Histopathologic image-based deep learning classifier for predicting platinum-based treatment responses in high-grade serous ovarian cancer.

Platinum-based chemotherapy is the cornerstone treatment for female high-grade serous ovarian carcinoma (HGSOC), but choosing an appropriate treatment for patients hinges on their responsiveness to it. Currently, no available biomarkers can promptly predict responses to platinum-based treatment. Therefore, we developed the Pathologic Risk Classifier for HGSOC (PathoRiCH), a histopathologic image-based classifier. PathoRiCH was trained on an in-house cohort (n = 394) and validated on two independent external cohorts (n = 284 and n = 136). The PathoRiCH-predicted favorable and poor response groups show significantly different platinum-free intervals in all three cohorts. Combining PathoRiCH with molecular biomarkers provides an even more powerful tool for the risk stratification of patients. The decisions of PathoRiCH are explained through visualization and a transcriptomic analysis, which bolster the reliability of our model's decisions. PathoRiCH exhibits better predictive performance than current molecular biomarkers. PathoRiCH will provide a solid foundation for developing an innovative tool to transform the current diagnostic pipeline for HGSOC.

Federated learning with knowledge distillation for multi-organ segmentation with partially labeled datasets.

The state-of-the-art multi-organ CT segmentation relies on deep learning models, which only generalize when trained on large samples of carefully curated data. However, it is challenging to train a single model that can segment all organs and types of tumors since most large datasets are partially labeled or are acquired across multiple institutes that may differ in their acquisitions. A possible solution is Federated learning, which is often used to train models on multi-institutional datasets where the data is not shared across sites. However, predictions of federated learning can be unreliable after the model is locally updated at sites due to 'catastrophic forgetting'. Here, we address this issue by using knowledge distillation (KD) so that the local training is regularized with the knowledge of a global model and pre-trained organ-specific segmentation models. We implement the models in a multi-head U-Net architecture that learns a shared embedding space for different organ segmentation, thereby obtaining multi-organ predictions without repeated processes. We evaluate the proposed method using 8 publicly available abdominal CT datasets of 7 different organs. Of those datasets, 889 CTs were used for training, 233 for internal testing, and 30 volumes for external testing. Experimental results verified that our proposed method substantially outperforms other state-of-the-art methods in terms of accuracy, inference time, and the number of parameters.

A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma.

PURPOSE: Clinical implications of neoadjuvant immunotherapy in patients with locally advanced but resectable head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. PATIENTS AND METHODS: Patients with resectable HNSCC were randomized to receive a single dose of preoperative durvalumab (D) with or without tremelimumab (T) before resection, followed by postoperative (chemo)radiotherapy based on multidisciplinary discretion and 1-year D treatment. Artificial intelligence (AI)-powered spatial distribution analysis of tumor-infiltrating lymphocytes and high-dimensional profiling of circulating immune cells tracked dynamic intratumoral and systemic immune responses. RESULTS: Of the 48 patients enrolled (D, 24 patients; D+T, 24 patients), 45 underwent surgical resection per protocol (D, 21 patients; D+T, 24 patients). D±T had a favorable safety profile and did not delay surgery. Distant recurrence-free survival (DRFS) was significantly better in patients treated with D+T than in those treated with D monotherapy. AI-powered whole-slide image analysis demonstrated that D+T significantly reshaped the tumor microenvironment toward immune-inflamed phenotypes, in contrast with the D monotherapy or cytotoxic chemotherapy. High-dimensional profiling of circulating immune cells revealed a significant expansion of T-cell subsets characterized by proliferation and activation in response to D+T therapy, which was rare following D monotherapy. Importantly, expansion of specific clusters in CD8+ T cells and non-regulatory CD4+ T cells with activation and exhaustion programs was associated with prolonged DRFS in patients treated with D+T. CONCLUSIONS: Preoperative D±T is feasible and may benefit patients with resectable HNSCC. Distinct changes in the tumor microenvironment and circulating immune cells were induced by each treatment regimen, warranting further investigation.

Reduction of Osteoclastic Differentiation of Raw 264.7 Cells by EMF Exposure through TRPV4 and p-CREB Pathway.

In this study, we investigated the effect of EMF exposure on the regulation of RANKL-induced osteoclast differentiation in Raw 264.7 cells. In the EMF-exposed group, the cell volume did not increase despite RANKL treatment, and the expression levels of Caspase-3 remained much lower than those in the RANKL-treated group. TRAP and F-actin staining revealed smaller actin rings in cells exposed to EMF during RANKL-induced differentiation, indicating that EMF inhibited osteoclast differentiation. EMF-irradiated cells exhibited reduced mRNA levels of osteoclastic differentiation markers cathepsin K (CTSK), tartrate-resistant acid phosphatase (TRAP), and matrix metalloproteinase 9 (MMP-9). Furthermore, as measured by RT-qPCR and Western blot, EMF induced no changes in the levels of p-ERK and p-38; however, it reduced the levels of TRPV4 and p-CREB. Overall, our findings indicate that EMF irradiation inhibits osteoclast differentiation through the TRPV4 and p-CREB pathway.

Extremely Low-Frequency Electromagnetic Fields Increase Cytokines in Human Hair Follicles through Wnt/ß-Catenin Signaling.

Hair loss is a chronic disorder that affects many people; however, a complete treatment has not yet been developed. Therefore, new therapeutic agents for preventing hair loss must be developed, and electromagnetic field (EMF) therapy has been proven to be a promising medical treatment in various fields, including hair loss treatment. This study evaluated the effect of extremely low-frequency electromagnetic field (ELF-EMF) intensity and exposure time by analyzing the expression of cytokines and anagen-related molecules, which influence hair activation and growth, in hair bulb spheroid (HBS) and hair follicle (HF) organ cultures. ELF-EMFs did not induce toxicity in the HBSs, as verified via the lactate dehydrogenase (LDH) assay. Moreover, an ELF-EMF intensity of 5-20 G promoted the expression of ALP, versican, ß-catenin, and several cytokines (VEGF, PDGF, FGF-10, and ET-1) in HBSs. Immunohistochemical staining showed that ELF-EMF at an intensity of 5-20 G upregulated ALP and ß-catenin and decreased TUNEL staining in HBS. Moreover, HFs exposed to ELF-EMF for 60 min exhibited an increase in hair length and a 1.5-fold increase in IL-4, ICAM-1, ALP, and versican mRNA expression compared to the control. Immunohistochemical staining indicated that 60 min of ELF-EMF can increase the expression of ALP and ß-catenin and decreases TUNEL staining in organ cultures. Collectively, our results demonstrated that ELF-EMF exposure at a 10 G intensity for 60 min promoted hair shaft growth in HFs due to the effect of cytokines and adhesion molecules via the Wnt/ß-catenin pathway. Therefore, ELF-EMF is a promising treatment for hair loss.

Induced Neurodifferentiation of hBM-MSCs through Activation of the ERK/CREB Pathway via Pulsed Electromagnetic Fields and Physical Stimulation Promotes Neurogenesis in Cerebral Ischemic Models.

Stroke is among the leading causes of death worldwide, and stroke patients are more likely to live with permanent disabilities even after treatment. Several treatments are being developed to improve the quality of life of patients; however, these treatments still have important limitations. Our study thus sought to evaluate the neural differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) at various pulsed electromagnetic field (PEMF) frequencies. Furthermore, the effects of selected frequencies in vivo were also evaluated using a mouse ischemia stroke model. Cell proliferation decreased by 20% in the PEMF group, as demonstrated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, and lactate dehydrogenase (LDH) secretion increased by approximately 10% in an LDH release assay. Fluorescence-activated cell sorting (FACS) analysis demonstrated that CD73 and CD105 were downregulated in the PEMF group at 60 Hz. Moreover, microtubule-associated protein 2 (MAP-2) and neurofilament light chain (NF-L) were upregulated in cell cultures at 60 and 75 Hz. To assess the effects of PEMF in vivo, cerebral ischemia mice were exposed to a PEMF at 60 Hz. Neural-related proteins were significantly upregulated in the PEMF groups compared with the control and cell group. Upon conducting rotarod tests, the cell/PEMF group exhibited significant differences in motor coordination at 13 days post-treatment when compared with the control and stem-cell-treated group. Furthermore, the cell and cell/PEMF group exhibited a significant reduction in the expression of matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) in the induced ischemic area compared with the control. Collectively, our findings demonstrated that PEMFs at 60 and 75 Hz could stimulate hBM-MSCs neural differentiation in vitro, in addition to promoting neurogenesis to enhance the functional recovery process by reducing the post-stroke inflammatory reaction.

Induction of PLXNA4 Gene during Neural Differentiation in Human Umbilical-Cord-Derived Mesenchymal Stem Cells by Low-Intensity Sub-Sonic Vibration.

Human umbilical-cord-derived mesenchymal stem cells (hUC-MSC) are a type of mesenchymal stem cells and are more primitive than other MSCs. In this study, we identify novel genes and signal-activating proteins involved in the neural differentiation of hUC-MSCs induced by Low-Intensity Sub-Sonic Vibration (LISSV). RNA sequencing was used to find genes involved in the differentiation process by LISSV. The changes in hUC-MSCs caused by LISSV were confirmed by PLXNA4 overexpression and gene knockdown through small interfering RNA experiments. The six genes were increased among genes related to neurons and the nervous system. One of them, the PLXNA4 gene, is known to play a role as a guide for axons in the development of the nervous system. When the PLXNA4 recombinant protein was added, neuron-related genes were increased. In the PLXNA4 gene knockdown experiment, the expression of neuron-related genes was not changed by LISSV exposure. The PLXNA4 gene is activated by sema family ligands. The expression of SEMA3A was increased by LISSV, and its downstream signaling molecule, FYN, was also activated. We suggest that the PLXNA4 gene plays an important role in hUC-MSC neuronal differentiation through exposure to LISSV. The differentiation process depends on SEMA3A-PLXNA4-dependent FYN activation in hUC-MSCs.

Hopeless tooth and less posterior occlusion is related to a greater risk of low handgrip strength: A population-based cross-sectional study.

The effect of severely compromised teeth on masticatory function has not been properly evaluated in previous studies, as they were often considered equivalent to the healthy tooth or excluded as if absent in the dentition. Hopeless teeth, which refer to non-salvageable teeth that require extraction, can interfere with masticatory function. As posterior occlusion is directly related to the masticatory function, we evaluated pairs opposing posterior teeth (POPs) that reflect the arrangement as well as the number of remaining posterior teeth. This study investigated the relationship of a hopeless tooth to handgrip strength according to POPs in the elderly. This cross-sectional study used data from the Korea National Health and Nutrition Examination Survey (KNHANES). Among the data of 23,466 participants from 2015 to 2018, participants aged 60 years or older (n = 4,729) were included. In males with POPs scores of 0-7, considered poor posterior occlusion, the association with low handgrip strength persisted in the multivariate logistic regression model adjusted for all confounding variables. The odds ratio (OR) in the absence of hopeless teeth (OR = 1.91, 95% CI: 1.02-3.59) increased in the presence of a hopeless tooth (OR = 2.78, 95% CI: 1.42-5.47). Even with POPs scores of 8-11, considered good posterior occlusion, the association was significantly high in the presence of a hopeless tooth (OR = 2.82, 95% CI: 1.06-7.52). In females, the association disappeared in adjusted models. The fewer pairs of natural posterior teeth with occlusion, the greater the risk of low handgrip strength. Dentition containing hopeless teeth increases the risk of low handgrip strength, even in dentition with sufficient posterior occlusion. Preserving the posterior teeth in a healthy condition through personal oral hygiene and regular dental management is essential for maintaining components of physical function such as handgrip strength.

Fluorine-incorporated TiO2 nanotopography enhances adhesion and differentiation through ERK/CREB pathway.

This study compared the topography of different titanium surface structures (TiO2 nanotube and grain) with similar elemental compositions (TiO2 and fluorine [F]) on the Ti surface. High magnification indicated that the surfaces of the control and etching groups were similar to each other in a flat, smooth form. The group anodized for 1 h was observed with TiO2 nanotubes organized very neatly and regularly. In the group anodized for 30 min after etching, uneven wave and nanopore structures were observed. In addition, MTT assay showed that the F of the surface did not adversely affect cell viability, and the initial cell adhesion was increased in the 2.8% F-incorporated TiO2 nanograin. At the edge of adherent cells, filopodia were observed in spreading form on the surfaces of the anodizing and two-step processing groups, and they were observed in a branch shape in the control and etching groups. Moreover, cell adhesion molecule and osteogenesis marker expression was increased at the F-incorporated TiO2 nanostructure. In addition, it was found that the expression of p-extracellular signal-regulated kinase (ERK) and p-cAMP response element-binding protein (CREB) increased in the TiO2 nanograin with the nanopore surface compared to the micro rough and nanotube surfaces relative to the osteogenic-related gene expression patterns. As a result, this study confirmed that the topographic structure of the surface is more affected by osteogenic differentiation than the pore size and that differentiation by specific surface composition components is by CREB. Thus, the synergy effect of osteogenic differentiation was confirmed by the simultaneous activation of CREB/ERK.

Highly bioavailable curcumin powder suppresses articular cartilage damage in rats with mono-iodoacetate (MIA)-induced osteoarthritis.

This study was performed to investigate the effects of highly bioavailable curcumin as Theracurmin® (TC) in rats with monosodium iodoacetate (MIA)-induced osteoarthritis (OA). Seventy-seven male Wistar rats were divided into six groups: normal, negative control (MIA only), positive control (Cerebrex), and three experimental groups treated with 500, 1300, or 2600 mg/kg of TC for 5 weeks. MIA injection-induced OA caused 30% weight-bearing imbalance whereas weight bearing imbalance was significantly improved in the TC groups. Mankin scores revealed TC treatment had significantly ameliorated cartilage damage and chondrocyte decrease. The expressions of nitrotyrosine, tumor necrosis factor-α, phosphorylated nuclear factor kappa B cells, and cleaved caspase-3 were markedly increased in rat with MIA-induced OA, but the TC-treated groups exhibited a significant reduction in the number of immunoreactive cells in a dose-dependent manner. In conclusion, administration of TC contributes to the anti-arthritic effect in rat with MIA-induced OA.

Clinicopathologic study of 60 cases of urothelial neoplasms with inverted growth patterns: Reclassification by international consultation on urologic disease (ICUD) recommendations.

BACKGROUND: Most urothelial neoplasms of the bladder show an exophytic papillary pattern, but some show an inverted growth pattern. In 2004, the World Health Organization (WHO) released a detailed histologic classification system for papillary urothelial neoplasms, but not for inverted forms. The International Consultation on Urologic Disease (ICUD) recommendations of 2012 are applicable to inverted/endophytic papillary lesions as follows: 1) inverted papilloma (IP), 2) inverted papillary urothelial neoplasm of low malignant potential (IPUNLMP), 3) inverted papillary urothelial carcinoma, low grade, non-invasive (IPUCLG-NI), 4) inverted papillary urothelial carcinoma, high grade, non-invasive (IPUCHG-NI), 5) inverted papillary urothelial carcinoma, high grade, invasive (IPUCHG-I). However, only atypical cellular morphology was considered for classification in the 2012 ICUD recommendations, and data to support to validate this new grading system are lacking. METHODS: Sixty cases of inverted urothelial papillary tumors were classified into 5 categories according to 2012 ICUD and 2016 WHO/ISUP recommendations to evaluate their clinical, pathological, and immunohistochemical characteristics. Two subgroups were defined as subgroup 1, IP and IPUNLMP, and subgroup 2, IPUCLG-NI, IPUCHG-NI, and IPUCHG-I. Clinical features (age, sex, history of urothelial carcinoma, smoking history, size, and multifocality) and histologic features (nuclear pleomorphism, mitotic count, mitosis level, apoptosis, luminal necrosis, trabecular thickening, anastomosing trabeculae, hypercellularity, loss of polarity, peripheral palisading, palisading with central streaming, and discohesiveness) were evaluated. Immunohistochemical stains for CK20, CD44, P53, p16, Ki-67, cyclin D1 and c-erbB2 were performed. RESULTS: A total of 60 cases were classified as 10 cases of IP, 29 cases of IPUNLMPs, 15 cases of IPUCLG-NI, 4 cases of IPUCHG-NI, and 2 cases of IPUCHG-I. Compared to subgroup 1, subgroup 2 showed larger tumor size, more nuclear irregularity, higher mitotic count (hot spot and per 10 high power fields), more upper level mitosis (>1/2), and more frequent apoptosis, luminal necrosis, surface papillary component, trabecular thickening, anastomosing irregular trabeculae, hypercellularity, loss of polarity, peripheral palisading with central streaming, and discohesiveness, and absence of umbrella cells and urothelial eddies. CK20, Ki67, and c-erbB2 were the only markers that were differently expressed in the two subgroups, with more expression in subgroup 2. CONCLUSIONS: The 2012 ICUD recommendations are valid to classify inverted papillary urothelial tumors. However, other histologic features besides atypical cellular morphology should also be considered to distinguish subgroup 1 and subgroup 2 inverted papillary urothelial tumors.

Children's Dental Sealant Use and Caries Prevalence Affected by National Health Insurance Policy Change: Evidence from the Korean National Health and Nutrition Examination Survey (2007-2015).

We evaluated the effect of the National Health Insurance (NHI) policy including dental sealant on changes in the prevalence of sealant and caries, and examined how NHI affected sealant utilization and untreated caries in children from diverse income groups in South Korea. We used a multivariate logistic regression analysis to explore the effects of three stages of dental sealant policy (pre-policy: 2007-2009, first post-policy: 2010-2012, and second post-policy: 2013-2015) on the prevalence of dental sealant and untreated caries. Participant data (N = 8161, aged 6-14 years) were derived from the Korea National Health and Nutrition Examination Survey (2007-2015). We also conducted subgroup analysis to determine the effects of the NHI policy on dental sealant and untreated caries by income level. Implementation of dental insurance coverage was associated with higher likelihood of using dental sealant (odds ratio (OR) = 1.39 (95% confidence interval (CI): 1.18-1.63) for the first period and OR = 1.58 (95% CI: 1.33-1.87) for the second period) and lower odds of having untreated caries (OR = 0.79 (95% CI: 0.64-0.98) for the first period and OR = 0.65 (95% CI: 0.51-0.83) for the second period) after controlling for covariates. Results revealed that there was a greater prevalence of dental sealant and a lower prevalence of untreated caries in both middle- and low-income households compared to high-income households. The higher prevalence of dental sealant and lower untreated caries after the policy implementation. Moreover, we demonstrated children from low-or middle-income households were more associated with increasing dental sealant use and a declining prevalence of caries.

Mesalazine Activates Adenosine Monophosphate-activated Protein Kinase: Implication in the Anti-inflammatory Activity of this Anti-colitic Drug.

OBJECTIVE: Mesalazine, 5-aminosalicylic acid (5-ASA), is an anti-inflammatory drug that is most widely used for the treatment of Inflammatory Bowel Disease (IBD). Despite extensive clinical use, the exact pharmacological mechanism underlying the anti-colitic effects of 5-ASA has not yet been elucidated. A potential molecular mechanism underlying 5-ASA-mediated anti-colitic activity was investigated. METHODS: An anti-inflammatory pharmacology of 5-ASA was scrutinized in human colon carcinoma cells and murine macrophages and in a TNBS-induced rat colitis model. RESULTS: 5-ASA induced phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrate acetyl-CoA carboxylase in cells. 5-ASA activation of AMPK occurred regardless of the presence of the pro-inflammatory mediators, Tumor Necrosis Factor Alpha (TNF-α) and lipopolysaccharide. 5-ASA inhibits TNF-α-dependent Nuclear Factor-Kappa B (NF-κB) activation, which was dampened by AMPK inhibition. Oral gavage of sulfasalazine (a colon-specific prodrug of 5- ASA) or rectal administration of 5-ASA ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS)- induced rat colitis and activated AMPK in the inflamed colonic tissues while markedly diminishing the levels of NF-κB-regulated pro-inflammatory mediators cyclooxygenase-2, inducible nitric oxide synthase, and cytokine-induced neutrophil chemoattractant-3, elevated by the induction of inflammation. Rectal co-administration of 5-ASA and an AMPK inhibitor undermined 5-ASA-mediated activation of AMPK and its anti-colitic effects. CONCLUSION: These findings suggest that the activation of AMPK is involved in 5-ASA-mediated anticolitic effects at least partly via interference with pro-inflammatory NF-κB signaling.

Sensorimotor outcomes in children with prenatal exposure to methadone.

PURPOSE: To report the presentation and characteristics of strabismus in children with prenatal methadone exposure. METHODS: The medical records of children with prenatal methadone exposure were retrospectively reviewed. Those who were evaluated by pediatric ophthalmology were included. Information on the timing and types of prenatal exposure by trimester of pregnancy was then collected from the patients' mothers' charts. The children's perinatal histories and ophthalmologic findings were collected from their pediatric clinic charts and ophthalmology clinic charts, respectively. RESULTS: A total of 210 children with prenatal methadone exposure were identified, of whom 32 (15.2%) underwent eye examinations and 21 (10%) had strabismus. Five patients had esodeviations, with a mean age of onset of 11.6 months; 16 had exodeviations, with a mean age of onset of 6.8 months. Three patients with strabismus were born prematurely, and 2 had intracranial disease. Two patients underwent strabismus surgery. CONCLUSIONS: The incidence of strabismus in patients with prenatal methadone exposure was higher than in the general population (10% vs 3%-4%). Intermittent exotropia was the most common type of strabismus and presented earlier than in the general population, with no association with other systemic disease. Prenatal exposure to methadone was likely confounded by exposure to other substances, environmental factors, and genetics. Poor compliance with follow-up reduced the power of the study.

Germ Cell Tumor Targeting Chemotherapy in Gastric Adenocarcinoma with an Endodermal Sinus Tumor Component: A Case Report.

The most common sites for extragonadal germ cell tumors are the midline mediastinum, retroperitoneum and, much less frequently, the stomach. The stomach-originated primary germ cell tumor carries a poor prognosis, especially when metastasis occurs to the liver, with a mean survival time of 1 month. We describe the case of a 77-year-old male who presented with usual symptoms of gastric malignancy. Gastrectomy was performed. Histopathology of surgically resected tissue revealed a mixture of adenocarcinoma and endodermal sinus tumor components with α-fetoprotein production. After liver metastasis was identified, oxaliplatin and capecitabine were administered as palliative chemotherapy. The response was poor. For the second-line therapy, bleomycin, etoposide, and cisplatin (BEP) therapy was initiated. The overall response to these drugs was a partial response and the residual liver lesion was considered to be resectable. The patient died of pneumonia 11 months following the BEP session, representing an overall survival time of 22 months. Gastric adenocarcinoma with a germ cell tumor component is uncommon and an effective combination of chemotherapeutic agents is not yet clear. In this case, the patient received germ cell tumor-targeting chemotherapy and showed a durable response. Hence, germ cell-targeting cytotoxic agents have potential as the 'front-line regimen'.

The value of cytoplasmic Y-box-binding protein 1 as a prognostic marker for breast cancer in Korean.

BACKGROUND: The human Y-box-binding protein 1 (YB-1) is a member of the DNA/RNA-binding family of proteins that regulates transcription and translation of genes. Previous studies suggest that YB-1 may have an oncogenic role in various cancers. In this study, we evaluate the prognostic value of cytoplasmic YB-1 with respect to breast cancer. METHODS: Immunohistochemical staining study was performed with YB-1 using tissue block from 233 patients with invasive ductal carcinoma. Patients were divided into two groups according to expression of cytoplasmic YB-1 in tumor cell (high versus low). The relationship between the expression of YB-1, clinicopathological characteristics and breast cancer prognosis was analyzed. RESULTS: Hormone receptor negativity, worse histologic and nuclear grade, high tumor stage, lymphovascular invasion and high Ki67 (≥14 %) were related with the increased expression of cytoplasmic YB-1 in tumor cell (p < 0.05). Although there was no significant difference in relapse-free survival (RFS) between the two groups (p = 0.412), difference in overall survival (OS) was statistically significant (p = 0.035). In multivariate analysis for OS, YB-1 was an independent prognostic factor (p = 0.043). CONCLUSION: This suggests that the increased expression of cytoplasmic YB-1 in tumor cells can be regarded as an independent prognostic factor for breast cancer, related to poor prognostics. Expression of cytoplasmic YB-1 in cancer cell could be used as an independent prognostic marker for predicting OS in breast cancer.

Stromal nodules in benign prostatic hyperplasia: morphologic and immunohistochemical characteristics.

BACKGROUND: One hundred forty nine stromal nodules (SNs) from transurethral resection of benign prostatic hyperplasia specimens in 39 patients (57-85 years with mean of 70.9) were investigated to characterize the SNs and to outline the etiopathogenesis of solitary fibrous tumors (SFTs) and gastrointestinal stromal tumors (GISTs) of prostate by immunohistochemistry performed on tissue microarray sections. METHODS: Antibodies used included smooth muscle actin, desmin, vimentin, and S-100 protein for subtyping, vascular endothelial growth factor, insulin-like growth factor-1, fibroblast growth factor, and TGF-ß as growth factors; CD133, c-KIT, CD34, and CD44 as stem cell markers; and estrogen (ER), progesterone (PR), and androgen receptor (AR) as hormone receptors. RESULTS: SNs were classified into four subtypes: (1) immature mesenchymal (n = 7, 4.7%); (2) fibroblastic (n = 74, 49.7%); (3) fibromuscular (n = 53, 35.6%); and (4) smooth muscular (n = 15, 10.1%) types. There were linear trends of the expression of all growth factors (VEGF, IGF-1, FGF, TGF-ß), but only CD44 stem cell marker and AR hormone receptor as maturation progressed from immature mesenchymal to smooth muscular type (Ptrend < 0.05). S-100, c-KIT, and ER were not expressed in any types of SNs. CD34 was positive in 55% of the SNs (82/149). CONCLUSIONS: The data suggest that AR and growth factors are important factors for maturation of SNs, but not influenced by the administration of 5-alpha reductase inhibitor (5ARI). Although the cells comprising the SNs seem to be not associated with the origin of prostatic GISTs, there is a possibility of a tentative link of SFTs arising from SNs of the prostate.

Prognostic value of human apurinic/apyrimidinic endonuclease 1 (APE1) expression in breast cancer.

Human apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein for DNA base excision repair (BER) and redox regulation. The ability of cancer cells to recognize DNA damage and initiate DNA repair is an important mechanism for therapeutic resistance. Several recent studies have suggested that APE1 expression levels and/or subcellular dysregulation may be used to indicate the sensitivity of tumors to radiotherapy or chemotherapy. In this study, we assessed the prognostic significance of APE1 and differences in APE1 expression levels according to breast cancer molecular subtypes. We analyzed formalin-fixed, paraffin-embedded tumor tissue sections from 243 cases diagnosed as invasive breast cancer at Ewha Womans University Medical Center between January 2003 and December 2008. Immunohistochemistry was performed and the nuclear level of APE1 was scored by taking into account the percentage of positive cells. Medical records were reviewed to investigate clinicopathologic characteristics. We found that nuclear APE1 high-level expression (proportion ≥50%) in breast cancer showed a tendency towards unfavorable prognosis regarding disease-free survival (p = 0.093). However, there was no significant difference in overall survival between low and high-level expression groups (p = 0.294). Interestingly, within the Ki-67 low-level expression group, APE1 low-level expression was significantly associated with poor overall survival (p = 0.007). A significant positive correlation was observed between APE1 nuclear expression and estrogen receptor status (75.7% vs. 59.7%, p = 0.022). Also, the luminal A subtype was the most commonly observed breast cancer subtype in the APE1 high-level expression group (61.6% vs. 45.2%, p = 0.000). This study suggests that APE1 expression may be associated with breast cancer prognosis. In particular, its role as a prognostic factor would be significant for breast cancers with a low Ki-67 proliferation index. It is proposed that nuclear APE1 may be a novel target in breast cancer with a low proliferation rate to obtain better outcome.

Silk and collagen scaffolds for tendon reconstruction.

In this study, silk thread (Bombyx mori) was braided to a tube-like shape and sericin was removed from the silk tube. Thereafter, collagen/chondroitin-6-sulfate solution was poured into the silk tube, and the lyophilization process was performed. To assess the inflammatory response in vivo, raw silk and sericin-free silk tubes were implanted in the subcutaneous layer of mice. After 10 days of in vivo implantation, mild inflammatory responses were observed around the sericin-free silk tubes, and severe inflammation with the presence of neutrophils and macrophages was observed around the raw silk tubes. At 24 weeks post implantation, the regenerated tendon had a thick, cylindrical, grayish fibrous structure and a shiny white appearance, similar to that of the native tendon in the rabbit model of tendon defect. The average tensile strength of the native tendons was 220 ± 20 N, whereas the average tensile strength of the regenerated tendons was 167 ± 30 N and the diameter of the regenerated tendon (3 ± 0.2 mm) was similar to that of the native tendons (4 ± 0.3 mm). Histologically, the regenerated tendon resembled the native tendon, and all the regenerated tissues showed organized bundles of crimped fibers. Masson trichrome staining was performed for detecting collagen synthesis, and it showed that the artificial tendon was replaced by new collagen fibers and extracellular matrix. However, the regenerated tendon showed fibrosis to a certain degree. In conclusion, the artificial tendon, comprising a braided silk tube and lyophilized collagen sponge, was optimal for tendon reconstruction. Thus, this study showed an improved regeneration of neo-tendon tissues, which have the structure and tensile strength of the native tendon, with the use of the combination of collagen and silk scaffold.