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The purpose of this study was to examine the characteristics of proximal and distal gastroesophageal reflux in patients with gastroesophageal reflux disorder and analyze their clinical symptoms. A total of 67 patients with typical esophageal symptoms were selected for this study. All participants completed the reflux disease questionnaire and a questionnaire survey of extraesophageal symptoms. Diagnosis was made using a 24-h impedance-pH detection and proton pump inhibitor. The results showed that the proximal reflux group had a higher number of acid reflux episodes compared to the distal reflux group ( P < 0.05). Similarly, the proximal reflux group also had a higher number of gas reflux episodes compared to the distal reflux group ( P < 0.05). On the other hand, the distal reflux group had a higher number of mixed reflux episodes compared to the proximal reflux group ( P < 0.05). These differences were statistically significant. This study revealed that acid reflux and gas reflux were more predominant in the proximal reflux group, while mixed reflux was more predominant in the distal reflux group., Competing Interests: Conflict of interest: The authors declare that they have no competing interests., (© 2023 the author(s), published by De Gruyter.)

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm birth survivors characterized by inflammation, impaired alveolarization and dysmorphic vasculature. Activated IL-17A+ lymphocytes are key drivers of inflammation in preterm infants. We have shown that in immature mice chronic airway exposure to lipopolysaccharide (LPS) induces pulmonary inflammation, increased IL-17a expression, and hypoalveolarization, a BPD-like phenotype. The source of IL-17a and contribution to lung pathology is unknown. The natural-killer group 2, member D (NKG2D) receptor mediates activation and IL-17a production in γδ T cells by binding to stress molecules. LPS induces NKG2D ligand expression, including Rae-1 and MULT1. We hypothesized that IL-17a+ γδ T cells and NKG2D signaling mediate neonatal LPS-induced lung injury. Immature C57BL/6J (wild type), Nkg2d-/- or Tcrd-/- (lacking γδ T cells) mice were inoculated with 3ug/10ul of LPS from E. coli O26:B6 or 10ul of PBS intranasally on day of life 3, 5, 7, and 10. Selected mice were treated with neutralizing antibodies against IL-17a, or NKG2D intraperitoneally. Lung immune cells were assessed by flow cytometry and gene expression was analyzed by qPCR. Alveolar growth was assessed by lung morphometry. We established that anti-IL-17a antibody treatment attenuated LPS-induced hypoalveolarization. We found that LPS induced the fraction of IL-17a+NKG2D+ γδ T cells, a major source of IL-17a in the neonatal lung. LPS also induced lung mRNA expression of NKG2D, Rae-1, MULT1, and the DNA damage regulator p53. Anti-NKG2D treatment attenuated the effect of LPS on γδ T cell IL-17a expression, immune cell infiltration and hypoalveolarization. LPS-induced hypoalveolarization was also attenuated in Nkg2d-/- and Tcrd-/- mice. In tracheal aspirates of preterm infants IL-17A and its upstream regulator IL-23 were higher in infants who later developed BPD. Also, human ligands of NKG2D, MICA and MICB were present in the aspirates and MICA correlated with median FiO2. Our novel findings demonstrate a central role for activated IL-17a+ γδ T cells and NKG2D signaling in neonatal LPS-induced lung injury. Future studies will determine the role of NKG2D ligands and effectors, other NKG2D+ cells in early-life endotoxin-induced lung injury and inflammation with a long-term goal to understand how inflammation contributes to BPD pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cui, Brady, Zhang, Anderson and Popova.)

Premature infants with chronic lung disease, bronchopulmonary dysplasia (BPD), develop recurrent cough and wheezing following respiratory viral infections. The mechanisms driving the chronic respiratory symptoms are ill-defined. We have shown that hyperoxic exposure of neonatal mice (a model of BPD) increases the activated lung CD103+ dendritic cells (DCs) and these DCs are required for exaggerated proinflammatory responses to rhinovirus (RV) infection. Since CD103+ DC are essential for specific antiviral responses and their development depends on the growth factor Flt3L, we hypothesized that early-life hyperoxia stimulates Flt3L expression leading to expansion and activation of lung CD103 + DCs and this mediates inflammation. We found that hyperoxia numerically increased and induced proinflammatory transcriptional signatures in neonatal lung CD103+ DCs, as well as CD11b hi DCs. Hyperoxia also increased Flt3L expression. Anti-Flt3L antibody blocked CD103+ DC development in normoxic and hyperoxic conditions, and while it did not affect the baseline number of CD11b hi DCs, it neutralized the effect of hyperoxia on these cells. Anti-Flt3L also inhibited hyperoxia-induced proinflammatory responses to RV. In tracheal aspirates from preterm infants mechanically-ventilated for respiratory distress in the first week of life levels of FLT3L, IL-12p40, IL-12p70 and IFN-γ were higher in infants who went on to develop BPD and FLT3L levels positively correlated with proinflammatory cytokines levels. This work highlights the priming effect of early-life hyperoxia on lung DC development and function and the contribution of Flt3L in driving these effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cui, Brady, Zhang, Fulton, Goldsmith and Popova.)

To compare the effects of aminosalicylic acid, glucocorticoids and immunosuppressants on the expression levels of multidrug resistance genes in patients with ulcerative colitis (UC), with the aim of providing a theoretical and therapeutic basis for the diagnosis, treatment, and prevention of UC. Fresh colonic mucosal tissues or postoperative pathological biopsies from 148 UC patients were collected, and the distribution sites and morphology of P-glycoprotein (P-gp) were detected using immunohistochemical staining. RT-PCR was used to quantify the expression levels of multidrug resistance gene (MDR1) mRNA before and after the corresponding treatment, and the effects of aminosalicylic acid, glucocorticoids and immunosuppressive drugs on P-gp were compared. In addition, the effects of the three drugs on MDR1 mRNA were analyzed. Administration of 5-aminosalicylic acid (5-ASA) drugs did not correlate with MDR1 expression in UC, whereas administration of glucocorticoids and immunosuppressive drugs was positively correlated with MDR1 expression profile. The expression levels of MDR1 mRNA and its product P-gp were significantly upregulated in patients who did not respond to glucocorticoids and immunosuppressive drugs. 5-ASA had no effect on the expression levels of MDR1 and its product P-gp in patients with a confirmed diagnosis of UC. However, the use of glucocorticoids and immunosuppressants can increase the expression level of MDR1., (© 2022. The Author(s).)

Prematurity and bronchopulmonary dysplasia (BPD) increase the risk of asthma later in life. Supplemental oxygen therapy is a risk factor for chronic respiratory symptoms in infants with BPD. Hyperoxia induces cell injury and release of damage-associated molecular patterns (DAMPs). Cytoskeletal filamentous actin (F-actin) is a DAMP which binds Clec9a, a C-type lectin selectively expressed on CD103+ dendritic cells (DCs). Co-stimulation of Clec9a and TLR3 induces maximal proinflammatory responses. We have shown that neonatal hyperoxia (a model of BPD) increases lung IL-12+Clec9a+CD103+ DCs, pro-inflammatory responses and airway hyperreactivity following rhinovirus (RV) infection. CD103+ DCs and Clec9a are required for these responses. Hyperoxia increases F-actin levels in bronchoalveolar lavage fluid (BALF). We hypothesized that the F-actin severing protein gelsolin attenuates neonatal hyperoxia-induced Clec9a+CD103+ DC-dependent pro-inflammatory responses to RV and preserves alveolarization. We exposed neonatal mice to hyperoxia and treated them with gelsolin intranasally. Subsequently we inoculated the mice with RV intranasally. Alternatively, we inoculated normoxic neonatal mice with BALF from hyperoxia-exposed mice (hyperoxic BALF), RV and gelsolin. We analyzed lung gene expression two days after RV infection. For in vitro studies, lung CD11c+ cells were isolated from C57BL/6J or Clec9a gfp-/- mice and incubated with hyperoxic BALF and RV. Cells were analyzed by flow cytometry. In neonatal mice, gelsolin blocked hyperoxia-induced Il12p40, TNF-α and IFN-γ mRNA and protein expression in response to RV infection. Similar effects were observed when gelsolin was co-administered with hyperoxic BALF and RV. Gelsolin decreased F-actin levels in hyperoxic BALF in vitro and inhibited hyperoxia-induced D103lo DC expansion and inflammation in vivo . Gelsolin also attenuated hyperoxia-induced hypoalveolarization. Further, incubation of lung CD11c+ cells from WT and Clec9a gfp-/- mice with hyperoxic BALF and RV, showed Clec9a is required for maximal hyperoxic BALF and RV induced IL-12 expression in CD103+ DCs. Finally, in tracheal aspirates from mechanically ventilated human preterm infants the F-actin to gelsolin ratio positively correlates with FiO2, and gelsolin levels decrease during the first two weeks of mechanical ventilation. Collectively, our findings demonstrate a promising role for gelsolin, administered by inhalation into the airway to treat RV-induced exacerbations of BPD and prevent chronic lung disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cui, Brady, Zhang, Fulton and Popova.)

Infectious diseases, including COVID-19, are crucial public health issues and may lead to considerable fear among the general public and stigmatization of, and discrimination against, specific populations. This meta-analysis aimed to estimate the pooled prevalence of stigma in infectious disease epidemics. We systematically searched PubMed, PsycINFO, Embase, MEDLINE, Web of Science, and Cochrane databases since inception to June 08, 2021, and reported the prevalence of stigma towards people with infectious diseases including SARS, H1N1, MERS, Zika, Ebola, and COVID-19. A total of 50 eligible articles were included that contributed 51 estimates of prevalence in 92722 participants. The overall pooled prevalence of stigma across all populations was 34% [95% CI: 28-40%], including enacted stigma (36% [95% CI: 28-44%]) and perceived stigma (31% [95% CI: 22-40%]). The prevalence of stigma in patients, community population, and health care workers, was 38% [95% CI: 12- 65%], 36% [95% CI: 28-45%], and 30% [95% CI: 20-40%], respectively. The prevalence of stigma in participants from low- and middle-income countries was 37% [95% CI: 29-45%], which is higher than that from high-income countries (27% [95% CI: 18-36%]) though this difference was not statistically significant. A similar trend of prevalence of stigma was also observed in individuals with lower education (47% [95% CI: 23-71%]) compared to higher education level (33% [95% CI: 23-4%]). These findings indicate that stigma is a significant public health concern, and effective and comprehensive interventions are needed to counteract the damaging effects of the infodemics during infectious disease epidemics, including COVID-19, and reduce infectious disease-related stigma., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Multidrug resistance gene (MDR1a) and P-glycoprotein (P-gp) play an important role in the development of ulcerative colitis (UC) and influence the therapeutic effect of glucocorticoids, which may lead to drug resistance mechanically. UC may be related to miR-145 to some extent, and the relationship still needs further exploration. In this study we found that the expression of miR-145 was downregulated in the colonic tissues of rats with Dextran sodium sulfate (DSS)-induced UC. Also, the expression of MDR1a in colon tissues of each group negatively correlated with the expression of miR-145 in rats. The change in the plasma peak concentration (C max ) in each group positively related to the miR-145 level. Mechanistically, miR-145 negatively regulated the expression and function of P-gp via acting directly on the 3'-UTR of MDR1 mRNA. Overall, these results indicated that miR-145 had a protective effect on the colorectal mucosa, and its downregulation may enhance the expression and function of MDR1a and P-gp, promoting the occurrence and development of UC. The downregulation of miR-145 reduced the drug sensitivity of 5-aminosalicylic acid (5-ASA) and glucocorticoids in treating UC, indicating that miR-145 might be a potential therapeutic target for UC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The undergraduate program of psychiatry has been widely established in recent years to improve the education and recruitment of psychiatrists in China. We aim to investigate the career choice of medical students majoring in psychiatry in China and the influential factors., Method: This multicenter study was conducted in 26 medical schools in China from May to October of 2019. Participants included 4610 medical students majoring in psychiatry and 3857 medical students majoring in clinical medicine. Multivariable logistic regression was used to investigate the influential factors of students' choices of psychiatry at matriculation and as a career., Results: 44.08% of psychiatry majored students gave psychiatry as a first choice at matriculation, and 56.67% of them would choose psychiatry as a career, which was in sharp contrast to the proportion of clinical medicine majored students who would choose psychiatry as a career (0.69%). Personal interest (59.61%), suggestions from family members (27.96%), and experiencing mental problems (23.19%) were main reasons for choosing psychiatry major at matriculation. Personal interest (odds ratio [OR] = 2.12, 95% confidence interval [CI] = 1.87-2.40), experiencing a psychiatry clerkship (OR = 1.99, 95% CI = 1.28-3.08), being female (OR = 1.50, 95% CI = 1.30-1.68), experiencing mental problems (OR = 1.33, 95% CI = 1.28-1.56), and suggestions from family members (OR = 1.25, 95% CI = 1.08-1.46) correlated positively with students' choice of psychiatry as career. Students who lacked psychiatry knowledge (OR = 0.49, 95% CI = 0.29-0.85) or chose psychiatry because of lower admission scores (OR = 0.80, 95% CI = 0.63-0.97) were less likely to choose psychiatry as a career., Conclusion: More than half of psychiatry majored medical school students planned to choose psychiatry as their career, whereas very few students in the clinic medicine major would make this choice. Increasing students' interest in psychiatry, strengthening psychiatry clerkships, and popularizing psychiatric knowledge are modifiable factors to increase the psychiatry career intention. The extent to which medical students' attitudes toward psychiatry can be changed through medical school education and greater exposure to psychiatry will need further investigation.

Premature infants, especially those with bronchopulmonary dysplasia (BPD), develop recurrent severe respiratory viral illnesses. We have shown that hyperoxic exposure of immature mice, a model of BPD, increases lung IL-12-producing Clec9a + CD103 + dendritic cells (DCs), pro-inflammatory responses, and airway hyperreactivity following rhinovirus (RV) infection. However, the requirement for CD103 + DCs and Clec9a, a DAMP receptor that binds necrotic cell cytoskeletal filamentous actin (F-actin), for RV-induced inflammatory responses has not been demonstrated. To test this, 2-day-old C57BL/6J, CD103 + DC-deficient Batf3 -/- or Clec9a gfp-/- mice were exposed to normoxia or hyperoxia for 14 days. Also, selected mice were treated with neutralizing antibody against CD103. Immediately after hyperoxia, the mice were inoculated with RV intranasally. We found that compared with wild-type mice, hyperoxia-exposed Batf3 -/- mice showed reduced levels of IL-12p40, IFN-γ, and TNF-α, fewer IFN-γ-producing CD4 + T cells, and decreased airway responsiveness following RV infection. Similar effects were observed in anti-CD103-treated and Clec9a gfp-/- mice. Furthermore, hyperoxia increased airway dead cell number and extracellular F-actin levels. Finally, studies in preterm infants with respiratory distress syndrome showed that tracheal aspirate CLEC9A expression positively correlated with IL12B expression, consistent with the notion that CLEC9A + cells are responsible for IL-12 production in humans as well as mice. We conclude that CD103 + DCs and Clec9a are required for hyperoxia-induced pro-inflammatory responses to RV infection. In premature infants, Clec9a-mediated activation of CD103 + DCs may promote pro-inflammatory responses to viral infection, thereby driving respiratory morbidity.

The histopathology of bronchopulmonary dysplasia (BPD) includes hypoalveolarization and interstitial thickening due to abnormal myofibroblast accumulation. Chorioamnionitis and sepsis are major risk factors for BPD development. The cellular mechanisms leading to these lung structural abnormalities are poorly understood. We used an animal model with repeated lipopolysaccharide (LPS) administration into the airways of immature mice to simulate prolonged airway exposure to gram-negative bacteria, focusing on the role of C-C chemokine receptor type 2-positive (CCR2+) exudative macrophages (ExMf). Repetitive LPS exposure of immature mice induced persistent hypoalveolarization observed at 4 and 18 days after the last LPS administration. LPS upregulated the expression of lung pro-inflammatory cytokines (TNF- α , IL-17a, IL-6, IL-1 β ) and chemokines (CCL2, CCL7, CXCL1, and CXCL2), while the expression of genes involved in lung alveolar and mesenchymal cell development (PDGFR- α , FGF7, FGF10, and SPRY1) was decreased. LPS induced recruitment of ExMf, including CCR2+ ExMf, as well as other myeloid cells like DCs and neutrophils. Lungs of LPS-exposed CCR2-/- mice showed preserved alveolar structure and normal patterns of α -actin and PDGFR α expression at the tips of the secondary alveolar crests. Compared to wild type mice, a significantly lower number of ExMf, including TNF- α + ExMf were recruited to the lungs of CCR2-/- mice following repetitive LPS exposure. Further, pharmacological inhibition of TLR4 with TAK-242 also blocked the effect of LPS on alveolarization, α -SMA and PDGFR α expression. TNF- α and IL-17a induced α -smooth muscle actin expression in the distal airspaces of E16 fetal mouse lung explants. In human preterm lung mesenchymal stromal cells, TNF- α reduced mRNA and protein expression of PDGFR- α and decreased mRNA expression of WNT2, FOXF2, and SPRY1. Collectively, our findings demonstrate that in immature mice repetitive LPS exposure, through TLR4 signaling increases lung inflammation and impairs lung alveolar growth in a CCR2-dependent manner., (Copyright © 2020 Cui, Brady, Fulton, Zhang, Rosenbloom, Goldsmith, Moore and Popova.)

Bombyx mori nucleopolyhedrovirus (BmNPV) is a primary silkworm pathogen, and the molecular mechanism of silkworm defense to BmNPV infection is still unclear. Herein, comparative metabolomics was adopted to analyze the variations in the hemolymph metabolites of different resistant silkworm strains following BmNPV inoculation using a 1 H NMR method. Trehalose, as an instant source of energy, plays a crucial role in the response to pathogen infections in insects. The level of trehalose was persistently upregulated in the hemolymph of the resistant silkworm strain YeA following infection with BmNPV, compared to that of the susceptible strain YeB, indicating that trehalose metabolism plays a vital role in the response to BmNPV infection. The significant upregulation of TCA cycle relevant metabolites, including malate, fumarate, citrate, succinate, and α-ketoglutarate, was identified at 0 h, 12 h, 48 h, and 96 h post-infection in YeA hemolymph, whereas a significant upregulation in YeB hemolymph was only detected at an early stage of infection (0 h-24 h). The expression level of selected key metabolic enzymes, determined using RT-qPCR, validated the differences in trehalose and TCA cycle relevant metabolite levels. The variations in branched-chain amino acid (BCAA) pathway relevant metabolites in resistant silkworm strains following BmNPV infection showed a regular undulation at different times after infection. A significant accumulation of phenylalanine and tyrosine was observed in YeA following BmNPV infection compared to YeB. The glycolysis and gluconeogenesis pathways showed a relatively low activity in YeA following BmNPV infection. Moreover, the levels of other metabolites related to fat metabolism, transamination, energy metabolism, and glycometabolism, such as glycine, threonine, glutamine, and glutamate, were unstable in the two silkworm strains following BmNPV infection. Thus, our study provides an overview of the metabolic response of the silkworm in response to BmNPV infection, which lays the foundation for clarifying the mechanism of silkworm resistance to BmNPV infection., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: This study evaluated the effect of technetium-99m ( 99m Tc)-labeled prostate-specific membrane antigen (PSMA)-based image-guided surgery on the oncologic outcomes for patients with primary or recurrent prostate cancer (PCa)., Methods: This study retrospectively analyzed 54 consecutive patients with PCa who underwent 99m Tc-labeled PSMA-based image-guided surgery between January 2016 and September 2017. These patients received a radical prostatectomy (RP) with pelvic lymph node dissection (PLND) or salvage lymph node dissection (sLND). The resected specimens were compared with findings of postoperative histologic analysis. The responses to the treatment were recorded during the follow-up period., Results: In 31 patients, PSMA single-photon emission computerized tomography (SPECT) and computed tomography (CT) could find 52 suspicious lymph node metastases (LNMs). With the help of PSMA SPECT/CT, 12 patients with recurrence received sLND, 19 primary PCa patients received RP with extended PLND, and 23 primary PCa patients received RP with standard PLND. The findings showed that PSMA SPECT/CT could detect LNMs with high sensitivity and specificity. In six patients, PSMA SPECT/CT could find more LNMs that were not found by MRI and help to modify the extent of lymphadenectomy. At the latest follow-up evaluation, 39 patients showed a biochemical response (BR), 9 patients showed a biochemical recurrence (BCR) after BR, and 6 patients never exhibited BR. The patients who received RP with standard PLND or extended PLND had a better prostate-specific antigen (PSA) response than the patients who received sLND. The patients with pelvic LNMs also had a better PSA response than the patients with retroperitoneal LNMs., Conclusions: This study showed that 99m Tc-PSMA SPECT/CT-guided surgery can remove more LNMs than conventional imaging with high sensitivity and specificity and delay disease progression in PCa patients.

This study aims to investigate the gastrointestinal functions of patients with liver failure (LF) based on gastrointestinal dysfunction (GD) scores and serum gastrointestinal hormone levels.The GD in LF patients was scored using the gastrointestinal dysfunction scoring criteria. Serum gastrin (GAS), cholecystokinin (CCK), and motilin (MTL) levels were determined in LF patients. In addition, liver function and prothrombin activity were detected, and ultrasonography was performed.The GD score was significantly higher in the LF groups than in the control group. Compared with the control group, serum GAS, CCK, and MTL levels significantly increased in the LF groups, and was positively correlated with the severity of LF. Furthermore, in the LF groups, GD was positively correlated with the severity of LF. However, the GD score and serum GAS, CCK, and MTL levels in the acute LF group were not statistically different, when compared with those in the subacute LF group, acute-on-chronic LF group and chronic LF group.LF plays a key role in the development of GD, and may be the main cause of obvious gastrointestinal symptoms, such as abdominal distension, nausea, vomiting and anorexia, in LF patients. The severity of GD is not associated with LF type, but is positively correlated with the severity of LF, suggesting that GD in LF patients may have complicated mechanisms.

This study aims to investigate the relationship between gastrointestinal dysfunction (GD) and cirrhosis severity in cirrhotic patients, to provide evidences for the prevention and treatment of GD in cirrhotic patients.A total of 95 cirrhotic inpatients and outpatients, who were treated in the Department of Gastroenterology of Xinqu Hospital of the First Affiliated Hospital of Henan University of Science and Technology, were enrolled in the present study, and assigned as the experimental group (cirrhosis group). According to Child-Pugh classification, these patients were divided into 3 groups: group A (n = 45), group B (n = 23), and group C (n = 27). Forty healthy adults who received health check-ups during the same period served as the control group. The gastrointestinal (GI) symptoms of cirrhotic patients were scored, and the fasting serum gastrin (GAS), motilin (MTL), and vasoactive intestinal peptide (VIP) levels were measured in all subjects.The potential correlations of GI symptom scores of patients in these cirrhosis groups with GI hormone levels and cirrhosis severity were analyzed. In cirrhotic patients, the GI symptom scores significantly increased. Furthermore, the symptom scores gradually increased along with the aggravation of liver damage. Moreover, serum GAS and VIP levels were significantly higher in the cirrhosis groups than in the control group, whereas MTL levels were significantly lower. These changes were significantly correlated with cirrhosis severity. The linear correlation analysis revealed that the GI symptom score was positively correlated with GAS and VIP levels, and negatively correlated with MTL level. In addition, the linear correlation analysis revealed that GI symptom score and GAS and VIP levels were positively correlated with cirrhosis severity, whereas MTL level was negatively correlated with cirrhosis severity.Cirrhotic patients have more obvious GI symptoms and higher GI hormone levels, which are closely correlated with the progression of liver cirrhosis and the degree of liver function damage.

Objective This study was performed to examine serum microRNA-375 (miR-375) expression in patients with osteosarcoma and determine its diagnostic and prognostic value. Methods Serum samples were obtained from 95 patients with osteosarcoma and 95 healthy individuals. miR-375 expression was detected by real-time polymerase chain reaction. The associations of serum miR-375 expression with the patients' clinicopathological characteristics and prognosis were then evaluated. Receiver operating characteristic curve analysis was performed to obtain the potential value of serum miR-375 as a biomarker for osteosarcoma diagnosis and chemosensitivity prediction. Results Serum miR-375 expression was significantly lower in patients with osteosarcoma than in healthy individuals. Low serum miR-375 levels were associated with advanced clinical stages, large tumor size, positive distant metastasis, and poor tumor response to preoperative chemotherapy. Receiver operating characteristic curve analysis illustrated that serum miR-375 could distinguish patients with osteosarcoma from healthy individuals and distinguish patients with a good pathologic response from those with a poor response. Multivariate analysis confirmed low serum miR-375 expression as a statistically significant independent unfavorable prognostic factor. Conclusions Serum miR-375 expression was downregulated in patients with osteosarcoma and might serve as a biomarker for its diagnosis, prognosis, and chemosensitivity prediction.

Long noncoding RNA (lncRNA) small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) acts a tumor promoter in several malignancies; however, its roles in colon cancer remain unclear. Herein, we demonstrated that SUMO1P3 expression was significantly higher in colon cancer tissues and cell lines than the corresponding non-tumor samples and normal colonic epithelial cells, respectively. The upregulation of SUMO1P3 was positively correlated with the advanced histological stages, metastases, angiogenesis and poor prognosis of colon cancer patients. SUMO1P3 knockdown repressed the proliferation, migration, invasion, and pro-angiogenesis of colon cancer cells in vitro. SUMO1P3 silencing reduced the growth, liver metastasis, and vascularization of colon cancer in vivo. Mechanistically, SUMO1P3 depletion decreased the levels of cyclin D1, Vimentin, and VEGFA while increased E-cadherin expression in xenograft tumor tissues. Overall, these results indicate that SUMO1P3 expedites the malignant behaviors of colon cancer and may be as a potential therapeutic target., Competing Interests: None.

Objective: The effect of the silica nanoparticles (SNs) on lungs injury in rats was investigated to evaluate the toxicity and possible mechanisms for SNs., Methods: Male Wistar rats were instilled intratracheally with 1 mL of saline containing 6.25, 12.5, and 25.0 mg of SNs or 25.0 mg of microscale SiO2 particles suspensions for 30 d, were then sacrificed. Histopathological and ultrastructural change in lungs, and chemical components in the urine excretions were investigated by light microscope, TEM and EDS. MDA, NO and hydroxyproline (Hyp) in lung homogenates were quantified by spectrophotometry. Contents of TNF-α, TGF-β1, IL-1β, and MMP-2 in lung tissue were determined by immunohistochemistry staining., Results: There is massive excretion of Si substance in urine. The SNs lead pulmonary lesions of rise in lung/body coefficients, lung inflammation, damaged alveoli, granuloma nodules formation, and collagen metabolized perturbation, and lung tissue damage is milder than those of microscale SiO2 particles. The SNs also cause increase lipid peroxidation and high expression of cytokines., Conclusion: The SNs result into pulmonary fibrosis by means of increase lipid peroxidation and high expression of cytokines. Milder effect of the SNs on pulmonary fibrosis comparing to microscale SiO2 particles is contributed to its elimination from urine due to their ultrafine particle size., (Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

The present study aimed to investigate the proteomic difference between melanosis coli (MC) alone and melanosis coli with colon cancer (MCCC). Protein expression in patients with different diseases was analyzed using two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/TOF-MS). A total of 14 protein differences with a confidence level of >95% were found. There were six differences between MC and normal tissues, in which two proteins exhibited upregulated expression levels and four proteins exhibited downregulated expression levels in MC. Furthermore, one protein was expressed only in MC (P<0.05). In addition, there were differences in the expression of eight proteins between MC and MCCC tissues, in which one protein had an upregulated expression in MC tissues and seven proteins had an upregulated expression in MCCC tissues. Furthermore, two proteins were only expressed in MCCC tissues (P<0.05). Eight proteins were identified using mass spectrometry and database search. In conclusion, comparative proteomics accurately displayed the expression differences in eight proteins between MC, MCCC and normal colon tissues.

Objective : Antiangiogenesis therapy (AAT) has provided substantial benefits regarding improved outcomes and survival for suitable patients in clinical settings. Therefore, the early definition of therapeutic effects is urgently needed to guide cancer AAT. We aimed to optimize the early response monitoring and prediction of AAT efficacy, as indicated by the multi-targeted anti-angiogenic drug sunitinib in U87MG tumors, using noninvasive positron emission computed tomography (PET) molecular imaging strategies of multifactorial bioparameters. Methods: U87MG tumor mice were treated via intragastric injections of sunitinib (80 mg/kg) or vehicle for 7 consecutive days. Longitudinal MicroPET/CT scans with 18 F-FDG, 18 F-FMISO, 18 F-ML-10 and 18 F-Alfatide II were acquired to quantitatively measure metabolism, hypoxia, apoptosis and angiogenesis on days 0, 1, 3, 7 and 13 following therapy initiation. Tumor tissues from a dedicated group of mice were collected for immunohistochemical (IHC) analysis of key biomarkers (Glut-1, CA-IX, TUNEL, α ν β 3 and CD31) at the time points of PET imaging. The tumor sizes and mouse weights were measured throughout the study. The tumor uptake (ID%/g max ), the ratios of the tumor/muscle (T/M) for each probe, and the tumor growth ratios (TGR) were calculated and used for statistical analyses of the differences and correlations. Results: Sunitinib successfully inhibited U87MG tumor growth with significant differences in the tumor size from day 9 after sunitinib treatment compared with the control group (P < 0.01). The uptakes of 18 F-FMISO (reduced hypoxia), 18 F-ML-10 (increased apoptosis) and 18 F-Alfatide II (decreased angiogenesis) in the tumor lesions significantly changed during the early stage (days 1 to 3) of sunitinib treatment; however, the uptake of 18 F-FDG (increased glucose metabolism) was significantly different during the late stage. The PET imaging data of each probe were all confirmed via ex vivo IHC of the relevant biomarkers. Notably, the PET imaging of 18 F-Alfatide II and 18 F-FMISO was significantly correlated (all P < 0.05) with TGR, whereas the imaging of 18 F-FDG and 18 F-ML-10 was not significantly correlated with TGR. Conclusion : Based on the tumor uptake of the PET probes and their correlations with MVD and TGR, 18 F-Alfatide II PET may not only monitor the early response but also precisely predict the therapeutic efficacy of the multi-targeted, anti-angiogenic drug sunitinib in U87MG tumors. In conclusion, it is feasible to optimize the early response monitoring and efficacy prediction of cancer AAT using noninvasive PET molecular imaging strategies of multifactorial bioparameters, such as angiogenesis imaging with 18 F-Alfatide II, which represents an RGD-based probe., Competing Interests: The authors have declared that no competing interest exists.

Resistance of cancer cells to chemoradiotherapy is a major clinical problem in pancreatic cancer treatment. Therefore, understanding the molecular basis of cellular resistance and identifying novel targets are essential for improving treatment efficacy for pancreatic cancer patients. Previous studies have demonstrated a significant role for Pim-3 in pancreatic cancer survival against gemcitabine-induced genotoxic stress. Here, we observed that radiation treatment enhanced Pim-3 expression in human pancreatic cancer cells in vitro. Stable overexpression of Pim-3 in pancreatic cancer cells significantly protected cells against radiation treatment by attenuating G2/M phase cell cycle arrest and DNA damage response. Silencing of Pim-3 expression significantly elevated the phosphorylation of histone variant H2AX, a marker of DNA double strand breaks, and decreased the activation of ataxia-telangiectasia-mutated (ATM) kinase, along with its downstream targets, eventually enhancing the radiosensitivity of human pancreatic cancer cells in vitro and in vivo. Hence, we demonstrated a novel function for Pim-3 in human pancreatic cancer cell survival against radiation. Targeting Pim-3 may be a promising way to improve treatment efficacy in combination with radiotherapy in human pancreatic cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Our goal was to validate the feasibility of(99m)Tc-duramycin as a potential apoptosis probe for monitoring tumor response to paclitaxel in breast cancer xenografts. The binding of(99m)Tc-duramycin to phosphatidylethanolamine was validated in vitro using paclitaxel-treated human breast carcinoma MDA-MB-231 cells. Female BALB/c mice (n = 5) bearing breast cancer xenografts were randomized into 2 groups and intraperitoneally injected with 40 mg/kg paclitaxel or phosphate-buffered saline.(99m)Tc-duramycin (37-55.5 MBq) was injected at 72 hours posttreatment, and single-photon emission computed tomography/computed tomography was performed at 2 hours postinjection. Apoptotic cells and activated caspase 3 in explanted tumor tissue were measured by flow cytometry. Cellular ultrastructural changes were assessed by light and transmission electron microscopy.(99m)Tc-duramycin with radiochemical purity of >90% exhibited rapid blood clearance and predominantly renal clearance. The tumor-to-muscle ratio in the paclitaxel-treated group (5.29 ± 0.62) was significantly higher than that in the control. Tumor volume was decreased dramatically, whereas tumor uptake of(99m)Tc-duramycin (ex vivo) significantly increased following paclitaxel treatment, which was consistent with apoptotic index, histological findings, and ultrastructural changes. Our data demonstrated the feasibility of(99m)Tc-duramycin for early detection of apoptosis after paclitaxel chemotherapy in breast carcinoma xenografts., (© The Author(s) 2016.)

We estimated the dosimetry of (18)F-alfatide II with the method established by MIRD based on biodistribution data of mice. Six mice (three females and three males) were scanned for 160min on an Inveon MicroPET/CT scanner after injection of (18)F-alfatide II via tail vein. Eight source organs were delineated on the CT images and their residence times calculated. The data was then converted to human using scaling factors based on organ and body weight. The absorbed doses for human and the resulting effective dose were computed by OLINDA 1.1 software. The highest absorbed doses was observed in urinary bladder wall (male 0.102mGy/MBq, female 0.147mGy/MBq); and the lowest one was detected in brain (male 0.0030mGy/MBq, female 0.0036). The total effective doses were 0.0127mSv/MBq for male and 0.0166 mSv/MBq for female, respectively. A 370-MBq injection of (18)F-alfatide II led to an estimated effective dose of 4.70mSv for male and 6.14mSv for female. The potential radiation burden associated with (18)F-alfatide II/PET imaging therefore is comparable to other PET examinations., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: The aim of the study was to evaluate the predictive value of fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) pretreatment on local control (LC) and survival after radical radiotherapy or chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (SCC) and to discuss its potential value for establishing optimal radiation treatment plans., Methods: Fifty-eight patients with pathologically proven esophageal SCC who underwent ¹⁸F-FDG PET/CT pretreatment in our center were retrospectively reviewed. We examined the correlation between the PET parameters of primary tumors and LC and overall survival. The coefficient of variation was used to estimate the ¹⁸F-FDG uptake in heterogeneity., Results: The mean duration of follow-up for surviving patients was 38 months, and 36 patients died because of tumor recurrence or other diseases. The rates of 3-year overall survival and LC were 40.4 and 50.4%, respectively. Multivariate analysis of LC revealed that metabolic tumor volume (MTV) greater than 16.08 ml was the only predictor of outcome, with a lower 3-year LC (P=0.017, hazard ratio: 1.608, 95% confidence interval: 1.090-2.371). The coefficient of variations of their primary lesion were higher compared with those of patients who had smaller MTVs., Conclusion: In this study, MTV assessed by PET/CT might be an adverse factor for predicting LC in esophageal SCC. For those with higher MTVs, higher intratumor heterogeneity suggests that irradiation may need to be boosted in stable high-uptake regions to improve LC. These results need to be prospectively validated in larger cohorts.

Purpose: To observe the safety of selective dose boost to the pre-treatment high (18)F-deoxyglucose (FDG) uptake areas of the esophageal GTV., Methods: Patients with esophageal squamous cell carcinoma were treated with escalating radiation dose of 4 levels, with a simultaneous integrated boost (SIB) to the pre-treatment 50% SUVmax area of the primary tumor. Patients received 4 monthly cycles of cisplatin and fluorouracil. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher acute toxicities causing continuous interruption of radiation for over 1 week., Results: From April 2012 to February 2014, dose has been escalated up to LEVEL 4 (70Gy). All of the 25 patients finished the prescribed dose without DLT, and 10 of them developed Grade 3 acute esophagitis. One patient of LEVEL 2 died of esophageal hemorrhage within 1 month after completion of radiotherapy, which was not definitely correlated with treatment yet. Late toxicities remained under observation. With median follow up of 8.9months, one-year overall survival and local control was 69.2% and 77.4%, respectively., Conclusions: Dose escalation in esophageal cancer based on (18)FDG-PET/CT has been safely achieved up to 70Gy using the SIB technique. Acute toxicities were well tolerated, whereas late toxicities and long-term outcomes deserved further observation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired β-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic β-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage.

Purpose: Tumour burden is one of the most important prognosticators for pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the predictive significance of metabolic tumour burden measured by (18)F-FDG PET/CT in patients with resectable PDAC., Methods: Included in the study were 122 PDAC patients who received preoperative (18)F-FDG PET/CT examination and radical pancreatectomy. Metabolic tumour burden in terms of metabolic tumour volume (MTV) and total lesion glycolysis (TLG), pathological tumour burden (tumour size), serum tumour burden (baseline serum CA19-9 level), and metabolic activity (maximum standard uptake value, SUVmax) were determined, and compared for their performance in predicting overall survival (OS) and recurrence-free survival (RFS)., Results: MTV and TLG were significantly associated with baseline serum CA19-9 level (P = 0.001 for MTV, P < 0.001 for TLG) and tumour size (P < 0.001 for MTV, P = 0.001 for TLG). Multivariate analysis showed that MTV, TLG and baseline serum CA19-9 level as either categorical or continuous variables, but not tumour size or SUVmax, were independent risk predictors for both OS and RFS. Time-dependent receiving operating characteristics analysis further indicated that better predictive performances for OS and RFS were achieved by MTV and TLG compared to baseline serum CA19-9 level, SUVmax and tumour size (P < 0.001 for all)., Conclusion: MTV and TLG showed strong consistency with baseline serum CA19-9 level in better predicting OS and RFS, and might serve as surrogate markers for prediction of outcome in patients with resectable PDAC.

Background/aims: To study the effect of drugs on the expression of multidrug resistance gene in ulcerative colitis., Methodology: The expressions of multidrug resistance (MDR) 1 gene and its product P-Gp were detected by reverse transcription-polymerase chain reaction and immunohistochemistry to realize the impact of drugs on ulcerative colitis., Results: MDR1 gene and P-Gp did not exhibit significant difference (P > 0.05) before and after amino salicylic acid drug treatment. Compared with the control group, their expressions before treatment in the ineffective corticosteroid- and immunosuppressant-treated groups did not exhibit significant difference (P > 0.05). Their pre- and post-treatment expressions in the ineffective groups were compared with those in the normal control group and in the effective group, and significant differences were observed (P < 0.05)., Conclusions: 5-Amino salicylic acid drugs have little effect on the expression of MDR1 and its product P-Gp. The expressions of MDR1 and P-Gp were much higher in groups that showed ineffectiveness for corticosteroids and immunosuppressants after treatment.

Aim: It was aimed to monitor early treatment response of Sunitinib in U87MG models mimicking glioblastoma multiforme by longitudinal (18)F-FLT microPET/CT imaging in this study., Methods: U87MG tumor mice were intragastrically injected with Sunitinib at a dose of 80 mg/kg for consecutive 7 days. (18)F-FLT microPET/CT scans were acquired on days 0, 1, 3, 7, and 13 after therapy. Tumor sizes and body weight were measured. Tumor samples were collected for immunohistochemical analysis of proliferation and microvessel density (MVD) with anti-Ki67 and anti-CD31, respectively., Results: The uptake ratios of tumor to the contralateral muscle (T/M) of (18)F-FLT in the Sunitinib group decreased from baseline to day 3 (T/M0 = 2.98 ± 0.33; T/M3 = 2.23 ± 0.36; P < 0.001), reached the bottom on day 7 (T/M7 = 1.96 ± 0.35; P < 0.001), and then recovered on day 13. The T/M of (18)F-FLT uptake in the control group remained around 3.0. There was no difference for the tumor size between both groups until day 11. (18)F-FLT uptakes of tumor were correlated with Ki67 staining index and MVD., Conclusion: Early therapy response to Sunitinib could be predicted via (18)F-FLT PET, which will contribute to monitoring antiangiogenesis treatment.

Purpose: Efficient tumor volume delineation by the combined use of PET/CT scanning is necessary for the proper treatment of non-small cell lung cancer (NSCLC). To understand the effect of variation in background intensity on PET-based gross tumor volume (GTV) delineation, we determined the background standard uptake values (SUVs) in normal lung, aorta (blood pool), and liver tissues and determined GTVs using different methods., Methods: Thirty-seven previously untreated patients with pathologically confirmed NSCLC underwent PET/CT scanning with (18)F-fluorodeoxyglucose ((18)F-FDG). To obtain (18)F-FDG uptake values in normal tissues, regions of interest in the lung lobes (left upper, left lower, right upper, right middle, and right lower), aorta, and liver zones (left, intermediate, and right) were measured. The coefficient of variation (CV) of the SUV was measured for each normal structure. The CT-based GTV (GTV(CT)) was considered as the standard to which all PET-based GTVs were compared, and the correlation coefficient was analyzed to compare GTV obtained by the various delineation methods. Linear and logarithmic regression analyses were used to determine the relationship between GTV(CT) and GTV(PET)., Results: Normal lung tissue showed a significantly lower SUV and less stability than tissue of the aorta or liver. For the lung, aorta, and liver, the maximum SUV (SUV(max)) was 0.82 ± 0.32, 2.35 ± 0.37, and 3.24 ± 0.50 (CV: 38.79%, 15.82%, and 15.30%) and average SUV (SUV(ave)) was 0.49 ± 0.18, 1.68 ± 0.32, and 2.34 ± 0.36 (CV: 36.38%, 18.92%, and 15.44%), respectively. The SUVs of the lung varied from lobe to lobe. The GTV delineation method using the SUV(ave) of the lung lobe in which the tumor was found as background in the source-to-background ratio (SBR) method showed the best correlation with the volume of CT-based GTV (r=0.81)., Conclusions: Our results show vast variation in the SUV among normal tissues, as well as in the different lung lobes. The tumor volume delineated using the SBR method correlated well with the CT-based tumor volume. We conclude that it is reasonable and precise to contour GTV in patients with NSCLC after taking into account the background intensity of the lung lobe in which the tumor is found., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: To investigate the expression of Galectins in umbilical cord mesenchymal stem cells (UC-MSCs) from Wharton's jelly., Methods: Umbilical cords were obtained sterilely from full term caesarean infants, then mesenchymal stem cells (MSCs) were isolated from Wharton's jelly of the umbilical cord via tissue cultivation. The morphology of UC-MSCs was observed under the optical microscope, and its immunophenotypes were analyzed by flow cytometry. The differentiation of UC-MSCs into the osteoblasts and adipocytes was determined utilizing von Kossa calcium node staining and oil red O staining, respectively. The expression of Galectins at mRNA level was measured by RT-PCR. The levels of secretory Galectin-3 in culture supernatants were detected by sandwich enzyme-linked immunosorbent assay., Results: The UC-MSCs could be generated by tissue cultivation. Flow cytometry showed they highly expressed membrane molecules, such as CD29, CD44, CD73, CD90 and CD105, but did not express hematopoietic specific markers (CD14, CD34, and CD45) and immune rejection related molecule HLA-DR. UC-MSCs could differentiate into osteoblasts or adipocytes under appropriate experimental conditions. At the mRNA level, Galectin-1, 3, 4, 8 and 9 were detected in UC-MSCs. And they also could secrete soluble Galectin-3 in a cell number dependent manner. Statistical differences were obtained among the different cell number incubation groups (F=16.901,P=0.002). However, the secretory manner of Galectin-3 was not time dependent., Conclusion: UC-MSCs, derived from Wharton's jelly, were successfully cultured via tissue cultivation, and they could express secretory Galectin-3. All these data laid the foundation for further detecting the immunomodulatory mechanism of UC-MSCs.

Objectives: Maximum standardized uptake value (SUV(max)) is a marker of tumor glucose metabolism detected by [(18)F]-fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (PET/CT) and reflects tumor aggressiveness. The aim of the study was to evaluate the value of SUV(max) in differentiating benign from malignant solitary pancreatic lesions and explore the correlation between SUV(max) and tumor proliferative activity., Materials and Methods: F-FDG PET/CT scans were performed in 80 patients with solitary pancreatic lesions who were scheduled for resective surgery. The relationships between SUV(max) and postoperative pathologic diagnosis, histologic grade, and Ki-67 proliferation index (PI) were analyzed., Results: Of these 80 patients, 54 had malignant lesions. The SUV(max) of malignant tumors (6.3 ± 2.4) was significantly greater than that of benign lesions (2.9 ± 2.0) (P<0.001). Receiver-operating characteristic curve analysis showed that the SUV(max) cutoff value of 3.5 had a high sensitivity (92.6%) and specificity (76.9%) for the diagnosis of malignancies. Among pancreatic cancers with low (Ki-67<5%), moderate (5% ≤ Ki-67<50%), and high (Ki-67 ≥ 50%) PI, SUV(max) increased significantly from 4.2 ± 1.2, through 6.0 ± 1.7, to 8.6 ± 2.5 (P<0.001). The SUV(max) had a positive correlation with Ki-67 PI (P<0.001, r=0.60)., Conclusion: The SUV(max) of F-FDG PET/CT can be used in the differential diagnosis of solitary pancreatic lesions and can also aid in the prediction of proliferative activity of pancreatic cancer.

Aim: The objectives of this study were to determine if the baseline SUVmax measured by F-FDG PET/CT correlates with molecular subtype and to explore the impact of baseline SUVmax on the survival of patients with metastatic breast cancer (MBC)., Methods: Patients with MBC were screened with PET/CT from February 2007 until December 2010. Multivariate linear regression analysis was performed to identify independent variable correlation with SUVmax. Prognostic variables identified by univariate analysis, with P < 0.1, were analyzed in the multivariate Cox model., Results: A total of 244 MBC patients were eligible for this study. Multivariate linear regression analysis showed that molecular subtype, visceral metastasis, and number of metastatic organs could be used to predict the logarithmic values of SUVmax (lgSUVmax) for previous untreated MBC patients, whereas for those with 1 or more line previous treatment, the number of metastatic organs was identified as the only independent variable correlating with lgSUVmax. Cox regression analysis indicated that only in patients with previously untreated MBC did baseline SUVmax (continuous variable) act as an independent prognostic factor (hazard ratio = 1.049 for progression-free survival, 1.124 for overall survival)., Conclusions: Baseline SUVmax correlates with molecular subtypes only in previously untreated MBC patients. PET/CT imaging can be used as a potential prognostic tool for patients with newly diagnosed MBC.

There is an increasing need to develop non-invasive molecular imaging strategies for visualizing and quantifying apoptosis status of diseases (especially for cancer) for diagnosis and monitoring treatment response. Since externalization of phosphatidylserine (PS) is one of the early molecular events during apoptosis, Annexin B1 (AnxB1), a member of Annexins family with high affinity toward the head group of PS, could be a potential positron emission tomography (PET) imaging probe for imaging cell death process after labeled by positron-emitting nuclides, such as (18)F. In the present study, we investigated a novel PET probe, (18)F-labeled Annexin B1 ((18)F-AnxB1), for apoptosis imaging. (18)F-AnxB1 was prepared reliably by conjugating AnxB1 with a (18)F-tag, N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB), in a radiolabeling yield of about 20 % within 40 min. The in vitro binding of (18)F-AnxB1 with apoptotic cells induced by anti-Fas antibody showed twofold increase compared to those without treatment, confirmed by flow cytometric analysis with AnxV-FITC/PI staining. Stability tests demonstrated (18)F-AnxB1 was rather stable in vitro and in vivo without degradation. The serial (18)F-AnxB1 PET/CT scans in healthy rats outlined its biodistribution and pharmacokinetics, indicating a rapid renal clearance and predominant accumulation into kidney and bladder at 2 h p.i. (18)F-AnxB1 PET/CT imaging was successfully applied to visualize in vivo apoptosis sites in tumor induced by chemotherapy and in kidney simulated by ischemia-reperfusion injury. The high-contrast images were obtained at 2 h p.i. to delineate apoptotic tumor. Apoptotic region could be still identified by (18)F-AnxB1 PET 4 h p.i., despite the high probe retention in kidneys. In summary, we have developed (18)F-AnxB1 as a PS-specific PET probe for the apoptosis detection and quantification which could have broad applications from disease diagnosis to treatment monitoring, especially in the cases of cancer.

Background: Whether PET scan maximum standard uptake value (SUVmax) could differentiate luminal A from luminal B and help predict the survival of metastatic breast cancer (MBC) patients with luminal subtype is still unknown and need to be investigated., Methods: 305 MBC patients with luminal subtypes were screened with PET/CT. Eligible patients were prospectively followed up., Results: In total, 134 patients were eligible for this study. SUVmax was significantly related to the number of metastatic sites and presence of visceral metastasis on univariate analysis. SUVmax could not effectively differentiate patients with luminal A from luminal B subtype. Although luminal subtype at diagnosis could predict the relapse-free interval, it could not predict progression-free survival (PFS) or overall survival (OS) after developing relapse. In contrast, SUVmax was predictive of both PFS and OS and this effect was maintained in multivariate COX regression model., Conclusions: SUVmax of MBC did not correlate with molecular subtypes of primary tumor. While molecular subtype may be a valuable prognostic factor at primary diagnosis of breast cancer, the SUVmax, rather than molecular subtype, does have a potential to predict independently in multivariate analysis for the PFS and OS in patients with metastatic disease of luminal subtype.

Two cases of postoperative female patients with ovarian serous papillary carcinoma were referred for F-18 Fluorodeoxyglucose (F-18 FDG) PET/CT to evaluate suspicious recurrence and/or metastasis. One patient presented with multiple extensive calcified lesions with increased FDG uptake in the abdominopelvic cavity and the series of PET/CT scans showed progression of disease after chemotherapy. The other patient presented with three calcified masses with intensive uptake of FDG located in the left pelvis, the right subphrenic region, and the right supradiaphragmatic area, respectively. These suggest that F-18 FDG PET/CT can be useful in identifying malignant calcification and assessing therapeutic response of calcified malignancy.

IgG4-related sclerosing disease(IgG4-RSD) is a kind of lymphoplasmacytic disease with multi-organ involvement and is characterized by serum IgG4 elevation and tissue IgG4 positive plasma cell infiltration. Autoimmune pancreatitis, sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis and lymphadenopathy make up its main clinical manifestations. This difficult case was a middle-aged female with onset as muiltiple lymph nodes and glands enlargement, including lacrimal gland, salivary glands and pancreas. Meanwhile, repeated examinations of auto-antibodies and serum IgG4 were all negative. The patient didn't respond well to glucocorticoid therapy, and further progressed to rare lung involvement presenting as lung nodule. This complex entity was eventually diagnosed as IgG4-RSD by the support of histopathology evidence of IgG4 immunohistochemistry stain. Though IgG4-RSD has been known for years, it is still underappreciated in China and case reports are scarce. The case report here with literature review is just to enhance the recognition of this disease regarding its pathogenesis, various clinical manifestations, diagnosis and therapy.

We estimated the dosimetry of [(18)F]fluoroacetate (FAC) with the method established by MIRD based on biodistribution data of rats. We selected some important organs and computed their residence time, their absorbed doses and effective dose with the (%ID(Organ)) (human) data using OLINDA/EXM 1.1 program. We observed the highest absorbed doses in the heart wall (0.025mGy/MBq) and the lowest in skin (0.0079mGy/MBq). The total mean absorbed doses and the effective doses were 0.011mGy/MBq and 0.014mSv/MBq, respectively. A 370-MBq injection of FAC leads to an estimated effective dose of 5.2mSv. The potential radiation risk associated with FAC/PET imaging is well within the accepted limits., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: To determine an optimal standardized uptake value (SUV) threshold for detecting lymph node (LN) metastases in esophageal cancer using (18)F-Fluorodeoxyglucose positron emission tomography/computer tomography (18FDG PET/CT) and to define the resulting nodal target volume, using histopathology as a "gold standard.", Methods: Sixteen patients with esophageal squamous cell carcinoma who underwent radical esophagectomy and three-field LN dissection after 18FDG PET/CT and CT scans were enrolled into this study. Locations of LN groups were recorded according to a uniform LN map. Diagnostic performance of different SUV thresholds was assessed by receiver operating characteristic analysis. The optimal cutoff SUV was determined by plotting the false-negative rate (FNR) and false-positive rate (FPR), the sum of both error rates (FNR+FPR), and accuracy against a hypothetical SUV threshold. For each patient, nodal gross tumor volumes (GTVNs) were generated with CT alone (GTVNCT), PET/CT (GTVNPET), and pathologic data (GTVNpath). GTVNCT or GTVNPET was compared with GTVNpath by means of a conformity index (CI), which is the intersection of the two GTVNs divided by the sum of them minus the intersection, e.g., CICT&path=GTVNCT&path/(GTVNCT+GTVNpath-GTVNCT&path)., Results: LN metastases occurred in 21 LN groups among the 144 specimens taken from the 16 patients. The area under the receiver operating characteristic curve was 0.9017±0.0410. The plot of error rates showed a minimum of FNR+FPR for an SUV of 2.36, at which the sensitivity, specificity, and accuracy were 76.19%, 95.93%, and 93.06%, respectively, whereas those of CT were 33.33%, 94.31%, and 85.42% (p values: 0.0117, 0.7539, and 0.0266). Mean GTVNCT, GTVNPET, and GTVNpath were 1.52±2.38, 2.82±4.51, and 2.68±4.16 cm3, respectively. Mean CICT&path and CIPET&path were 0.31 and 0.65 (p value=0.0352)., Conclusions: Diagnostic superiority of PET/CT at an SUV threshold of 2.36 over CT has potential value in nodal target volume definition, but whether this can contribute to better treatment outcomes needs prospective analyses of recurrences in a larger cohort of patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To evaluate the clinical value of F-fluorodeoxyglucose positron emission tomography and computed tomography (¹⁸F-FDG PET/CT) in postoperative patients with gastrointestinal mucinous adenocarcinoma., Methods: From July 2007 to March 2009, 30 patients who had previous surgical resection of histopathologically diagnosed gastrointestinal mucinous adenocarcinoma underwent ¹⁸F-FDG PET/CT scans in our center. The standard of reference for tumor recurrence, regional lymph node (LN) metastasis, peritoneal and distant metastasis consisted of histopathologic confirmation or clinical follow-up information for at least 6 months after PET/CT examinations., Results: With final diagnosis, tumor recurrences were confirmed in eight of the 30 patients (26.7%). If a maximum standardized uptake value (SUVmax) of 2.5 or more was used as a cut-off point, the sensitivity, specificity, and accuracy of PET/CT were 87.5, 77.3, and 80.0%, respectively. However, if an SUVmax of 4.0 or more was the criterion, the sensitivity, specificity, and accuracy were 25.0, 86.4, and 70.0%, respectively. A cut-off point of 2.5 showed a higher sensitivity (P=0.041), and there was no statistical difference in the specificity and the accuracy of these two criteria. For the diagnosis of metastasis in regional LNs and peritoneum, the detection rate was 95.2 and 86.4%, respectively. In addition, we followed up 20 patients with 26 suspicious distant lesions. The sensitivity, specificity, and accuracy were 58.3, 92.9, and 76.9%, respectively., Conclusion: ¹⁸F-FDG PET/CT may be effective to discriminate tumor recurrence, and to detect regional LNs, peritoneal and distant metastasis in postoperative patients with gastrointestinal mucinous adenocarcinoma.

Background: The authors prospectively evaluated the correlation between technetium-99m methoxyisobutyl isonitrile ((99m) Tc-MIBI) accumulation in tumors and response to induction chemotherapy in patients with nasopharyngeal carcinoma (NPC)., Methods: Eighty-six patients with locally advanced NPC underwent single-photon emission computed tomography 15 minutes after an intravenous injection of 740 megabecquerels (20 mCi) (99m) Tc-MIBI before chemotherapy. The tumor uptake ratio (TUR) was calculated. Two weeks after the second cycle of combined chemotherapy with 5-fluorouracil (5-FU) and cisplatin (DDP), the tumor response rate was evaluated. The correlation between (99m) Tc-MIBI accumulation in tumors and response to chemotherapy with 5-FU/DDP was examined., Results: Positive accumulation of (99m) Tc-MIBI in tumors was observed in 76 patients (88.4%). The tumor response was a complete response (CR) in 8 patients, a partial response (PR) in 68 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. The response rate (CR and PR) to 5-FU/DDP chemotherapy in patients who had positive (99m) Tc-MIBI accumulation (tumor uptake ratio [TUR] >1.1) was higher than that in patients who had negative (99m) Tc-MIBI accumulation (TUR ≤ 1.1; 98.7% vs 10%; P < .001)., Conclusions: Patients with negative (99m) Tc-MIBI accumulation were resistant to 5-FU/DDP chemotherapy. (99m) Tc-MIBI imaging in patients with NPC was capable of predicting tumor response to chemotherapy with 5-FU/DDP and can help in the selection of patients for induction chemotherapy., (Copyright © 2010 American Cancer Society.)

Objective: To study the relationship between the solar term of onset of acute myocardial infarction (AMI) and its syndrome types in traditional Chinese medicine (TCM)., Methods: The clinical data about 430 patients with AMI hospitalized in Foshan Hospital of TCM from February 4th 2003 (Beginning of Spring) to February 3rd 2008 (Beginning of Spring) were collected, and the solar term of onset as angle coordinate was regarded, then the peak phase of the onset solar term in each syndrome type of AMI was calculated by circular statistical analysis., Results: Among 430 patients with AMI, 134 patients were considered to have qi stagnancy and blood stasis syndrome, 188 patients showed the syndrome of turbid sputum obstruction, 29 of them showed deficiency of yin-blood, and 79 showed deficiency of yang qi. The clinical manifestation of AMI was mainly asthenia syndrome (qi stagnancy and blood stasis+turbid sputum obstruction, 74.9%). According to the circular statistical analysis, the peak of the solar terms of AMI onset occurred at the Beginning of Spring in all cases (r=0.127 4, P<0.01), and standard deviation (s)=116.300 6 degree angle, showed it mainly occurred in winter and spring. As the peak of the onset of qi stagnancy and blood stasis occurred at Winter Solstice and Lesser Cold (r=0.200 5, P<0.01), its peak occurred in winter; the turbid sputum obstruction syndrome occurred at Spring Equinox (r=0.147 0, P<0.05), mainly in spring, yet the symptoms of above two peaks were generally mild. Besides, there was no significant difference in onset of the solar term in regard to onset of deficiency of yin-blood and deficiency of yang qi (both P>0.05)., Conclusion: There is a close relationship between periodicity of the solar terms and onset of AMI. The main treatment for AMI is to expel turbid sputum, activate blood to resolve stasis and promote blood circulation to relieve pain; also the method of activating blood to resolve stasis is frequently contemplated in winter, and the method of expelling turbid sputum is the main strategy in spring.

The objective of this study was to determine whether antigenic determinants localized within the extracellular domain of the neuroendocrine autoantigen tyrosine phosphatase-like protein IA-2 are targets of humoral responses in type 1 diabetes (T1DM). Previous studies indicated that the immunodominant region of IA-2 is localized within its intracellular domain (IA-2ic; amino acids 601-979). We analyzed 333 subjects from the Children's Hospital of Pittsburgh study, 102 of whom progressed to insulin-requiring diabetes (prediabetics). Autoantibodies from these individuals were initially assayed for ICA512bdc (Barbara Davis Center amino acids 257-556; 630-979), IA-2ic (amino acids 601-979), and IA-2 full-length (amino acids 1-979) in addition to islet cell antibody (ICA), glutamic acid decarboxylase, 65-kDa isoform, and insulin autoantibodies. We identified an autoantibody response reactive with the extracellular domain of IA-2 that is associated with very high risk of T1DM progression. Relatives with no detectable autoantibodies against ICA512bdc (or IA-2ic) exhibited antibody responses against the IA-2 full-length peptide (log rank, P = 0.008). This effect was also observed in first-degree relatives who were positive for glutamic acid decarboxylase, 65-kDa isoform (log rank, P = 0.026) or at least two islet autoantibodies but were negative for ICA512bdc (log rank, P = 0.022). Competitive binding experiments and immunoprecipitation of the IA-2 extracellular domain (amino acid residues 26-577) further lend support for the presence of autoantibodies reactive with new antigenic determinants within the extracellular domain of IA-2. In summary, the addition of measurements of autoantibodies reactive with the IA-2 extracellular domain to assays geared to assess the progression of autoimmunity to clinical T1DM may more accurately characterize this risk. This has considerable implications not only for stratifying high diabetes risk but also facilitating the search for pathogenic epitopes to enable the design of peptide-based immunotherapies that may prevent the progression to overt T1DM at its preclinical stages.

Purpose: To find optimal threshold of length and GTV delineation for esophageal cancer using 18FDG PET/CT., Materials and Methods: Sixteen patients with esophageal carcinoma underwent surgery. For each patient, six GTVs were defined. GTVCT was based on CT data alone. GTV20%, GTV40%, GTV2.5 and GTV40%M were generated by PET/CT, using SUVbgd + 20%(SUVmax(slice)--SUVbgd), SUVbgd + 40%(SUVmax(slice)--SUVbgd), 2.5 and 40%SUVmax(total) as thresholds. GTVpath was derived from pathology. Lengths of GTVs were recorded as LCT, L20%, L40%, L2.5, L40%M and Lpath, respectively. The former five GTVs/lengths were compared with GTVpath/Lpath by means of a conformity index CI/CI', which is the square of intersection of two GTVs/lengths divided by their product., Results: Mean LCT, L20%, L40%, L2.5, L40%M and Lpath were 6.30 +/- 2.69, 5.55 +/- 2.48, 6.80 +/- 2.92, 6.65 +/- 2.66, 4.88 +/- 1.99 and 5.90 +/- 2.38 cm. Mean , , , and were 0.68 +/- 0.16, 0.84 +/- 0.17, 0.76 +/- 0.14, 0.78 +/- 0.15 and 0.80 +/- 0.11. and was significantly superior to (P < 0.05). Mean GTVCT, GTV20%, GTV40%, GTV2.5, GTV40%M and GTVpath were 29.16 +/- 18.56, 18.75 +/- 12.37, 12.52 +/- 8.08, 22.69 +/- 14.84, 9.18 +/- 5.96 and 28.16 +/- 17.02 cm3. Mean CIs increased significantly from CI40%&path(0.27 +/- 0.09) and CI'40% M&path (0.28 +/- 0.08) < CI'20% & path (0.52 +/- 0.16) and CI'2.5&path (0.52 +/- 0.20) < CICT&path(0.77 +/- 0.17)., Conclusions: The SUVbgd + 20% (SUVmax(slice)--SUVbgd) method optimally estimated gross tumor length, but only reached an unsatisfactory CI for GTV. Due to possible motion factor enveloped in PET images and lack of histopathologic transverse reference, the information from both PET and CT should be referred to complementarily when delineating GTV.

Objective: To explore the appropriate ways and contents of reproductive health education for middle school students and to understand reproductive health related sexual behavior and influencing factors among middle school students., Methods: Reproductive health related sexual behavior was evaluated among junior and senior middle school students in Luoyang by cluster sampling. The statistical software of SAS 8.1 was adopted for data analyses. Sexual behavior and influencing factors were analyzed by logistic regression., Results: Critical sexual behaviors were found significantly higher in senior students, including masturbation, sexual fantasy and sexual intercourse than that in junior students (P < 0.05), and boys had higher prevalence than girls (P < 0.05). Results from multivariate logistic regression model analyses indicated that incidence rate of sexual behavior among those who ever having had experiences was higher than those who were inexperienced (OR = 2.62, 95%CI: 1.21 - 5.66). Incidence rate of sexual behavior was related to access of reproductive health and STD/AIDS knowledge (OR = 3.09, 95%CI: 1.43 - 6.51). In addition, incidence rate of sexual behavior was related to attitude and relation of amour between boys and girls (OR = 2.24, 95%CI: 1.32 - 3.75)., Conclusion: Awareness on reproductive health knowledge among middle school students was not enough. Marginal sexual behaviors as masturbation and sexual fantasy had not been correctly and openly discussed to avoid inappropriate sexual activities.

Context: Autoantibodies (AA) to glutamic acid decarboxylase (GAD65), a determinant of risk for autoimmune diabetes, have been found in up to 10% of patients with type 2 diabetes. In older adults, this marker may also serve as a determinant of risk for autoimmune diabetes and enhance diabetes classification., Objective: The objective of this study was to evaluate the relationship between GAD65AA and glucose tolerance status, current diabetes treatment, and clinical measures in older adults., Design: GAD65AA were measured at baseline in 3318 participants from the Cardiovascular Health Study, a cohort study of 5888 individuals 65 or older., Setting: The population-based cohort was recruited from four U.S. sites., Patients: Patients included all Cardiovascular Health Study participants with known diabetes, newly diagnosed diabetes, impaired fasting glucose, impaired glucose tolerance, and a sample of normal glucose-tolerant participants., Main Outcome Measures: GAD65AA, body mass index, fasting glucose and insulin levels, blood pressure, lipid levels, and diabetes treatment at baseline were measured., Results: The prevalence of GAD65AA increased with decreasing glucose tolerance in both Blacks (n = 560) and Whites (n = 2730), being more pronounced in known diabetic individuals. GAD65AA were found in 2.3, 5.8, 7.8, and 8.3% of diabetic participants, reporting use of no diabetes medication, oral hypoglycemic agents, insulin only, and both oral hypoglycemic agents and insulin, respectively (P = 0.02, linear trend). Among diabetic participants, GAD65AA positivity was associated with diabetes treatment, higher fasting glucose, and lower body mass index., Conclusions: Even among older individuals with diabetes, GAD65AA may be a useful marker in identifying a subgroup of autoimmune diabetes, serve as a marker of insulin requirement, and remain stable over years.

The New Zealand obese (NZO) mouse strain shares with the related New Zealand black (NZB) strain a number of immunophenotypic traits. Among these is a high proportion of B-1 B lymphocytes, a subset associated with autoantibody production. Approximately 50% of NZO/HlLt males develop a chronic insulin-resistant type 2 diabetes syndrome associated with 2 unusual features: the presence of B lymphocyte-enriched peri-insular infiltrates and the development of anti-insulin receptor autoantibodies (AIRAs). To establish the potential pathogenic contributions of B lymphocytes and AIRAs in this model, a disrupted immunoglobulin heavy chain gene (Igh-6) congenic on the NZB/BlJ background was backcrossed 4 generations into the NZO/HlLt background and was then intercrossed to produce mice that initially segregated for wild-type versus the mutant Igh-6 allele and thus permitted comparison of syndrome development. A new flow cytometric assay (AIRA binding to transfected Chinese hamster ovary cells stably expressing mouse insulin receptor) showed IgM and IgG subclass AIRAs in serum from Igh-6 intact males, but not in Igh-6null male serum. However, the absence of B lymphocytes and antibodies distinguishing mutant from wild-type males failed to significantly affect diabetes-free survival. The Igh-6null males gained weight less rapidly than wild-type males, probably accounting for a retardation, but not prevention, of hyperglycemia. Thus, AIRA and the B-lymphocyte component of the peri-insulitis in chronic diabetics were not essential either to development of insulin resistance or to eventual pancreatic beta cell failure and loss. A new substrain, designated NZL, was generated by inbreeding Igh-6 wild-type segregants. Currently at the F10 generation, NZL mice exhibit the same juvenile-onset obesity as NZO/HlLt males, but develop type 2 diabetes at a higher frequency (> 80%). Also, unlike NZO/HlLt mice that are difficult to breed, the NZL/Lt strain breeds well and thus offers clear advantages to obesity/diabetes researchers.

Markers of humoral islet cell autoimmunity, such as autoantibodies (AAs) against the 65-kDa isoform of GAD (GAD65), serve as determinants of risk for autoimmune diabetes. Despite the high prevalence of diabetes in U.S. racial and ethnic minority adult populations, little is known concerning the prevalence of GAD65 AA in these groups. We estimated the prevalence of GAD65 AA in 1,064 diabetic and 1,036 nondiabetic participants who were 40-90 years of age from the Third National Health and Nutrition Examination Survey (NHANES III), which provides a representative ethnic sample of the U.S. diabetic population. The prevalence of GAD65 AA was higher in diabetic participants compared with nondiabetic participants in non-Hispanic whites (n = 920; 6.3% vs. 2.0%; P = 0.001) and non-Hispanic blacks (n = 534; 3.7% vs. 1.3%; P = 0.08) but not in Mexican Americans (n = 646; 1.2% vs. 2.6%; P = 0.18). Among diabetic non-Hispanic whites and non-Hispanic blacks, being GAD65 AA positive was associated with lower BMI and C-peptide (P < 0.05). These results may reflect the outcome of an autoimmune process leading to beta-cell destruction/dysfunction in non-Hispanic white and non-Hispanic black adult diabetic patients as it occurs in a similar manner in type 1 diabetes. Among diabetic Mexican Americans, the lower prevalence of GAD65 AA suggests a lower frequency of autoimmune-related diabetes.