE: To determine the expression of O6-methylguanine-DNA methyltransferase (MGMT) in pituitary adenomas and its association with tumour aggressiveness. METHODS: From October 2011 to August 2012, all the patients with pathologically confirmed pituitary adenomas in our hospital were recruited for this study. The expression of MGMT in the tumor tissues was detected with immunohistochemistry. RESULTS: A total of 138 (including 71 male) patients participated in this study. The majority of the participants had nonfunctional (71%) and macroadenomas (92.8%). Aggressive and relapsed pituitary adenomas accounted for 31.2% and 8.7% of the cases, respectively. Low MGMT expression was found in 79 cases. The MGMT expression had no significant associations with gender, age, aggressiveness and relapse of tumors. However, prolactinomas were more likely to have low MGMT expression than nonfunctional adenomas (P = 0.025) and growth hormone adenomas (P = 0.043). CONCLUSION: The expression of MGMT has no associations with the aggressiveness and relapse of pituitary adenomas. Prolactinomas are more likely to have low expression of MGMT, which indicates that temozolomide might become an alternative treatment for aggressive and dopamine resistant prolactinomas.

Artesunate inhibits cell proliferation and decreases growth hormone synthesis and secretion in GH3 cells.

To determine the effect of artesunate (ART) on the rat pituitary adenoma GH3 cell line to evaluate its potential as a novel agent in growth hormone (GH) adenoma and to investigate its underlying mechanisms of action. The MTT assay was used to assess cell proliferation. DAPI staining was used to visualise apoptotic changes in the nucleus. We also analyzed cell apoptosis and cell cycle stage by flow cytometry, semi-quantitative RT-PCR analysis for the expression of GH mRNA and apoptosis-induced factor (AIF) mRNA, analysis of GH protein by western blot, ELISA detection of secreted GH, and the caspase inhibition assay. We found that ART inhibited the proliferation of GH3 cells in a dose- and time-dependent manner, with an IC50 of 9.53 ± 4.12 µM. The IC50s of ART against of two normal cell lines (mouse embryonic fibroblasts, and rat bone mesenchymal cells) were much higher than the IC50 recorded for the GH3 cells. ART induced apoptosis and blocked GH3 at G2/M arrest. The pan caspase inhibitor V-ZAD-FMK partly attenuated the inhibitory effect of ART. ART increased the expression of AIF mRNA and reduced GH mRNA levels, GH synthesis and the secretion of GH level in GH3 cells. ART can inhibit proliferation and induce apoptosis in GH3 cells by caspase-dependent pathways. Additionally, ART can inhibit GH synthesis and secretion. Thus, we propose ART as a probably anti-tumour candidate drug in the treatment of GH adenoma.

[Impact of Enclosure Culture on Heavy Metal Content in Surface Sediments of Hongze Lake and Ecological Risk Assessment].

In order to explore the concentrations of heavy metals and the influence of fencing on Hongze lake, the content, source, and spatial distribution characteristics of heavy metals in surface sediments and ecological risks were analyzed in 2018 after part of the fence around Hongze Lake was removed. The results showed that the average contents of Cr, Ni, Cu, Zn, As, Cd, and Pb in the surface sediments in Hongze Lake were 66.78, 33.89, 25.35, 74.77, 16.55, 0.23, and 27.20 mg·kg-1, respectively. Cr, Ni, Cu, Zn, and Pb contents were at non-polluting levels, with As and Cd at the lowest level, based on the accumulation index evaluation. Except for Cd, all the elements showed low potential ecological risk. The results showed that the heavy metal content in the fenced, dismantled, and peripheral areas increased and accumulated towards the center of the lake. The removal of the fence did not significantly reduce the heavy metal content in the short-term. Overall, Hongze Lake presented a state of low ecological risk. In the future, environmental policies should include surface sediment accumulation areas and fencing culture in the north and northeast of Hongze Lake.

TRAIL-induced apoptosis of human melanoma cells involves activation of caspase-4.

Although it is conventionally regarded as an inflammatory caspase, recent studies have shown that caspase-4 plays a role in induction of apoptosis by endoplasmic reticulum (ER) stress. We report here that activation of caspase-4 is also involved in induction of apoptosis by TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells. Treatment with TRAIL resulted in activation of caspase-4. This appeared to be mediated by caspase-3, in that caspase-4 was activated later than caspase-8, -9, and -3, and that inhibition of caspase-3 blocked TRAIL-induced caspase-4 activation. Notably, TRAIL triggered ER stress in melanoma cells as shown by up-regulation of the GRP78 protein and the spliced form of XBP-1 mRNA. This seemed to be necessary for activation of caspase-4, as activation of caspase-3 by agents that did not trigger ER stress did not cause activation of caspase-4. Importantly, inhibition of caspase-4 also partially blocked caspase-3 activation, suggesting that activation of caspase-4 may be positive feed-back mechanism to further enhance caspase-3 activation. Collectively, these results show that activation of caspase-4 contributes to TRAIL-induced apoptosis and is associated with induction of ER stress by TRAIL in melanoma cells, and may have important implications for improving therapeutic efficacies of TRAIL in melanoma.

[Clinical application of review criteria for complete blood analysis].

OBJECTIVE: To evaluate the review criteria for complete blood analysis. METHODS: total of 8820 blood samples taken at our hospital were detected both by the Sysmex XE-2100 automated blood cell analyzer and double-blind method microscopy. The performance of two review criteria were evaluated by statistical analysis. The parameters, such as true and false positive rates, true and false negative rates, sensitivity, specificity, positive predictive value, negative predictive value, total effective rate, test effectiveness and re-examination rate were calculated according to the criteria of XE-2100 hematology analyzer re-examination standards coordination group of Society of Laboratory Medicine of Chinese Medical Association. And a study was conducted to determine the improved clinical effectiveness over the criteria. RESULTS: The values of true and false positive rates, true and false negative rates, sensitivity, specificity, positive predictive values, negative predictive value, total effective rate, test effectiveness and reexamination rate were 13.0%, 27.2%, 55.3%, 4.5%, 74.3%, 67.0%, 32.4%, 92.5%, 68.3%, 21.2%, and 40.2% respectively. The re-examination rate decreased to 33.8% and the total effective rate increased to 74.7% according to our improved review criteria. And there was no missed diagnosis of leukemic cells. It was found that 2069 samples (23.5%) needed manual microscopy for WBC differential analysis, 847 had abnormal cells and no leukemia was missed. CONCLUSIONS: The automatic blood cell analyzer and WBC differential analysis review criteria have great clinical utilities. The review criteria of blood cell analysis may be improved according to patient source and instrument performance so as to better meet the needs of clinical application.

[Distribution and Risk Assessment of OCPs in Surface Water, Sediments, and Fish from Lake Gucheng and Inflow and Outflow Rivers].

To investigate the distribution, source, and ecological risk of organochlorine pesticides (OCPs) residues in Lake Gucheng, surface water, sediment, and biological samples were collected from 12 sampling sites of Lake Gucheng and its inlets and outlets during summer and winter, and the concentrations of 19 OCPs were analyzed. The results showed that the concentration (dry weight) of OCPs in Lake Gucheng ranged from 26.74 to 48.12 ng·L-1 in surface water, 9.01 to 35.34 ng·g-1 in sediment, and 13.39 to 124.29 ng·g-1 in organisms. The pollution characteristics of OCPs in surface water showed that the concentration was much higher in summer than in winter, and much higher at inflow and outflow rivers than in farming ponds and the central region of Lake Gucheng; the seasonal pollution characteristics in sediment were not obvious. All 19 kinds of OCPs in water, sediment, and organisms were detected in different degrees, and the dominant contaminants were HCHs and DDTs. α-HCH was the main pollutant at all sites in both surface water and sediment, with 21% to 42% of total HCHs in two seasons. p,p'-DDD was the main pollutant in surface water with 30% to 76% of total DDTs, whereas p,p'-DDT was the main pollutant in sediment with 68% to 93% of total DDTs in two seasons. Source analysis based on ratios of HCHs isomers and DDTs isomers indicated that there was a new input of OCPs under anaerobic conditions in the study area. The ecological risk assessment showed that the OCPs in surface water did not lead to significant health risks, but the OCPs in sediments might pose ecological risks to the Lake Gucheng ecosystem. The organisms were within the acceptable potential carcinogenic risk range.

Glucose-regulated protein 78 antagonizes cisplatin and adriamycin in human melanoma cells.

Resistance of melanoma cells to chemotherapeutics remains a major obstacle to successful treatment of melanoma once it has spread beyond locoregional sites. We report in this study that activation of the unfolded protein response (UPR) is involved in resistance of melanoma cells to two chemotherapeutic drugs, cisplatin (CDDP) and adriamycin, and this is associated with glucose-regulated protein 78 (GRP78)-mediated inhibition of activation of caspase-4 and -7. The UPR was constitutively activated in cultured melanoma cell lines and fresh melanoma isolates as evidenced by elevated expression levels of the GRP78 protein and the active form of x-box-binding protein 1 messenger RNA. Treatment with CDDP or adriamycin further increased the levels, indicative of induction of endoplasmic reticulum stress and activation of the UPR by the drugs. Inhibition of GRP78 by small-interference RNA (siRNA)-sensitized melanoma cells to CDDP- and adriamycin-induced apoptosis. This was associated with enhanced caspase-4 and -7 activation as siRNA knockdown of the caspases blocked induction of apoptosis. In contrast, overexpression of GRP78 attenuated activation of caspase-4 and -7 and induction of apoptosis by the drugs. CDDP- and adriamycin-induced activation of caspase-4 and -7 appeared to be mediated by calpain activity in that it was blocked by the calpain inhibitors calpeptin and PD150606 even when GRP78 was inhibited by siRNA. These results provide new insights into resistance mechanisms of melanoma cells to CDDP and adriamycin and identify GRP78 as a potential target for enhancing chemosensitivity in melanoma.

[Combined myocardial injury markers for diagnosis of acute myocardial infarction].

OBJECTIVE: To compare the diagnostic accuracy of different myocardial injury markers and their combinations in diagnosing acute myocardial infarction (AMI). METHODS: The myocardial injury markers: AST, CK, CK-MB, LDH, HBDH, cTnI, CK-MB mass were detected in patients with acute chest pain-onset who were hospitalized in Sichuan University West China Hospital from July 2005 to October 2006. The accuracy of those markers in diagnosing AMI were evaluated by their sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio. Student t-test and one-way ANOVA were performed to compare the diagnostic accuracy of the markers. RESULTS: cTnI had the highest diagnostic accuracy, with 85% of sensitivity and 92.5% of specificity (P < 0.05). cTnI in parallel with myocardial enzymes produced the highest combined diagnostic accuracy, with 100% of sensitivity and 37.29% of specificity (P < 0.05). Myocardial enzymes in sequence with cTnI produced the highest sequential diagnostic accuracy, with 50% of sensitivity and 100% of specificity (P < 0.05). CONCLUSION: cTnI is the best indicator for diagnosis and differential diagnosis of AMI. Myocardiozymogram is poor in sensitivity and specificity, which should be used only in combination with cTnI or CK-MB mass. Parallel testing can increase sensitivity, while sequential testing can improve specificity.

Cerebrospinal fluid rhinorrhea following trans-sphenoidal pituitary macroadenoma surgery: experience from 592 patients.

OBJECTIVES: To determine the incidence, risk factors, diagnostic procedures, and management of cerebrospinal fluid (CSF) leaks following trans-sphenoidal pituitary macroadenoma surgery. METHODS: Retrospective analysis of 592 patients. RESULTS: Intra- and post-operative CSF leaks occurred in 14.2 and 4.4% of patients, respectively. Surgical revision, tumor consistency, and tumor margins were independently associated with intra-operative leaks, while the tumor size, consistency, and margins were risk factors of post-operative leaks. The intra-operative leak rate of ACTH adenomas was greater than all other types combined; the incidence of post-operative CSF leaks was highest for FSH adenomas. There were no significant differences among various techniques and we achieved an initial repair success rates of 83.3 and 92.9% for intra- and post-operative CSF leaks, respectively. Of the 26 patients with post-operative CSF leaks, five were complicated by meningitis and four by post-infectious hydrocephalus which required ventriculoperitoneal shunts. CONCLUSIONS: CSF leaks have a propensity to occur in cases with fibrous tumors or tumors with indistinct margin and may have some relationship with the tumor type. Endoscopic and microscopic repairs were shown to be effective techniques in managing these types of leaks. Post-infectious hydrocephalus may influence the outcome of the repair and ventriculoperitoneal shunts were necessary in some cases.