Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is rare,benign lesion using modified stringent diagnostic criteria: Reclassification and outcome study

BackgroundRigid diagnostic criteria for NIFTP have been recently proposed. The frequency of NIFTP using the new criteria is unknown, and whether abortive papillae are associated with BRAF^V600E mutation has not been studied. The aim of this study is to identify NIFTP by a retrospective review of Follicular Variant of Papillary Thyroid Carcinoma (FVPTC), and to study its incidence as well as the association between immunohistochemical BRAF^V600E expression and abortive papillae in NIFTP.DesignThyroid tumors diagnosed as FVPTC or NIFTP over a period of 18 years (2000–2017) were identified using the laboratory information system. The final pathology reports were reviewed and potential NIFTP were retrieved. The archived slides for these cases were independently reviewed by 2 pathologists. BRAF^V600E (clone: VE1) immunostain was performed on representative tumor blocks. Clinical information including follow-up data was obtained from the electronic medical records.ResultsAmong the 1918 cases with the diagnosis of papillary thyroid carcinoma (PTC), 589 (30.7%) of FVPTC and 136 cases of potential NIFTP were identified. After the review of the archived pathology slides, 29 lesions were morphologically reclassified as NIFTP. Four (13.7%) of these were positive for BRAF^V600E; no association was found between the presence of abortive papillae and BRAF^V600Eexpression (p=0.3). Exclusion of the 4 cases with BRAF^V600Eexpression resulted in 25 lesions of final NIFTP, representing 4.2% of the FVPTC and 1.3% of the PTC. The mean age of the NIFTP patients was 50 years, 87.5% were females. The mean size of the lesions was 1.4 cm (0.1–4.0 cm). Intranuclear pseudoinclusions were not identified, and abortive papillae were identified in 60% of NIFTP. The average follow-up was 70 (28–166) months. There were no adverse events (recurrence or metastasis) in the NIFTP group.ConclusionWhen strictly defined, NIFTP comprises 1.3% of cases perviously classified as PTC. In morphological NIFTP, no correlation is found between the presence of abortive papillae and the BRAF^V600E expression. Intranuclear pseudo-inclusions are not observed in NIFTP. Modification of current morphological criteria to include BRAF^V600E immunohistochemistry test may stratify NIFTP with benign outcome.     

CD34low and SMAhigh represent stromal signature in uterine cervical cancer and are markers for peritumoral stromal remodeling

Peritumoral desmoplastic stromal reaction (DSR) with myofibroblastic phenotype may be of prognostic impact in uterine cervical carcinoma. The present study evaluates the immunostaining (CD34 and smooth muscle actin; SMA) of 97 squamous cell cancers. Staining was scored as low/negative (< 5% stroma positive), moderate (patchy/focal expression, 5%-50%), or high (diffuse expression throughout peritumoral stroma, > 50%) and DSR as negative/weak and moderate/strong. The staining results were correlated to patient survival. Of the cases, 78.3% showed a decreased of CD34 (< 5% stromal positivity) and 71.9% an increased SMA staining with more than 50% SMA positive stromal cells. Tumors representing moderate/strong DSR showed a significant decreased CD34 (P = .001) and an increased but not statistically significant SMA staining (P = 0.345). Cases with low CD34 and high SMA staining showed reduced 5-year overall survival when compared to cases with high CD34 and low SMA positivity (59.9 vs 81.0%; P = 0.025 and 64.6 vs 81.1%; P = 0.243). Peritumoral stromal response in cervical carcinoma is immunohistochemically characterized by CD34^low/SMA^high and associated reduced overall survival.     

<Emphasis Type="Italic">BRAF</Emphasis><Superscript><Emphasis Type="Italic">V600E</Emphasis></Superscript> Mutation Analysis from May-Grünwald Giemsa-Stained Cytological Samples as an Adjunct in Identification of High-Risk Papillary Thyroid Carcinoma

The BRAF ^V600E mutation is specific for thyroid papillary cancer (PTC) and correlates with PTCs invasiveness. This study investigated whether detection of BRAF ^V600E mutation can be performed on routinely stained FNABs. We also examined if establishment of the BRAF ^V600E mutation could help in identification of patients at higher risk for metastatic disease. DNA was isolated from 134 FNABs samples (20 follicular neoplasm, ten suspicious for malignancy, and 104 malignant) using Pinpoint Slide DNA Isolation System. BRAF ^V600E mutation was detected by PCR followed by sequencing. DNA was successfully extracted from all examined FNABs samples. In follicular neoplasm, suspicious for malignancy and malignant FNABs, BRAF ^V600E mutation was found in 0/20 (0%), 2/10 (20%), and 47/104 (45.2%) of cases, respectively. Extra-thyroidal extension was detected in 35/47 (74.4%) BRAF ^V600E positive and in 24/57 (42.1%) wild-type BRAF cases (p = 0.001). Metastases were detected in 37/47 (78.7%) BRAF ^V600E positive and in 28/57 (49.1%) wild-type BRAF cases (p = 0.002). Our results showed that stained FNAB specimens can be used for DNA extraction and assessment of BRAF ^V600E mutation. Detection of BRAF ^V600E mutation had limited value in diagnoses of malignancy in follicular neoplasms but can ascertain malignancy in subset of suspicious for malignancy FNABs. In malignant FNABs, BRAF ^V600E mutation was significantly associated with presence of extra-thyroidal extension and metastases after surgery.     

Determinants of vitamin D status in healthy men and women aged 40–80 years

ObjectivesTo determine the contribution of life style and health related factors on vitamin D status in middle-aged and older men and women.Study designA cross-sectional single-center study in 400 male subjects (40–80 years) and 402 postmenopausal female subjects (56–73 years), conducted in a University Medical Center in the central part of the Netherlands (52 degrees northern latitude).Main outcome measuresMedical history, vitamin D, calcium and alcohol intake, physical activity, Body Mass Index, Blood pressure, smoking, total fat body mass and total lean body mass were measured using DEXA. Laboratory analysis included 25-hydroxyvitamin D (25OHD) and sex hormones.ResultsThirty-six percent of men and 51% of women had 25OHD less than 50 nmol/L. In summertime men had significant higher 25OHD as compared to women (81.5 vs 53.3 nmol/L, P = .000) but this difference disappeared come winter. In a saturated model, male gender (B = .16, P = .008), and season (summer vs winter B = .30, P = .000) remained statistically significant. In men, physical activity and season explained 21% of the variance. In women, household physical activity (B = .13, P = .03), sport physical activity (B = .02, P = .02) and estradiol (B = ?.003, P = .048) remained in the model,.ConclusionIn healthy middle-aged and older men and postmenopausal women, male gender and season were important predictors of vitamin D status. In men, physically activity and season, explained 21% of the variance in vitamin D status. In women, physical activity and estradiol explained 9.3% of the variance in vitamin D.     

Viro-immunological dynamics in HIV-1-infected subjects receiving once-a-week emtricitabine to delay treatment change after failure: A pilot randomised trial

BackgroundIn HIV-1-infected patients harbouring the M184V mutation (M184V), lamivudine monotherapy leads to a smaller decrease in CD4 percentages (CD4%) than treatment interruption, possibly due to the reduced fitness of the mutated virus.ObjectiveWe assessed whether a minimal dose of a cytidine analogue that is theoretically sufficient to maintain M184V (one emtricitabine tablet once-weekly) may be as effective.Study designIn a proof-of-concept, randomised clinical trial, HIV-1-infected patients with CD4 cells >400/mm³, failing on lamivudine- or emtricitabine-containing combination antiretroviral therapy (cART), received emtricitabine once-a-week (A), or emtricitabine once-a-day (B), or lamivudine once-a-day (C). The primary endpoint was the proportion of subjects without a 12-week loss in CD4%. The patients resumed cART after 24 weeks or in the case of CD4 cells <350/mm³.ResultsThe 38 enrolled patients had similar baseline characteristics across groups. The primary endpoint was reached by 5/13 patients (38.5%) in arm A, 3/13 (23.1%) in arm B, and 3/12 (25%) in arm C (P = 0.644), and respectively 4/13 (30.8%), 4/13 (30.8%) and 5/12 (41.7%) had to resume cART within 24 weeks (P = 0.805). The immunological changes over 24 weeks were similar in the three groups, but there was a higher median viral rebound in once-weekly treatment recipients (A) than in once-daily (B + C): 0.97 versus 0.52 log₁₀ copies/ml (P = 0.033). M184V was maintained in all the participants.ConclusionsOnce-weekly emtricitabine led to a higher viral rebound than once-daily monotherapy, but similar immunological changes, thus suggesting a role of M184V in slowing the decrease in CD4% in treatment failing subjects.     

Human papillomavirus is detectable in Barrett's esophagus and esophageal carcinoma but is unlikely to be of any etiologic significance

Barrett's esophagus (BE), a known precursor of esophageal adenocarcinoma has recently been associated with human papillomavirus (HPV). p16^INK4a expression is a recognized surrogate marker of HPV infection in the cervix.ObjectivesThis study has assessed the possible role of human papillomavirus (HPV) infection in BE and esophageal adenocarcinoma, in the North American population by screening esophageal tissues for HPV by a combination of assays.Study designFormalin-fixed, paraffin-embedded blocks from cases of Barrett's esophagus (n = 84), esophageal adenocarcinoma (n = 36) and normal gastro-esophageal junction (n = 29) were examined for HPV by PCR, chromogenic in situ hybridization, and p16^INK4a immunohistochemistry.ResultsHPV DNA was detected by PCR in 23 of 84 (27.4%) BE cases, 11 of 36 (31%) cases of adenocarcinoma and in 7 of 29 (24%) normal control cases (p = 0.82). p16^INK4a staining was positive in 10 (12%) cases of BE, 15 (42%) cases of adenocarcinoma and 6 (21%) cases of the control group. Positive p16^INK4a staining was not statistically different between the three groups whether positive or negative for HPV DNA (p = 0.91 and p = 0.91 respectively). Similarly, negative p16^INK4a staining did not show a difference between the three groups for whether positive or negative for HPV DNA (p = 0.50 and p = 0.28, respectively). HPV was not detected by CISH in the adenocarcinomas while in BE and control groups, CISH was non-contributory.ConclusionsThese data suggest that while HPV is detectable in a subset of esophageal lesions and tumors, the HPV detected is unlikely to be of etiologic significance or a factor accounting for the increase in BE and esophageal adenocarcinoma cases in the United States.     

Estradiol biodisponible (non-SHBG-bound E2). Dosage ou calcul en relation avec la densité minérale osseuse lombaire (L1–L4) chez l'homme âgé

With age, decreased levels of bioavailable T and E₁ + E₂ are mainly the result of the increase of SHBG levels. Several studies have shown the association of low levels < 11 pg/ml (40 pM) of bioavailable estradiol with vertebral fractures and osteoporosis in older men. They used assayed E₂ Bio or calculated non-SHBG-bound E₂ calculated using the equation derived from the law of mass action for the model: two binding proteins (SHBG, Albumin) and two ligands (T, E₂) (FE₂c_II Södergard) while serum SHBG, albumin, T and E₂ are determined experimentally in every sample. The aim of the study is to evaluate the performance of E₂ Bio and FE₂c_II associated with vertebral osteoporosis on 62 men (median age: 64 years). As expected, SHBG increases markedly with age (P = 0.003) and Ttot increases with SHBG (P = 0.0003). DMO and T score are positively correlated (P = 0.086–0.048) with E₂ Bio in men with E₂ Bio < 40 pM and are not correlated (P = 0.70–0.48) in men with E₂ Bio > 40 pM. E₂ Bio (P < 0.003) is inversely associated with SHBG levels but FE₂c_II is not correlated with SHBG (P > 0.45) and with DMO or T score adjusted for body weight (P = 0.48). Considering the lack of sensitivity of calculated FE₂c_II to estimate the "non-SHBG-bound E₂", the bioavailable estradiol assay by ammonium sulfate precipitation is the preferred method for detecting elderly men in the lowest quartile for E₂ Bio and at risk for developing osteoporosis later in life.     

Cyclin D1 is significantly associated with stage of tumor and predicts poor survival in endometrial carcinoma patients

Cyclin D1 overexpression has been described to have oncogenic role and association with diagnosis, prognosis and survival in various tumors. This study will describe the immunohistochemical phenotype of cyclin D1, and investigate the correlation between these patterns of expression and clinicopathological parameters of endometrial carcinomas, to conclude the clinical relevance of cyclin D1 expression in the evolution of endometrial neoplasms. This study employed 101 endometrial tissue samples which include 71 endometrial carcinomas and thirty normal and benign endometrium cases. All these tissue samples were used in the assembly of tissue microarrays which have been utilized afterward in immunohistochemistry staining to detect cyclin D1 expression. Forty (56.3%) cases of endometrial carcinomas showed brown nuclear expression of cyclin D1 including 36 (61%) cases of endometrioid carcinomas, and 3 (33.3%) cases of serous carcinomas. Twenty three (76.6%) cases of control group demonstrated nuclear expression. High score cyclin D1 immunohistochemical staining has been significantly linked with patient age (P = 0.0001). Large proportion of high score cyclin D1 immunohistochemical staining was observed in females who are < 40 years of age while high proportions of negative staining were observed in older age groups. Histologic type of tissue was also significantly related to cyclin D1 immunohistochemical staining (P-value = 0.0001), high staining is more common in normal proliferative and secretory endometrium while serous carcinoma is more prevalent with negative staining. Stage of tumor was significantly associated with cyclin D1 immunohistochemical staining (P-value = 0.029), proportion of stage III and IV are higher in negative cyclin D1 immunostaining. Significantly higher proportion of high score cyclin D1 immunostaining is observed in controls while higher proportion of negative cyclin D1 immunostaining is observed among carcinoma cases (P-value = 0.0001). No significant associations between cyclin D1 immunohistochemical staining and grade, recurrence and alive status were observed. Significant different survival distributions were observed (P-value = 0.011) and poor survival behavior was correlated with negative cyclin D1 immunohistochemical staining. In conclusion, greater frequency of cyclin D1 expression was revealed in normal endometrial tissues in comparison with carcinomas. The distribution pattern of cyclin D1 immunoexpression suggests poor prognoses in endometrial carcinoma patients.     

KIR alloreactivity based on the receptor–ligand model is associated with improved clinical outcomes of allogeneic hematopoietic stem cell transplantation: Result of single center prospective study

Receptors on natural killer (NK) cells, named killer immunoglobulin-like receptors (KIRs), recognize HLA class I alleles. Patients (n = 59) who received allogeneic hematopoietic stem cell transplantation (HSCT) from either a related (n = 17) or unrelated donor (n = 42) in Samsung Medical Center (Seoul, South Korea) were included. KIR mismatch was defined as incompatibility between the donor KIR and recipient KIR ligand (receptor–ligand model), and all cases were classified into the two broad haplotypes of KIR A and B. Patients with acute leukemia (n = 51, 86.4%) or myelodysplastic syndrome (n = 8, 13.6%) were included. Peripheral blood was used as the source of stem cells in all patients. Kaplan–Meier survival curves for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR) favored recipients with a KIR-mismatched donor, although the differences were not statistically significant. In multivariate analysis, KIR mismatch was an independent prognostic indicator of a better OS (P = 0.010, HR = 0.148, 95% CI 0.034–0.639), DFS (P = 0.022, HR = 0.237, 95% CI 0.069–0.815), and CIR (P = 0.031, HR = 0.117, 95% CI 0.017–0.823). OS, DFS, and CIR did not differ significantly between the KIR A and B haplotypes.     

Can Ultrasound Be as a Surrogate Marker for Diagnosing a Papillary Thyroid Cancer? Comparison with BRAF Mutation Analysis

Purpose

We investigated the merit of ultrasound (US) features and BRAF^V600E mutation as an additional study of cytology and compared the diagnostic performances of cytology alone, cytology with US correlation, cytology with BRAF^V600E mutation, and a combination of cytology, US, and BRAF^V600E mutation all together.

Materials and Methods

This study included 185 patients (mean age, 48.4 years; range 20-77 years) with 191 thyroid nodules who underwent US-guided fine-needle aspiration (FNA) with an additional BRAF^V600E mutation test. Three radiologists highly experienced in thyroid imaging retrospectively reviewed US images and classified each nodule into two categories (positive for malignancy or negative for malignancy). Interobserver variability (IOV) of US assessment between the three readers was estimated using the generalized kappa statistic of Landis and Koch. We also calculated the diagnostic performances of these studies.

Results

There were 131 cases of malignancy (131/191, 68.6%) and 60 cases of benign nodules (60/191, 31.4%). In terms of IOV of US assessment, the generalized kappa value was 0.242, indicating fair agreement was reached. The combination of cytology with BRAF^V600E showed higher specificity (100%) and positive predictive value (PPV) (100%) compared to the combination of cytology, BRAF^V600E, and US (specificity 28.3%, 66.7%, 68.3%; PPV 74.6%, 86.6%, 86.8%, respectively; p<0.001). However, cytology with BRAF^V600E showed lower sensitivity (84.7%) than cytology with BRAF^V600E and US (96.2%, 98.5%, 95.4%, respectively; p<0.001).

Conclusion

Considering the diagnostic performance and low reproducibility of US, the combination of FNA with BRAF^V600E is the most reliable and objective method for diagnosing thyroid malignancy.     

Association of IL-17A and IL-17F polymorphisms with gastric cancer risk in Asians: A meta-analysis

Increasing number of studies focused on the association of IL-17A rs2275913 and IL-17F rs763780 polymorphisms with gastric cancer (GC) risk. However, the results were inconsistent. To elucidate the exact association, we performed the present meta-analysis. Databases including PubMed, Web of knowledge and Chinese National Knowledge Infrastructure (CNKI) were systematically searched for potentially eligible literatures. Odds ratios (OR) and their 95% confidence interval (CI) were used to evaluate the strength of association. Eight studies for IL-17A rs2275913 (3345 cases and 4427 controls) and five studies for IL-17F rs763780 (1784 cases and 2592 controls) were finally included. The results indicated that individuals with AA genotype of IL-17A rs2275913 polymorphism were associated with increased GC risk compared with wild-type GG (OR = 1.61, 95% CI = 1.17–2.23, P = 0.004); A allele was significantly associated with increased GC risk compared with G allele (OR = 1.22, 95% CI = 1.06–1.41, P = 0.007). IL-17F rs763780 polymorphism was also significantly associated with increased GC risk (CC vs. CT: OR = 1.40, 95% CI = 1.04–1.88, P = 0.025; CT vs. TT: OR = 1.35, 95% CI = 1.16–1.58, P < 0.001; C allele vs. T allele: OR = 1.30, 95% CI = 1.15–1.47, P < 0.001). In summary, IL-17A rs2275913 A/G polymorphism and IL-17F rs763780 C/T polymorphism might be associated with increased GC risk in Asians. Further large-scale studies are still required to confirm the results of this meta-analysis.     

Efficacy of different antifungal drugs as initial treatment for patients with talaromycosis: A systematic review and meta-analysis

There are no standard choices on antifungal drugs for talaromycosis due to various factors, and related studies are also limited. This study summarizes and analyzes efficacy of different antifungal drugs for patients with talaromycosis, which can provide more reference evidence for drugs’ choices in practice. We conducted a meta-analysis on prognostic impacts of different antifungal drugs against talaromycosis, and primary outcome was all-cause mortality. A total of 975 patients from 8 studies were included. One of the 8 studies was a randomized controlled trial and the others were retrospective studies. Among these patients, 582 cases were initiated with amphotericin B, 31 cases died (9.28%). The other 393 cases were initiated with itraconazole, and 54 cases died (14.00%). The initial use of amphotericin B for talaromycosis significantly reduced mortality compared with itraconazole (risk ratio (RR): 0.61; 95% confidence interval (CI): 0.41–0.90; P = 0.01; I² = 4%). Initial treatment with amphotericin B for talaromycosis in different regions (internal and external) and studies (sample size < 100) had no obvious prognostic advantages over itraconazole (RR: 0.60, 95% CI: 0.32–1.13; P = 0.11; I² = 44%; RR: 0.61, 95% CI: 0.37– 1.00; P = 0.05; I² = 0%; RR: 0.71, 95% CI: 0.39–1.29; P = 0.26; I² = 0%, respectively). However, when study's sample size was ≥ 100, the mortality of amphotericin B group was significantly reduced (RR: 0.54, 95% CI: 0.32– 0.92; P = 0.02; I² = 46%). In conclusion, amphotericin B is a better choice as initial therapeutic drug for talaromycosis.     

An in vitro study on the maturation of conventional glass ionomer cements and their interface to dentin

The objective of the study was to investigate the influence of long-term storage (up to 1 year) and coating on the variation of micro-mechanical properties of four conventional restorative glass ionomer cements (GICs) within 3.5 mm deep class I cavities. Four commercially available GICs (Riva Self Cure (SDI), ChemFil Rock (Dentsply), Fuji IX Fast and Fuji IX GP Extra/Equia (GC)) were applied to 100 teeth. In each tooth, two similar 3.5 mm deep class I cavities were prepared and filled with the GICs, with and without resin coating. The samples were stored in artificial saliva at 37 °C for 1 week, 1 month, 3 months, 6 months and 1 year. The variation in mechanical properties (indentation modulus (E) and Vickers hardness (HV)) were determined in 100 μm steps starting from the filling surface, through the intermediate layer in between dentine and GIC, and ending 100 μm in dentin. HV and E were strongly influenced by the material (P < 0.05, partial eta-squared η_P² = 0.31 and 0.23) but less by aging duration (P < 0.05, η_P² = 0.02 and 0.12) and resin coating (P < 0.05, η_P² = 0.02 and 0.03). The depth of measurement (0–2 mm) has no influence on HV (P = 0.789). HV shows a gentle increase over the 1 year storage period (P = 0.002). A ～300 μm GIC zone at the areas close to dentin with weaker properties as those measured in dentin or GIC was identified in all fillings, irrespective of the presence of coating, and at all storage periods. The thickness of this zone is more strongly influenced by storage (P < 0.05, η_P² = 0.081) than by material type (P < 0.05, η_P² = 0.056), while coating showed no influence (P = 0.869). Filler morphology and dimension were similar to upper parts of the GIC filling; however, the amount of low cations was higher. We concluded that the development of an intermediate layer in between dentine and GIC with lower mechanical properties might be responsible for the bond quality of GIC to dentine. Moreover, class I GIC restorations are unlikely to feature constant mechanical properties throughout the cavity, regardless of conditions such as aging and coating.     

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

PurposeWe assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.MethodsRetrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.ResultsThe ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10⁻⁷²). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10⁻⁵⁰). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10⁻²²) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10⁻¹²) carriers. The associations in the prospective cohort were similar.ConclusionPopulation-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.     

Predicting bulk mechanical properties of cellularized collagen gels using multiphoton microscopy

Cellularized collagen gels are a common model in tissue engineering, but the relationship between the microstructure and bulk mechanical properties is only partially understood. Multiphoton microscopy (MPM) is an ideal non-invasive tool for examining collagen microstructure, cellularity and crosslink content in these gels. In order to identify robust image parameters that characterize microstructural determinants of the bulk elastic modulus, we performed serial MPM and mechanical tests on acellular and cellularized (normal human lung fibroblasts) collagen hydrogels, before and after glutaraldehyde crosslinking. Following gel contraction over 16 days, cellularized collagen gel content approached that of native connective tissues (～200 mg ml^–1). Young’s modulus (E) measurements from acellular collagen gels (range 0.5–12 kPa) exhibited a power-law concentration dependence (range 3–9 mg ml^–1) with exponents from 2.1 to 2.2, similar to other semiflexible biopolymer networks such as fibrin and actin. In contrast, cellularized collagen gel stiffness (range 0.5–27 kPa) produced concentration-dependent exponents of 0.7 uncrosslinked and 1.1 crosslinked (range ～5–200 mg ml^–1). The variation in E of cellularized collagen hydrogels can be explained by a power-law dependence on robust image parameters: either the second harmonic generation (SHG) and two-photon fluorescence (TPF) (matrix component) skewness (R² = 0.75, exponents of -1.0 and -0.6, respectively); or alternatively the SHG and TPF (matrix component) speckle contrast (R² = 0.83, exponents of ?0.7 and ?1.8, respectively). Image parameters based on the cellular component of TPF signal did not improve the fits. The concentration dependence of E suggests enhanced stress relaxation in cellularized vs. acellular gels. SHG and TPF image skewness and speckle contrast from cellularized collagen gels can predict E by capturing mechanically relevant information on collagen fiber, cell and crosslink density.     

An updated meta-analysis of transforming growth factor-β1 gene: Three well-characterized polymorphisms with asthma

The association between TGF-β1 polymorphisms and asthma risk has been widely reported, but results were controversial. We performed this meta-analysis based on the Preferred Reporting Items for Systematic Reviews and meta-analyses statement (PRISMA). Electronic database of Pub Med, Web of Science, CBM, and CNKI were searched for eligible articles published up to September, 2013. The effect summary odds ratio (OR) and 95% confidence intervals were obtained. Finally, a total of 20 articles were identified, 17 studies with 3694 cases and 5613 controls for C-509T polymorphism, 7 studies with 1109 cases and 1098 controls for T869C polymorphism and 5 studies with 849 cases and 829 controls for G915C polymorphism. For C-509T, significant associations with asthma were found in Asians (TT + TC vs. CC: P = 0.004, OR = 1.43, 95%CI = 1.12–1.81, P_{heterogeneity} = 0.001) and in Caucasians (P = 0.05, OR = 1.16, 95%CI = 1.00–1.34, P_{heterogeneity} = 0.36). With respect to T869C, a small significant association was observed in overall analysis of allele contrasts(C vs. T: OR = 1.14, 95%CI: 1.01–1.29, P = 0.03) and homozygote comparison (CC vs. TT: OR = 1.29, 95%CI: 1.00–1.65, P = 0.05), but no significant risks were found among Caucasian population and Asian population. For G915C polymorphism, no significant association with asthma risk was demonstrated in overall analysis and subgroup analyses according to ethnicity for all genetic models. This meta-analysis suggested that TGF-β1 C-509T and T869C polymorphisms may be risk factors for asthma.     

Improving chemotherapy processes with a protocol-based information system: A pre and post-implementation study

BackgroundThe medical application domain has been a great challenge for information technology solutions for decades, especially when the target process has been complex and multidisciplinary such as chemotherapy processes.ObjectiveTo evaluate the impact of a homegrown protocol based information system on the efficiency of chemotherapy workflow processes in an outpatient setting.MethodsA day care unit of the Hematology/Oncology outpatient clinic of Erasmus Medical Center was the setting for this study. The study consisted of comparison of pre- and post-implementation of four workflow efficiency related external indicators: turn-around times of a commonly administered chemotherapy course (Paclitaxel–Carboplatin), chemotherapy course administration postponing rate, the rate of recording course administration time, and patient admission rate of the outpatient clinic. The data was gathered retrospectively from patient charts and information systems’ log files. For the purpose of turn-around-time 109 Paclitaxel–Carboplatin chemotherapy courses of pre-implementation were compared to 118 those of post-implementation. For the other indicators: 247 chemotherapy courses pre-implementation were compared to 324 courses post-implementation. The process maps of pre- and post-implementation were also compared to each other.ResultsThe implementation of the system improved the process by removing repetition and sequencing of the tasks. Following the implementation, chemotherapy postponing decreased by 17.2% (Z = ?4.723, P = .000) and there were 5.7% less records with missing administration time (Z = ?3.047, P = .002). The admission rate increased 1.9 patient per working day (t(94) = ?5.974, P = .000). The overall turn-around-time reduced 18.9 min following the implementation (t(169) = 3.48, P = .001). In a multivariate multiple regression model the reduction in turn-around time was related to the implementation of the system (Pillai's Trace = 0.159, F(4,161) = 7.613, P = .000).ConclusionInformation systems based on treatment protocols can reduce communication and synchronization needs between the stakeholders in a complex workflow process. These systems can help reengineering the process and improve workflow efficiency by removing unnecessary sequencing and repetitions of tasks.     

Association of BRAFV600E mutation with clinicopathological features of papillary thyroid carcinoma: a study on a Chinese population

Background: The new finding of the heterogeneous distribution of BRAF^V600E mutation in primary papillary thyroid carcinoma suggested the percentage of BRAF^V600E alleles should be taken into consideration when evaluating its association with clinicopathological features of papillary thyroid carcinoma. The aim of this study was to detect both the presence and the percentage of BRAF^V600E alleles in fine-needle aspiration biopsy samples and to assess its association with clinicopathological characteristics of papillary thyroid carcinoma in a Chinese population. Materials and methods: Fine needle aspiration samples were collected in a total of 182 patients (132 conventional papillary thyroid carcinomas and 50 goiters). The associations of the presence and percentage of BRAF^V600E alleles genotyped by pyrosequencing with clinicopathological characteristics were evaluated in papillary thyroid carcinomas. Results: 80 (60.61%) of papillary thyroid carcinomas exhibited BRAF^V600E mutation in a range of 7.7% to 46.3% of the total BRAF alleles. The presence of BRAF^V600E mutation was significantly associated with extrathyroidal invasion. There was no significant difference between the presence of BRAF^V600E mutation and other clinicopathological features. It was not found that the significant relationship between percentage of BRAF^V600E alleles and clinicopathological characteristics. Conclusion: We concluded that the presence of BRAF^V600E could be preoperatively predictive of extrathyroidal invasion in a Chinese population.     

EphA2 knockdown attenuates atherosclerotic lesion development in ApoE−/− mice

BackgroundThe inflammatory response of vascular endothelial cells plays important roles in the initiation and progression of atherosclerotic lesions. EphA2 receptor activation promotes the endothelial cell inflammatory response, and its expression is increased in the endothelial cell layer of atherosclerotic plaques. However, the association between EphA2 and atherosclerosis has not been determined.MethodsEight-week-old male ApoE^−/− mice were systemically infected with adenoassociated virus serotype 9 carrying a small hairpin RNA specifically targeting the EphA2 gene to knock down EphA2 expression in aortic endothelial cells. These mice were then fed a high-cholesterol diet for 12 weeks. Blood was collected for the measurement of plasma lipids. The aortas were harvested to evaluate the atherosclerotic lesion size, macrophage components, and expression of proinflammatory genes using Oil Red O staining, immunofluorescence staining, and molecular biology analysis.ResultsThe lesions formed in the entire aorta and aortic sinus of the ApoE^−/− mice with EphA2 knockdown were significantly smaller than those in the control mice (10.7% ± 3.1% versus 25.1% ± 4.2%; 0.51 ± 0.02 mm² versus 0.85 ± 0.03 mm²; n = 10; P < .05). Furthermore, the lesions in the ApoE^−/− mice with EphA2 knockdown displayed reduced inflammation compared with the control mice, as reflected by the decreased macrophage infiltration (8.2% ± 2.9% versus 22.7% ± 4%; n = 10; P < .05); decreased nuclear factor-κβ activation; and diminished expression of vascular cell adhesion molecule-1, E-selectin, and monocyte chemotactic protein-1 (all P < .05).ConclusionsOur data demonstrate that the EphA2 receptor silencing attenuates the extent and inflammation of atherosclerotic lesions in ApoE^−/− mice. Thus, EphA2 knockdown in endothelial cells represents a novel therapeutic strategy for patients with atherosclerosis.     

Association study of rs924080 and rs11209032 polymorphisms of IL23R-IL12RB2 in a Northern Chinese Han population with Behcet’s disease

ObjectivesTwo genome-wide association studies (GWAS) have identified the IL-23 receptor- IL-12 receptor β2 (IL23R-IL12RB2) as the susceptibility genetic region in Turkish and Japanese population with Behçet’s disease (BD). We investigated the association of this region with BD in a Northern Chinese Han population.MethodsA total of 407 patients with BD and 421 healthy controls were genotyped for single nucleotide polymorphisms (SNPs) rs924080 and rs11209032 using the Sequenom MassArray system.ResultsStatistically significant associations with BD were detected at two SNPs namely, rs924080 and rs11209032, both, by allele analysis (OR = 1.58, 95% CI = 1.25–2.00, P_c = 2.52 × 10⁻⁴, and OR = 1.45, 95% CI = 1.19–1.76, P_c = 3.46 × 10⁻⁴, respectively), and genotype analysis (P_c = 1.22 × 10⁻³ and P_c = 1.77 × 10⁻³, respectively). Significant differences were observed in the genotype frequency distribution for these SNPs under the additive, dominant and recessive models (all P_c < 0.05). The haplotypes (AT and GC) formed by the two SNPs were associated with BD (all permutation P < 0.05). A meta-analysis also appeared to support the association of the two SNPs with BD.ConclusionSNPs (rs924080 and rs11209032) of the IL23R-IL12RB2 region were found to be associated with BD in a Northern Chinese Han population.