Is There an Added Value of Quantitative DCE-MRI by Magnetic Resonance Dispersion Imaging for Prostate Cancer Diagnosis?

In this multicenter, retrospective study, we evaluated the added value of magnetic resonance dispersion imaging (MRDI) to standard multiparametric MRI (mpMRI) for PCa detection. The study included 76 patients, including 51 with clinically significant prostate cancer (csPCa), who underwent radical prostatectomy and had an mpMRI including dynamic contrast-enhanced MRI. Two radiologists performed three separate randomized scorings based on mpMRI, MRDI and mpMRI+MRDI. Radical prostatectomy histopathology was used as the reference standard. Imaging and histopathology were both scored according to the Prostate Imaging-Reporting and Data System V2.0 sector map. Sensitivity and specificity for PCa detection were evaluated for mpMRI, MRDI and mpMRI+MRDI. Inter- and intra-observer variability for both radiologists was evaluated using Cohen's Kappa. On a per-patient level, sensitivity for csPCa for radiologist 1 (R1) for mpMRI, MRDI and mpMRI+MRDI was 0.94, 0.82 and 0.94, respectively. For the second radiologist (R2), these were 0.78, 0.94 and 0.96. R1 detected 4% additional csPCa cases using MRDI compared to mpMRI, and R2 detected 20% extra csPCa cases using MRDI. Inter-observer agreement was significant only for MRDI (Cohen's Kappa = 0.4250, p = 0.004). The results of this study show the potential of MRDI to improve inter-observer variability and the detection of csPCa.

Lesions hyper- to isointense to surrounding liver in the hepatobiliary phase of gadoxetic acid-enhanced MRI.

OBJECTIVES: Hyper- or isointensity in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced MRI has high specificity for focal nodular hyperplasia (FNH) but may be present in hepatocellular adenoma and carcinoma (HCA/HCC). This study aimed to identify imaging characteristics differentiating FNH and HCA/HCC. MATERIALS AND METHODS: This multicenter retrospective cohort study included patients with pathology-proven FNH or HCA/HCC, hyper-/isointense in the HBP of gadoxetic acid-enhanced MRI between 2010 and 2020. Diagnostic performance of imaging characteristics for the differentiation between FNH and HCA/HCC were reported. Univariable analyses, multivariable logistic regression analyses, and classification and regression tree (CART) analyses were conducted. Sensitivity analyses evaluated imaging characteristics of B-catenin-activated HCA. RESULTS: In total, 124 patients (mean age 40 years, standard deviation 10 years, 108 female) with 128 hyper-/isointense lesions were included. Pathology diagnoses were FNH and HCA/HCC in 64 lesions (50%) and HCA/HCC in 64 lesions (50%). Imaging characteristics observed exclusively in HCA/HCC were raster and atoll fingerprint patterns in the HBP, sinusoidal dilatation on T2-w, hemosiderin, T1-w in-phase hyperintensity, venous washout, and nodule-in-nodule partification in the HBP and T2-w. Multivariable logistic regression and CART additionally found a T2-w scar indicating FNH, less than 50% fat, and a spherical contour indicating HCA/HCC. In our selected cohort, 14/48 (29%) of HCA were B-catenin activated, most (13/14) showed extensive hyper-/isointensity, and some had a T2-w scar (4/14, 29%). CONCLUSION: If the aforementioned characteristics typical for HCA/HCC are encountered in lesions extensively hyper- to isointense, further investigation may be warranted to exclude B-catenin-activated HCA. CLINICAL RELEVANCE: Hyper- or isointensity in the HBP of gadoxetic acid-enhanced MRI is specific for FNH, but HCA/HCC can also exhibit this feature. Therefore, we described imaging patterns to differentiate these entities. KEY POINTS: FNH and HCA/HCC have similar HBP intensities but have different malignant potentials. Six imaging patterns exclusive to HCA/HCC were identified in this lesion population. These features in liver lesions hyper- to isointense in the HBP warrant further evaluation.

Automated Assessment of T2-Weighted MRI to Differentiate Malignant and Benign Primary Solid Liver Lesions in Noncirrhotic Livers Using Radiomics.

RATIONALE AND OBJECTIVES: Distinguishing malignant from benign liver lesions based on magnetic resonance imaging (MRI) is an important but often challenging task, especially in noncirrhotic livers. We developed and externally validated a radiomics model to quantitatively assess T2-weighted MRI to distinguish the most common malignant and benign primary solid liver lesions in noncirrhotic livers. MATERIALS AND METHODS: Data sets were retrospectively collected from three tertiary referral centers (A, B, and C) between 2002 and 2018. Patients with malignant (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) and benign (hepatocellular adenoma and focal nodular hyperplasia) lesions were included. A radiomics model based on T2-weighted MRI was developed in data set A using a combination of machine learning approaches. The model was internally evaluated on data set A through cross-validation, externally validated on data sets B and C, and compared to visual scoring of two experienced abdominal radiologists on data set C. RESULTS: The overall data set included 486 patients (A: 187, B: 98, and C: 201). The radiomics model had a mean area under the curve (AUC) of 0.78 upon internal validation on data set A and a similar AUC in external validation (B: 0.74 and C: 0.76). In data set C, the two radiologists showed moderate agreement (Cohen's κ: 0.61) and achieved AUCs of 0.86 and 0.82. CONCLUSION: Our T2-weighted MRI radiomics model shows potential for distinguishing malignant from benign primary solid liver lesions. External validation indicated that the model is generalizable despite substantial MRI acquisition protocol differences. Pending further optimization and generalization, this model may aid radiologists in improving the diagnostic workup of patients with liver lesions.

A Prospective Multicenter Comparison Study of Risk-adapted Ultrasound-directed and Magnetic Resonance Imaging-directed Diagnostic Pathways for Suspected Prostate Cancer in Biopsy-naïve Men.

BACKGROUND: European Association of Urology guidelines recommend a risk-adjusted biopsy strategy for early detection of prostate cancer in biopsy-naïve men. It remains unclear which strategy is most effective. Therefore, we evaluated two risk assessment pathways commonly used in clinical practice. OBJECTIVE: To compare the diagnostic performance of a risk-based ultrasound (US)-directed pathway (Rotterdam Prostate Cancer Risk Calculator [RPCRC] #3; US volume assessment) and a magnetic resonance imaging (MRI)-directed pathway. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective multicenter study (MR-PROPER) with 1:1 allocation among 21 centers (US arm in 11 centers, MRI arm in ten). Biopsy-naïve men with suspicion of prostate cancer (age ≥50 yr, prostate-specific antigen 3.0-50 ng/ml, ± abnormal digital rectal examination) were included. INTERVENTION: Biopsy-naïve men with elevated risk of prostate cancer, determined using RPCRC#3 in the US arm and Prostate Imaging Reporting and Data System scores of 3-5 in the MRI arm, underwent systematic biopsies (US arm) or targeted biopsies (MRI arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the proportion of men with grade group (GG) ≥2 cancer. Secondary outcomes were the proportions of biopsies avoided and GG 1 cancers detected. Categorical (nonparametric) data were assessed using the Mann-Whitney U test and χ2 tests. RESULTS AND LIMITATIONS: A total of 1965 men were included in the intention-to-treat population (US arm n = 950, MRI arm n = 1015). The US and MRI pathways detected GG ≥2 cancers equally well (235/950, 25% vs 239/1015, 24%; difference 1.2%, 95% confidence interval [CI] -2.6% to 5.0%; p = 0.5). The US pathway detected more GG 1 cancers than the MRI pathway (121/950, 13% vs 84/1015, 8.3%; difference 4.5%, 95% CI 1.8-7.2%; p < 0.01). The US pathway avoided fewer biopsies than the MRI pathway (403/950, 42% vs 559/1015, 55%; difference -13%, 95% CI -17% to -8.3%; p < 0.01). Among men with elevated risk, more GG ≥2 cancers were detected in the MRI group than in the US group (52% vs 43%; difference 9.2%, 95% CI 3.0-15%; p < 0.01). CONCLUSIONS: Risk-adapted US-directed and MRI-directed pathways detected GG ≥2 cancers equally well. The risk-adapted US-directed pathway performs well for prostate cancer diagnosis if prostate MRI capacity and expertise are not available. If prostate MRI availability is sufficient, risk assessment should preferably be performed using MRI, as this avoids more biopsies and detects fewer cases of GG 1 cancer. PATIENT SUMMARY: Among men with suspected prostate cancer, relevant cancers were equally well detected by risk-based pathways using either ultrasound or magnetic resonance imaging (MRI) to guide biopsy of the prostate. If prostate MRI availability is sufficient, risk assessment should be performed with MRI to reduce unnecessary biopsies and detect fewer irrelevant cancers.

Reproducibility of CT-Based Hepatocellular Carcinoma Radiomic Features across Different Contrast Imaging Phases: A Proof of Concept on SORAMIC Trial Data.

Handcrafted radiomic features (HRFs) are quantitative imaging features extracted from regions of interest on medical images which can be correlated with clinical outcomes and biologic characteristics. While HRFs have been used to train predictive and prognostic models, their reproducibility has been reported to be affected by variations in scan acquisition and reconstruction parameters, even within the same imaging vendor. In this work, we evaluated the reproducibility of HRFs across the arterial and portal venous phases of contrast-enhanced computed tomography images depicting hepatocellular carcinomas, as well as the potential of ComBat harmonization to correct for this difference. ComBat harmonization is a method based on Bayesian estimates that was developed for gene expression arrays, and has been investigated as a potential method for harmonizing HRFs. Our results show that the majority of HRFs are not reproducible between the arterial and portal venous imaging phases, yet a number of HRFs could be used interchangeably between those phases. Furthermore, ComBat harmonization increased the number of reproducible HRFs across both phases by 1%. Our results guide the pooling of arterial and venous phases from different patients in an effort to increase cohort size, as well as joint analysis of the phases.

Intra-observer agreements in multidisciplinary team assessments of pancreatic cancer patients.

BACKGROUND AND METHODS: Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (<50%), moderate (50%-75%), and high (>75%) agreement. RESULTS: Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors. CONCLUSIONS: We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment.

Non-invasive imaging prediction of tumor hypoxia: A novel developed and externally validated CT and FDG-PET-based radiomic signatures.

BACKGROUND: Tumor hypoxia increases resistance to radiotherapy and systemic therapy. Our aim was to develop and validate a disease-agnostic and disease-specific CT (+FDG-PET) based radiomics hypoxia classification signature. MATERIAL AND METHODS: A total of 808 patients with imaging data were included: N = 100 training/N = 183 external validation cases for a disease-agnostic CT hypoxia classification signature, N = 76 training/N = 39 validation cases for the H&N CT signature and N = 62 training/N = 36 validation cases for the Lung CT signature. The primary gross tumor volumes (GTV) were manually defined by experts on CT. In order to dichotomize between hypoxic/well-oxygenated tumors a threshold of 20% was used for the [18F]-HX4-derived hypoxic fractions (HF). A random forest (RF)-based machine-learning classifier/regressor was trained to classify patients as hypoxia-positive/ negative based on radiomic features. RESULTS: A 11 feature "disease-agnostic CT model" reached AUC's of respectively 0.78 (95% confidence interval [CI], 0.62-0.94), 0.82 (95% CI, 0.67-0.96) and 0.78 (95% CI, 0.67-0.89) in three external validation datasets. A "disease-agnostic FDG-PET model" reached an AUC of 0.73 (0.95% CI, 0.49-0.97) in validation by combining 5 features. The highest "lung-specific CT model" reached an AUC of 0.80 (0.95% CI, 0.65-0.95) in validation with 4 CT features, while the "H&N-specific CT model" reached an AUC of 0.84 (0.95% CI, 0.64-1.00) in validation with 15 CT features. A tumor volume-alone model was unable to significantly classify patients as hypoxia-positive/ negative. A significant survival split (P = 0.037) was found between CT-classified hypoxia strata in an external H&N cohort (n = 517), while 117 significant hypoxia gene-CT signature feature associations were found in an external lung cohort (n = 80). CONCLUSION: The disease-specific radiomics signatures perform better than the disease agnostic ones. By identifying hypoxic patients our signatures have the potential to enrich interventional hypoxia-targeting trials.

Anaplastic Large Cell T Cell Lymphoma in a Patient With Severe Therapy-refractory Crohn's Disease on Long-standing Immunosuppressive Medication During Ustekinumab Treatment: A Case Report and Review of the Literature.

Use of ustekinumab in Crohn's disease was approved in 2016, and consequently data regarding its real-world safety are still limited. We here present a 29-year-old woman with severe therapy-refractory Crohn's disease, who developed an anaplastic large cell T cell lymphoma during treatment with ustekinumab.

A Survey of Radiation Doses in CT Urography Before and After Implementation of Iterative Reconstruction.

OBJECTIVE: The purpose of this study was to survey the radiation dose used in CT urography (CTU) in routine clinical practice, both before and after implementation of a scanning protocol that uses iterative reconstruction (Adaptive Iterative Dose Reduction 3D [AIDR 3D]). MATERIALS AND METHODS: We retrospectively surveyed dose reports from consecutive CTU examinations performed in 2011 with the use of 64- and 320-MDCT scanners that were reconstructed with filtered back projection (FBP) and from CTU examinations performed from May 2012 through November 2013 that were reconstructed with the use of AIDR 3D. Findings from these dose reports were then correlated with such patient characteristics as weight and body mass index (BMI; weight in kilograms divided by the square of height in meters). Only dose reports from single-bolus three-phase CTU examinations were included in the study. The volume CT dose index, dose-length product (DLP), and effective dose were surveyed both per examination and per phase by use of published effective dose DLP conversion factors. Image quality was evaluated subjectively for a subset of patients. RESULTS: The two study cohorts included 82 patients (median patient weight, 75.0 kg; median BMI, 25.3) who underwent CTU with FBP and 85 patients (median patient weight, 78.0 kg; median BMI, 24.5) who underwent CTU with AIDR 3D. The median total DLP and median effective dose were 924 mGy · cm and 13.0 mSv, respectively, in the CTU with the FBP cohort and 433 mGy · cm and 6.1 mSv, respectively, in the CTU with the AIDR 3D cohort. The median DLP in the unenhanced, nephrogenic, and excretory phases was 218, 300, and 441 mGy · cm, respectively, in patients undergoing CTU with FBP and 114, 121, and 190 mGy · cm, respectively, in patients undergoing CTU with AIDR 3D. Image quality was diagnostic in both groups, with relatively fewer artifacts noted on scans obtained using CTU with AIDR 3D. CONCLUSION: Our study presents detailed dose data from three-phase CTU examinations performed both before and after implementation of iterative reconstruction. Implementation of a CTU protocol using iterative reconstruction resulted in a mean effective dose of 6.1 mSv with preservation of clinical diagnostic image quality.

Small molecule inhibitors of WNT/ß-catenin signaling block IL-1ß- and TNFα-induced cartilage degradation.

INTRODUCTION: In this study, we tested the ability of small molecule inhibitors of WNT/ß-catenin signaling to block interleukin 1ß (IL-1ß)- and tumor necrosis factor α (TNFα)-induced cartilage degradation. Proinflammatory cytokines such as IL-1ß and TNFα are potent inducers of cartilage degradation by upregulating matrix metalloproteinase (MMP) expression and activity. Because WNT/ß-catenin signaling was found to be involved in IL-1ß- and TNFα-induced upregulation of MMP activity, we hypothesized that inhibition of WNT/ß-catenin signaling might block IL-1ß- and TNFα-induced cartilage degradation. We tested the effect of small molecules that block the interaction between ß-catenin and TCF/Lef transcription factors on IL-1ß- and TNFα-induced cartilage degradation in mouse fetal metatarsals. METHODS: We used mouse fetal metatarsals treated with IL-1ß and TNFα as an ex vivo model for cytokine-induced cartilage degradation. Metatarsals were treated with IL-1ß and TNFα in combination with the small molecules PKF115-584, PKF118-310 and CGP049090 at different concentrations and then harvested them for histological and gene expression analysis. RESULTS: We found that IL-1ß- and TNFα-induced cartilage degradation in mouse fetal metatarsals was blocked by inhibiting WNT/ß-catenin signaling using small molecule PKF115-584 and partially using CGP049090 dose-dependently. In addition, we found that PKF115-584 blocked IL-1ß- and TNFα-induced MMP mRNA expression, but did not reverse the inhibitory effect of IL-1ß on the expression of cartilage anabolic genes. CONCLUSION: In this study, we show that inhibition of WNT/ß-catenin signaling by small molecules can effectively prevent IL-1ß- and TNFα-induced cartilage degradation by blocking MMP expression and activity. Furthermore, we elucidate the involvement of WNT/ß-catenin signaling in IL-1ß- and TNFα-induced cartilage degradation.

Apc bridges Wnt/ß-catenin and BMP signaling during osteoblast differentiation of KS483 cells.

The canonical Wnt signaling pathway influences the differentiation of mesenchymal cell lineages in a quantitative and qualitative fashion depending on the dose of ß-catenin signaling. Adenomatous polyposis coli (Apc) is the critical intracellular regulator of ß-catenin turnover. To better understand the molecular mechanisms underlying the role of Apc in regulating the differentiation capacity of skeletal progenitor cells, we have knocked down Apc in the murine mesenchymal stem cell-like KS483 cells by stable expression of Apc-specific small interfering RNA. In routine culture, KSFrt-Apc(si) cells displayed a mesenchymal-like spindle shape morphology, exhibited markedly decreased proliferation and increased apoptosis. Apc knockdown resulted in upregulation of the Wnt/ß-catenin and the BMP/Smad signaling pathways, but osteogenic differentiation was completely inhibited. This effect could be rescued by adding high concentrations of BMP-7 to the differentiation medium. Furthermore, KSFrt-Apc(si) cells showed no potential to differentiate into chondrocytes or adipocytes. These results demonstrate that Apc is essential for the proliferation, survival and differentiation of KS483 cells. Apc knockdown blocks the osteogenic differentiation of skeletal progenitor cells, a process that can be overruled by high BMP signaling.

APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis.

The canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, ß-catenin. Adenomatous polyposis coli (APC) represents the key intracellular gatekeeper of ß-catenin turnover, and heterozygous germ-line mutations in the APC gene cause familial adenomatous polyposis (FAP). Whether APC mutations affect bone mass has not been previously investigated. We conducted a cross-sectional study evaluating skeletal status in FAP patients with a documented APC mutation. Twenty-two FAP patients with a mean age of 42 years (54.5% women) were included in this study. Mean bone mineral density (BMD) Z-scores were significantly increased above normal at all measured sites: lumbar spine (p < .01), total hip (p < .01), femoral neck (p < .05), and trochanter (p < .01). Z-scores were +1 or greater in 14 patients (63.6%) and +2 or greater in 5 (22.7%). Mean values of bone turnover markers were within normal ranges. There was a significant positive correlation between procollagen type I N-terminal propeptide (P1NP) and ß-crosslaps (ß-CTX) (r = 0.70, p < .001) and between these markers and sclerostin and BMD measurements. We demonstrate that FAP patients display a significantly higher than normal mean BMD compared with age- and sex-matched healthy controls in the presence of a balanced bone turnover. Our data suggest a state of "controlled" activation of the Wnt signaling pathway in heterozygous carriers of APC mutations, most likely owing to upregulation of cytoplasmic ß-catenin levels.

Adenomatous polyposis coli-mediated control of beta-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors.

BACKGROUND: During skeletogenesis, protein levels of beta-catenin in the canonical Wnt signaling pathway determine lineage commitment of skeletal precursor cells to osteoblasts and chondrocytes. Adenomatous polyposis coli (Apc) is a key controller of beta-catenin turnover by down-regulating intracellular levels of beta-catenin. RESULTS: To investigate whether Apc is involved in lineage commitment of skeletal precursor cells, we generated conditional knockout mice lacking functional Apc in Col2a1-expressing cells. In contrast to other models in which an oncogenic variant of beta-catenin was used, our approach resulted in the accumulation of wild type beta-catenin protein due to functional loss of Apc. Conditional homozygous Apc mutant mice died perinatally showing greatly impaired skeletogenesis. All endochondral bones were misshaped and lacked structural integrity. Lack of functional Apc resulted in a pleiotropic skeletal cell phenotype. The majority of the precursor cells lacking Apc failed to differentiate into chondrocytes or osteoblasts. However, skeletal precursor cells in the proximal ribs were able to escape the noxious effect of functional loss of Apc resulting in formation of highly active osteoblasts. Inactivation of Apc in chondrocytes was associated with dedifferentiation of these cells. CONCLUSION: Our data indicate that a tight Apc-mediated control of beta-catenin levels is essential for differentiation of skeletal precursors as well as for the maintenance of a chondrocytic phenotype in a spatio-temporal regulated manner.

Meeting Report:The 7th ESPE Growth Plate Working Group Symposium - EUROGROP June 27th 2007, Helsinki, Finland.

UNLABELLED: Longitudinal bone growth occurs within the epiphyseal growth plate, a highly organized biological structure located at the distal ends of the long bones, via endochondral bone formation. This developmentally regulated process is finely tuned through the interaction of circulating systemic hormones and locally produced peptide growth factors, the net result of which is to trigger changes in gene expression by growth plate chondrocytes. These molecular events lead to carefully orchestrated alterations in chondrocyte size, extracellular matrix components, secreted enzymes, growth factors and receptor expression. These events finally result in calcification of the matrix, chondrocyte death, vascular invasion and the completion of endochondral bone formation. Although the past several years have seen important progress in the identification of numerous important factors, which, in a complex and integrated network, control longitudinal bone growth, many of the signaling pathways and their interactions in the growth plate remain poorly understood. The ESPE Growth Plate Working Group (EUROGROP) was established in 2000 with the aim of bringing together both basic and clinical European research groups with an interest in the biology and pathology of the growth plate. The 7th EUROGROP Symposium was held as an official ESPE working group of the 46th ESPE Annual Meeting held in Helsinki, Finland, 2007. It enabled researchers, coming from all parts of the world to discuss their ongoing studies and exchange technical information. The program consisted of three lectures and four original papers, all followed by attractive discussions. This report summarizes the data presented and provides some comments on each of the presentations. ABBREVIATIONS: 11beta-HSD: 11 Beta-Hydroxysteroid Dehydrogenase; Agc: Aggrecan; Aln: Alendronate; Asb- 4: Ankyrin Repeat and SOCS Box-Containing Protein 4; Atf6: Activating Transcription Factor6; BSP: Bisphosphonates; Calca: Calcitonin, Alpha Cdkn2a: Cyclin-Dependent Kinase Inhibitor 2A; Col1: Collagen 1; Col2: Collagen 2 Col10: Collagen 10; Dex: Dexamethasone; Elk1: Member of ETS Oncogene Family; Esr1: Estrogen Receptor 1 (Alpha); Fli1: Friend Leukemia Integration 1; Gabp: GA Repeat Binding Protein; GC: Glucocorticoids; Ghr: Growth Hormone Receptor; Hif-1alpha: Hypoxia-Inducible Factor 1 Alpha; hMSCs: Human Mesenchymal Stem Cells; Igf1: Insulin-Like Growth Factor 1; Igfbp1: Insulin-Like Growth Factor Binding Protein 1; Igf1r: Insulin-Like Growth Factor 1-Receptor; Igf2: Insulin-Like Growth Factor 2; Igf2r: Insulin-Like Growth Factor 2-Receptor; Nfe2l2: Nuclear Factor, Erythroid Derived 2, Like 2; Nrf1: Nuclear Respiratory Factor 1; Pam: Pamidronate; Prss11: HtrA Serine Peptidase 1; PTU: Propylthiouracil; Pycard: PYD and CARD Domain Containing; Rxrg: Retinoid X Receptor Gamma; Tam: Tamoxifen.

Novel early target genes of parathyroid hormone-related peptide in chondrocytes.

We have performed microarray analysis to identify PTHrP target genes in chondrocytes. ATDC5 cells were cultured as micromasses to induce chondrocyte differentiation. On d 8 of culture, the cells had a prehypertrophic appearance. This time point was chosen for isolation of RNA at 0, 1, 2, and 4 h after a challenge with 10(-7) M PTHrP. Samples were subjected to a cDNA microarray using competition hybridization. A list of 12 genes (P < 10(-3)), the expression regulation of which by PTHrP was confirmed by quantitative PCR analysis, was generated. This included seven up-regulated and five down-regulated genes. Three genes were known to be involved in PTHrP regulation, and six were previously found in growth plate chondrocytes. Most of the genes (10 of 12) were implicated in signal transduction and regulation. PTHrP also induced expression of the up-regulated genes in KS483 osteoblasts, suggesting involvement in a more generalized response to PTHrP. The vast majority of the up-regulated genes (six of seven) contained cAMP response element-binding protein- and/or activating protein-1 transcription factor-binding sites in their promoter regions. Remarkably, a number of PTHrP-regulated genes contained signal transducer and activator of transcription factor (Stat)-binding sites in their promoters. In transient transfection assays, we show that PTHrP is able to positively regulate the activity of Stat3-specific and negatively regulate the activity of Stat5-specific promoter-reporter constructs in ATDC5 and UMR106 cells. In combination with the expression regulation of genes involved in Janus kinase/Stat signaling, this data suggest a previously unrecognized interaction between PTHrP and Janus kinase/Stat signaling.

Investigation of human serum albumin (HSA) binding specificity of certain photosensitizers related to pyropheophorbide-a and bacteriopurpurinimide by circular dichroism spectroscopy and its correlation with in vivo photosensitizing efficacy.

A series of pyropheophorbide-a and bacteriopurpurinimides were investigated to understand the correlation between HSA (site II) binding affinity and in vivo photosensitizing activity. In our study, photosensitizers that bound to site II of HSA produced a significant difference in the circular dichroism spectra of the corresponding complexes, especially at Soret band region of the photosensitizers. Our results suggest that CD spectroscopy of the photosensitizer-HSA complexes could be a valuable tool in screening new photosensitizers before evaluating them for in vivo efficacy.