Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma.

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Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma.

J Pathol. 2016 Jan;238(2):185-96

Authors: King CM, Barbara C, Prentice A, Brenton JD, Charnock-Jones DS

Abstract
Endometriosis is a common benign gynaecological condition affecting at least 10% of women of childbearing age and is characterized by pain--frequently debilitating. Although the exact prevalence is unknown, the economic burden is substantial (∼$50 billion a year in the USA alone) and it is associated with considerable morbidity. The development of endometriosis is inextricably linked to the process of menstruation and thus the models that best recapitulate the human disease are in menstruating non-human primates. However, the use of these animals is ethically challenging and very expensive. A variety of models in laboratory animals have been developed and the most recent are based on generating menstrual-like endometrial tissue that can be transferred to a recipient animal. These models are genetically manipulable and facilitate precise mechanistic studies. In addition, these models can be used to study malignant transformation in epithelial ovarian carcinoma. Epidemiological and molecular evidence indicates that endometriosis is the most plausible precursor of both clear cell and endometrioid ovarian cancer (OCCA and OEA, respectively). While this progression is rare, understanding the underlying mechanisms of transformation may offer new strategies for prevention and therapy. Our ability to pursue this is highly dependent on improved animal models but the current transgenic models, which genetically modify the ovarian surface epithelium and oviduct, are poor models of ectopic endometrial tissue. In this review we describe the various models of endometriosis and discuss how they may be applicable to developing our mechanistic understanding of OCCA and OEA.

PMID: 26456077 [PubMed - indexed for MEDLINE]

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A Rare Case of Ovarian Cancer Presenting with Paraneoplastic Cerebellar Degeneration and Limbic Encephalitis.

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A Rare Case of Ovarian Cancer Presenting with Paraneoplastic Cerebellar Degeneration and Limbic Encephalitis.

Chin Med J (Engl). 2015 Oct 5;128(19):2685-7

Authors: Li WH, Cao DY, Shen K, Yang JX

PMID: 26415811 [PubMed - indexed for MEDLINE]

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A systematic review and meta-analysis of animal-type melanoma.

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A systematic review and meta-analysis of animal-type melanoma.

J Am Acad Dermatol. 2015 Dec;73(6):1031-9

Authors: Vyas R, Keller JJ, Honda K, Cooper KD, Gerstenblith MR

Abstract
BACKGROUND: Animal-type melanoma is a rare subtype of melanoma with heavily pigmented dermal epithelioid and spindled melanocytes. Its classification as a subtype of melanoma versus a borderline melanocytic tumor is debated.
OBJECTIVES: Our primary objective was to characterize the demographics, clinical presentation, histopathology, management, and outcomes of patients with animal-type melanoma.
METHODS: We performed a systematic review and meta-analysis of the English-language literature on animal-type melanoma.
RESULTS: We identified 190 cases of animal-type melanoma. They occurred equally in men and women, with Caucasians (53.7%) most commonly affected. The median Breslow depth was 3.8 mm; ulceration was reported present in 15.8%; and dermal mitoses greater than or equal to 1/mm(2) was reported in 27.4%. The most common initial management was wide local excision with sentinel lymph node biopsy (55.7%). In all, 78 patients underwent sentinel lymph node biopsy with 41.0% positivity rate. A total of 32 patients underwent completion lymph node dissection with 34.4% positivity rate. Locoregional recurrence was reported in 15 patients, recurrence with distant metastases in 6 patients, and death in 5 patients.
LIMITATIONS: Data were obtained from small studies with limited follow-up. There is no universally accepted definition of animal-type melanoma.
CONCLUSION: Prospective studies with complete staging information and molecular profiling may allow further characterization of this tumor.

PMID: 26412164 [PubMed - indexed for MEDLINE]

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Label-free in vivo cellular-level detection and imaging of apoptosis

Cell death plays a critical role in health and homeostasis as well as in the pathogenesis and treatment of a broad spectrum of diseases and can be broadly divided into two main categories: apoptosis, or programmed cell death, and necrosis, or acute cell death. While these processes have been characterized extensively in vitro, label-free detection of apoptosis and necrosis at the cellular level in vivo has yet to be shown. In this study, for the first time, fluorescence lifetime imaging microscopy (FLIM) of intracellular reduced nicotinamide adenine dinucleotide (NADH) was utilized to assess the metabolic response of in vivo mouse epidermal keratinocytes following induction of apoptosis and necrosis. Results show significantly elevated levels of both the mean lifetime of NADH and the intracellular ratio of protein bound-to-free NADH in the apoptotic compared to the necrotic tissue. In addition, the longitudinal profiles of these two cell death processes show remarkable differences. By identifying and extracting these temporal metabolic signatures, apoptosis in single cells can be studied in native tissue environments within the living organism.

Apoptosis, or programmed cell death plays a critical role in health and homeostasis as well as in the treatment of many diseases. While this process has been characterized extensively in vitro, label-free detection of cells in vivo has yet to be shown. In this study, fluorescence lifetime imaging microscopy of reduced nicotinamide adenine dinucleotide is utilized to assess the metabolic response of in vivo mouse keratinocytes following induction of apoptosis.

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A novel multiphoton microscopy images segmentation method based on superpixel and watershed

Multiphoton microscopy (MPM) imaging technique based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) shows fantastic performance for biological imaging. The automatic segmentation of cellular architectural properties for biomedical diagnosis based on MPM images is still a challenging issue. A novel multiphoton microscopy images segmentation method based on superpixels and watershed (MSW) is presented here to provide good segmentation results for MPM images. The proposed method uses SLIC superpixels instead of pixels to analyze MPM images for the first time. The superpixels segmentation based on a new distance metric combined with spatial, CIE Lab color space and phase congruency features, divides the images into patches which keep the details of the cell boundaries. Then the superpixels are used to reconstruct new images by defining an average value of superpixels as image pixels intensity level. Finally, the marker-controlled watershed is utilized to segment the cell boundaries from the reconstructed images. Experimental results show that cellular boundaries can be extracted from MPM images by MSW with higher accuracy and robustness.

Processing procedure of the images segmentation method based on superpixels and watershed (MSW) segmentation algorithm for multiphoton microscopy image.

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Induction of neuronal activation by femtosecond-pulsed laser irradiation and its potential application for amyloid-β–induced toxicity assessment

Manipulating neural activity is crucial for studying the neural connectivity and the pathophysiology of neurodegenerative disease. Among various techniques for neural activation, direct optical stimulation method with femtosecond-pulsed laser is simple and can be specifically applied on a single neuron. Brief irradiation of femtosecond laser pulses on a neuron elevates intracellular calcium, and it propagates to adjacent neurons. However, the mechanisms of laser-induced neural activation are still unclear. In this report, we have elucidated the mechanism of laser-induced neural activation which could be mediated by superoxide, specifically blocked by diphenyleneiodonium chloride, and depletion in intracellular calcium storage. Furthermore, we also showed that the propagation of calcium initiated by laser stimulation is dependent on the presence of extracellular calcium as well as electrical and chemical synapses. We verified the applicability of such mechanism for the assessment of neuronal functionality, by measuring calcium elevation, intracellular calcium propagation, ROS increase, and performing cell death assay in vehicle and Aβ-treated neurons. This work suggests promising applications of the potential for implementing such laser-induced neural activation for rapid and reliable drug screening.

Direct optical stimulation at a neuron using femtosecond-pulsed laser can induce calcium elevation and ROS generation mediated by superoxide. We verified the applicability of such mechanism for the assessment of neuronal functionality in vehicle and Aβ-treated neurons. This work suggests promising applications of the potential for implementing such laser-induced neural activation for rapid and reliable drug screening.

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The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury.

The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury.

Oncotarget. 2016 Apr 13;

Authors: Yu AM, Calvo JA, Muthupalani S, Samson LD

Abstract
Much of the global cancer burden is associated with longstanding inflammation accompanied by release of DNA-damaging reactive oxygen and nitrogen species. Here, we report that the Mbd4 DNA glycosylase is protective in the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model of inflammation-driven colon cancer. Mbd4 excises T and U from T:G and U:G mismatches caused by deamination of 5-methylcytosine and cytosine. Since the rate of deamination is higher in inflamed tissues, we investigated the role of Mbd4 in inflammation-driven tumorigenesis. In the AOM/DSS assay, Mbd4-/- mice displayed more severe clinical symptoms, decreased survival, and a greater tumor burden than wild-type (WT) controls. The increased tumor burden in Mbd4-/- mice did not arise from impairment of AOM-induced apoptosis in the intestinal crypt. Histopathological analysis indicated that the colonic epithelium of Mbd4-/- mice is more vulnerable than WT to DSS-induced tissue damage. We investigated the role of the Mbd4-/- immune system in AOM/DSS-mediated carcinogenesis by repeating the assay on WT and Mbd4-/- mice transplanted with WT bone marrow. Mbd4-/- mice with WT bone marrow behaved similarly to Mbd4-/- mice. Together, our results indicate that the colonic epithelium of Mbd4-/- mice is more vulnerable to DSS-induced injury, which exacerbates inflammation-driven tissue injury and cancer.

PMID: 27086921 [PubMed - as supplied by publisher]

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Changes in cytochrome P450s-mediated drug clearance in patients with hepatocellular carcinoma in vitro and in vivo: a bottom-up approach.

Changes in cytochrome P450s-mediated drug clearance in patients with hepatocellular carcinoma in vitro and in vivo: a bottom-up approach.

Oncotarget. 2016 Apr 12;

Authors: Gao J, Zhou J, He XP, Zhang YF, Gao N, Tian X, Fang Y, Wen Q, Jia LJ, Jin H, Qiao HL

Abstract
Hepatocellular carcinoma (HCC) accompanied by severe liver dysfunction is a serious disease, which results in altered hepatic clearance. Generally, maintenance doses depend upon drug clearance, so individual dosage regimens should be customized for HCC patients based on the condition of patients. Based on clearance of CYP isoform-specific substrates at the microsomal level (CLM), microsomal protein per gram of liver (MPPGL), liver weight, hepatic blood flow, hepatic clearance values (CLH) for 10 CYPs in HCC patients (n=102) were extrapolated using a predictive bottom-up pharmacokinetic model. Compared with controls, the CLM values for CYP2C9, 2D6, 2E1 were significantly increased in HCC patients. Additionally, CYP1A2, 2C8, 2C19 CLM values decreased while the values for CYP2A6, 2B6, 3A4/5 were unchanged. The MPPGL values in HCC tissues were significantly reduced. CLH values of HCC patients for CYP1A2, 2A6, 2B6, 2C8, 2C19, and 3A4/5 were significantly reduced, while this for CYP2E1 were markedly increased and those for CYP2C9 and 2D6 did not change. Moreover, disease (fibrosis and cirrhosis) and polymorphisms of the CYP genes have influenced the CLH for some CYPs. Prediction of the effects of HCC on drug clearance may be helpful for the design of clinical studies and the clinical management of drugs in HCC patients.

PMID: 27086920 [PubMed - as supplied by publisher]

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Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies.

Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies.

Oncotarget. 2016 Apr 12;

Authors: Frampton AE, Krell J, Prado MM, Gall TM, Abbassi-Ghadi N, Del Vecchio Blanco G, Funel N, Giovannetti E, Castellano L, Basyouny M, Habib NA, Kaltsidis H, Vlavianos P, Stebbing J, Jiao LR

Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Novel biomarkers are required to aid treatment decisions and improve patient outcomes. MicroRNAs (miRNAs) are potentially ideal diagnostic biomarkers, as they are stable molecules, and tumour and tissue specific.
RESULTS: Logistic regression analysis revealed an endoscopic-ultrasound fine-needle aspiration (EUS-FNA) 2-miRNA classifier (miR-21 + miR-155) capable of distinguishing benign from malignant pancreatic lesions with a sensitivity of 81.5% and a specificity of 85.7% (AUC 0.930). Validation FNA cohorts confirmed both miRNAs were overexpressed in malignant disease, while circulating miRNAs performed poorly.
METHODS: Fifty-five patients with a suspicious pancreatic lesion on cross-sectional imaging were evaluated by EUS-FNA. At echo-endoscopy, the first part of the FNA was sent for cytological assessment and the second part was used for total RNA extraction. Candidate miRNAs were selected after careful review of the literature and expression was quantified by qRT-PCR. Validation was performed on an independent cohort of EUS-FNAs, as well as formalin-fixed paraffin embedded (FFPE) and plasma samples.
CONCLUSIONS: We provide further evidence for using miRNAs as diagnostic biomarkers for pancreatic malignancy. We demonstrate the feasibility of using fresh EUS-FNAs to establish miRNA-based signatures unique to pancreatic malignant transformation and the potential to enhance risk stratification and selection for surgery.

PMID: 27086919 [PubMed - as supplied by publisher]

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Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants.

Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants.

Oncotarget. 2016 Apr 12;

Authors: Chowdhury S, Veyhl J, Jessa F, Polyakova O, Alenzi A, MacMillan C, Ralhan R, Walfish PG

Abstract
Programmed death-ligand 1(PD-L1) expression on tumor cells is emerging as a potential predictive biomarker in anti-PD-L1 directed cancer immunotherapy. We analyzed PD-L1 expression in papillary thyroid carcinoma (PTC) and its variants and determined its prognostic potential to predict clinical outcome in these patients. This study was conducted at an academic oncology hospital which is a prime referral centre for thyroid diseases. Immunohistochemical subcellular localization (IHC) analyses of PD-L1 protein was retrospectively performed on 251 archived formalin fixed and paraffin embedded (FFPE) surgical tissues (66 benign thyroid nodules and 185 PTCs) using a rabbit monoclonal anti-PD-L1 antibody (E1L3N, Cell Signaling Technology) and detected using VECTASTAIN rapid protocol with diaminobenzidine (DAB) as the chromogen. The clinical-pathological factors and disease outcome over 190 months were assessed; immunohistochemical subcellular localization of PD-L1 was correlated with disease free survival (DFS) using Kaplan Meier survival and Cox multivariate regression analysis. Increased PD-L1 immunostaining was predominantly localized in cytoplasm and occasionally in plasma membrane of tumor cells. Among all combined stages of PTC, patients with increased PD-L1 membrane or cytoplasmic positivity had significantly shorter median DFS (36 months and 49 months respectively) as compared to those with PD-L1 negative tumors (DFS, both 186 months with p < 0.001 and p < 0.01 respectively). Comparison of PD-L1+ and PD-L1- patients with matched staging showed increased cytoplasmic positivity in all four stages of PTC that correlated with a greater risk of recurrence and a poor prognosis, but increased membrane positivity significantly correlated with a greater risk of metastasis or death only in Stage IV patients. In conclusion, PD-L1 positive expression in PTC correlates with a greater risk of recurrence and shortened disease free survival supporting its potential application as a prognostic marker for PTC.

PMID: 27086918 [PubMed - as supplied by publisher]

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Lapatinib-loaded human serum albumin nanoparticles for the prevention and treatment of triple-negative breast cancer metastasis to the brain.

Lapatinib-loaded human serum albumin nanoparticles for the prevention and treatment of triple-negative breast cancer metastasis to the brain.

Oncotarget. 2016 Apr 12;

Authors: Wan X, Zheng X, Pang X, Pang Z, Zhao J, Zhang Z, Jiang T, Xu W, Zhang Q, Jiang X

Abstract
Brain metastasis from triple-negative breast cancer (TNBC) has continued to lack effective clinical treatments until present. However, the feature of epidermal growth factor receptor (EGFR) frequently overexpressed in TNBC offers the opportunity to employ lapatinib, a dual-tyrosine kinase inhibitor of human epidermal growth factor receptor-2 (HER2) and EGFR, in the treatment of brain metastasis of TNBC. Unfortunately, the low oral bioavailability of lapatinib and drug efflux by blood-brain barrier have resulted in low drug delivery efficiency into the brain and limited therapeutic effects for patients with brain metastasis in clinical trials. To overcome such disadvantages, we developed lapatinib-loaded human serum albumin (HSA) nanoparticles, named LHNPs, by modified nanoparticle albumin-bound (Nab) technology. LHNPs had a core-shell structure and the new HSA/phosphatidylcholine sheath made LHNPs stable in bloodstream. Compared to free lapatinib, LHNPs could inhibit the adhesion, migration and invasion ability of high brain-metastatic 4T1 cells more effectively in vitro. Tissue distribution following intravenous administration revealed that LHNPs (i.v., 10 mg/kg) achieved increased delivery to the metastatic brain at 5.43 and 4.36 times the levels of Tykerb (p.o., 100 mg/kg) and lapatinib solution (LS, i.v., 10 mg/kg), respectively. Compared to the marketed Tykerb group, LHNPs had markedly better inhibition effects on brain micrometastasis and significantly extended the median survival time of 4T1 brain metastatic mice in consequence. The improved anti-tumor efficacy of LHNPs could be partly ascribed to down-regulating metastasis-related proteins. Therefore, these results clearly indicated that LHNPs could become a promising candidate for clinical applications against brain metastasis of TNBC.

PMID: 27086917 [PubMed - as supplied by publisher]

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Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells.

Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells.

Oncotarget. 2016 Apr 12;

Authors: Mukherjee N, Lu Y, Almeida A, Lambert K, Shiau CW, Su JC, Luo Y, Fujita M, Robinson WA, Robinson SE, Norris DA, Shellman YG

Abstract
MCL-1 (BCL-2 family anti-apoptotic protein) is responsible for melanoma's resistance to therapy. Cancer initiating cells also contribute to resistance and relapse from treatments. Here we examined the effects of the MCL-1 inhibitor SC-2001 in killing non melanoma-initiating-cells (bulk of melanoma), and melanoma-initiating-cells (MICs). By itself, SC-2001 significantly kills melanoma cells under monolayer conditions in vitro and in a conventional mouse xenograft model. However, even at high doses (10μM), SC-2001 does not effectively eliminate MICs. In contrast, the combination of SC-2001 with ABT-737 (a BCL-2/BCL-XL/BCL-W inhibitor) significantly decreases ALDH+ cells, disrupts primary spheres, and inhibits the self-renewability of MICs. These results were observed in multiple melanomas, including short term cultures of relapsed tumors from current treatments, independent of the mutation status of BRAF or NRAS. Using a low-cell-number mouse xenograft model, we examined the effects of these treatments on the tumor initiating ability of MIC-enriched cultures. The combination therapy reduces tumor formation significantly compared to either drug alone. Mechanistic studies using shRNA and the CRISPR-Cas9 technology demonstrated that the upregulation of pro-apoptotic proteins NOXA and BIM contribute to the combination-induced cell death. These results indicate that the MCL-1 inhibitor SC-2001 combined with ABT-737 is a promising treatment strategy for targeting melanoma.

PMID: 27086916 [PubMed - as supplied by publisher]

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The toxic effects and possible mechanisms of Bisphenol A on oocyte maturation of porcine in vitro.

The toxic effects and possible mechanisms of Bisphenol A on oocyte maturation of porcine in vitro.

Oncotarget. 2016 Apr 11;

Authors: Wang T, Han J, Duan X, Xiong B, Cui XS, Kim NH, Liu HL, Sun SC

Abstract
Bisphenol A (BPA) and Di-(2-ethylhexyl) phthalate (DEHP) are widely used in the plastic industry such as water bottles, containers, packaging and toys. BPA and DEHP are shown to be the endocrine disruptors which disturb the endocrine system and are linked to several diseases including infertility. In this study, we investigated the effects of BPA exposure on porcine oocyte maturation and its possible reasons. Our results showed that: (i) the rates of oocyte maturation significantly decreased with 250 μM BPA treatment in vitro, but not DEHP. This might be due to the delayed cell cycle progression of oocyte maturation. (ii) BPA treatment resulted in abnormal cytoskeletons on porcine oocytes, showing with aberrant actin distribution, spindle morphology and chromosome alignment, which was further confirmed by the reduced p-MAPK level. (iii) The fluorescence intensity of histone methylation (H3K4me2) and DNA methylation (5 mC) levels were altered after BPA treatment, indicating that epigenetic modification was disturbed. (iv) BPA-exposed oocytes had higher rates of early stage apoptosis/autophagy, and this may be resulted from the increased level of oxidative stress. Collectively, our results indicated that porcine oocytes maturation was disrupted after BPA treatment through disrupting cytoskeletal dynamics, epigenetic modifications and inducing apoptosis/autophagy.

PMID: 27086915 [PubMed - as supplied by publisher]

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The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor.

The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor.

Oncotarget. 2016 Apr 11;

Authors: Mohyeldin MM, Akl MR, Ebrahim HY, Dragoi AM, Dykes S, Cardelli JA, El Sayed KA

Abstract
The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) signaling axis has gained considerable attention as an attractive molecular target for therapeutic blockade of cancer. Inspired by the chemical structure of S (-)-oleocanthal, a natural secoiridoid from extra-virgin olive oil with documented anticancer activity against c-Met-dependent malignancies, the research presented herein reports on the discovery of the novel olive-derived homovanillyl sinapate (HVS) as a promising c-Met inhibitor. HVS was distinguished for its remarkable potency against wild-type c-Met and its oncogenic variant in cell-free assays and confirmed by in silico docking studies. Furthermore, HVS substantially impaired the c-Met-mediated growth across a broad spectrum of breast cancer cells, while similar treatment doses had no effect on the non-tumorigenic mammary epithelial cell growth. In addition, HVS caused a dose-dependent inhibition of HGF-induced, but not epidermal growth factor (EGF)-induced, cell scattering in addition to HGF-mediated migration, invasion, and 3-dimensional (3D) proliferation of tumor cell spheroids. HVS treatment effects were mediated via inhibition of ligand-mediated c-Met activation and its downstream mitogenic signaling and blocking molecular mediators involved in cellular motility across different cellular contexts. An interesting feature of HVS is its good selectivity for c-Met and Abelson murine leukemia viral oncogene homolog 1 (ABL1) when profiled against a panel of kinases. Docking studies revealed interactions likely to impart high dual affinity for both ABL1 and c-Met kinases. HVS markedly reduced tumor growth, showed excellent pharmacodynamics, and suppressed cell proliferation and microvessel density in an orthotopic model of triple negative breast cancer. Collectively, the present findings suggested that the oleocanthal-based HVS is a promising c-Met inhibitor lead entity with excellent therapeutic potential to control malignancies with aberrant c-Met activity.

PMID: 27086914 [PubMed - as supplied by publisher]

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Intratumoral expression of CCR3 in breast cancer is associated with improved relapse-free survival in luminal-like disease.

Intratumoral expression of CCR3 in breast cancer is associated with improved relapse-free survival in luminal-like disease.

Oncotarget. 2016 Apr 11;

Authors: Gong DH, Fan L, Chen HY, Ding KF, Yu KD

Abstract
PURPOSE: The association chemokine receptor CCR3 with breast cancer subtypes and relapse-free survival is unknown.
RESULTS: The overall expression (either intratumoral or peritumoral) of CCR3 was not associated with tumor size, lymph node status, age, and subtype. When we confined the analysis in samples without peritumoral stromal CCR3 expression, intratumoral expression of CCR3 was associated with breast cancer subtype (P=0.04). Tumors with high expression of CCR3 were more likely to be luminal-like rather than TNBC or HER2-enriched cancers. Moreover, high mRNA expression of CCR3 was related with improved relapse-free survival in luminal-A/B (P<0.001). The subsequent sensitivity analysis using the systemically untreated patients confirmed that higher mRNA expression of CCR3 was a robust prognostic factor for luminal-A (P=0.0025) and luminal-B (P=0.088), but not for HER2-enriched (P=0.21) and TNBC (P=0.86). In the independent cohort, the positive association between increased expression of CCR3 and improved distant relapse-free survival was also observed.
METHODS: We determined the expression level of CCR3 in 150 cases with breast cancer by using immunohistochemistry (IHC) assay, for both intratumoral and peritumoral stroma, and investigated the effect of CCR3 expression on relapse-free survival according to subtype using cases from publicly available datasets, in the whole group (N=3557) and in the patients without adjuvant systemic treatment (N=1005), respectively. Moreover, the survival outcomes were validated in another independent cohort including 508 breast cancer patients treated with neoadjuvant chemotherapy.
CONCLUSIONS: Our data indicate that intratumoral expression of CCR3 in breast cancer is associated with improved relapse-free survival in patients with luminal-like disease.

PMID: 27086913 [PubMed - as supplied by publisher]

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Comparative proteomics of exosomes secreted by tumoral Jurkat T cells and normal human T cell blasts unravels a potential tumorigenic role for valosin-containing protein.

Comparative proteomics of exosomes secreted by tumoral Jurkat T cells and normal human T cell blasts unravels a potential tumorigenic role for valosin-containing protein.

Oncotarget. 2016 Apr 11;

Authors: Bosque A, Dietz L, Gallego-Lleyda A, Sanclemente M, Iturralde M, Naval J, Alava MA, Martínez-Lostao L, Thierse HJ, Anel A

Abstract
We have previously characterized that FasL and Apo2L/TRAIL are stored in their bioactive form inside human T cell blasts in intraluminal vesicles present in multivesicular bodies. These vesicles are rapidly released to the supernatant in the form of exosomes upon re-activation of T cells. In this study we have compared for the first time proteomics of exosomes produced by normal human T cell blasts with those produced by tumoral Jurkat cells, with the objective of identify proteins associated with tumoral exosomes that could have a previously unrecognized role in malignancy. We have identified 359 and 418 proteins in exosomes from T cell blasts and Jurkat cells, respectively. Interestingly, only 145 (around a 40%) are common. The major proteins in both cases are actin and tubulin isoforms and the common interaction nodes correspond to these cytoskeleton and related proteins, as well as to ribosomal and mRNA granule proteins. We detected 14 membrane proteins that were especially enriched in exosomes from Jurkat cells as compared with T cell blasts. The most abundant of these proteins was valosin-containing protein (VCP), a membrane ATPase involved in ER homeostasis and ubiquitination. In this work, we also show that leukemic cells are more sensitive to cell death induced by the VCP inhibitor DBeQ than normal T cells. Furthermore, VCP inhibition prevents functional exosome secretion only in Jurkat cells, but not in T cell blasts. These results suggest VCP targeting as a new selective pathway to exploit in cancer treatment to prevent tumoral exosome secretion.

PMID: 27086912 [PubMed - as supplied by publisher]

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MiR-320a inhibits gastric carcinoma by targeting activity in the FoxM1-P27KIP1 axis.

MiR-320a inhibits gastric carcinoma by targeting activity in the FoxM1-P27KIP1 axis.

Oncotarget. 2016 Apr 11;

Authors: Wang Y, Zeng J, Pan J, Geng X, Li L, Wu J, Song P, Wang Y, Liu J, Wang L

Abstract
MicroRNAs (miRNAs) regulate tumorigenesis by inhibiting gene expression. In this study, we showed that miR-320a expression is decreased in human gastric cancer tissues and correlates inversely with expression of FoxM1, a key cell cycle regulator involved in gastric carcinoma. By contrast, the expression of P27KIP1, a downstream effector of FoxM1, correlates positively with miR-320a levels. Luciferase assays indicate that miR-320a suppresses FoxM1 expression, and in vitro recovery tests using FoxM1 siRNA indicate miR-320a inhibits gastric cancer cell proliferation by suppressing activity in the FoxM1-P27KIP1 axis. In vivo, nude mice injected with BGC-823 gastric cancer cells expressing a miR-320a inhibitor exhibit faster tumor growth than mice injected with control cells. Analysis of FoxM1 and P27KIP1 expression in tumor tissues indicates that miR-320a suppression increases the tumor growth by enhancing FoxM1-P27KIP1 signaling. These results thus reveal the crucial role played by miR-320a in limiting gastric carcinoma by directly targeting FoxM1- P27KIP1 axis.

PMID: 27086911 [PubMed - as supplied by publisher]

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This Month in Radiology.

This Month in Radiology.

Radiology. 2016 May;279(2):3A-4A

Authors:

PMID: 27089199 [PubMed - as supplied by publisher]

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Prediction of specialty coffee cup quality based on near infrared spectra of green coffee beans

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A review of the relationships between implication, negation and aggregation functions from the point of view of material implication

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No indications that zinc and protein source affect Zn bioavailability in sows during, late gestation fed adequate dietary Zn concentrations

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On the decomposition of stochastic cellular automata

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An efficient semi-analytical simulation for the Heston model

With splitting technique, a new semi-analytical scheme with predictable strong convergence order 1.0 is proposed for the transformed Heston model, where the variance process is displaced by the corresponding volatility process. The volatility process is decomposed into a linear SDE and an ODE, both of which have the analytical solution, but the SDE is simulated by the Euler method while the ODE is approximated analytically with a slight modification. Numerical tests show its high efficiency and accuracy in the simulation for the mean-reverting square root process.

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The gross anatomy of the renal sympathetic nerves revisited

Catheter-based renal denervation techniques focus on reducing blood pressure in resistant hypertension. This procedure requires exact knowledge of the anatomical interrelation between the renal arteries and the targeted renal nervous plexus. The aim of this work was to build on classical anatomical studies and describe the gross anatomy and anatomical relationships of the renal arteries and nerve supply to the kidneys in a sample of human cadavers. Twelve human cadavers (six males and six females), age range 73 to 94 years, were dissected. The nervous fibers and renal arteries were dissected using a surgical microscope. The renal plexus along the hilar renal artery comprised a fiber-ganglionic ring surrounding the proximal third of the renal artery, a neural network along the middle and distal thirds, and smaller accessory ganglia along the course of the nerve fibers. The fibers of the neural network were mainly located on the superior (95.83%) and inferior (91.66%) surfaces of the renal artery and they were sparsely interconnected by diagonal fibers. Polar arteries were present in 33.33% of cases and the renal nerve pattern for these was similar to that of the hilar arteries. Effective renal denervation needs to target the superior and inferior surfaces of the hilar and polar arteries, where the fibers of the neural network are present. Clin. Anat., 2016. © 2016 Wiley Periodicals, Inc.

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Cover Image

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Compatibility of fuzzy relations

The notion of extensionality, introduced by Hohle and Blanchard, and the notion of compatibility, as coined by Belohlavek, of a fuzzy relation with respect to a fuzzy equality are trivially equivalent. Here, this compatibility property is dissected into left and right compatibility, mimicking the original twofold definition of extensionality, and studied in detail in the context of arbitrary fuzzy relations. Relying on the notions of left and right traces of a fuzzy relation, it is shown that compatibility can be characterized in terms of inclusions, shedding another light on the matter.

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Further advances in lead carboxylate coatings: coating unprimed heritage lead

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A survey on fingerprint minutiae-based local matching for verification and identification: taxonomy and experimental evaluation

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A survey of fingerprint classification, part I: taxonomies on feature extraction methods and learning models

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A survey of fingerprint classification, part II: experimental analysis and ensemble proposal

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UNILATERAL VARIATION OF THE RENAL VEIN AND TESTICULAR VEIN - A CASE REPORT

2016-04-19T02-04-05Z
Source: International Journal of Current Research and Review
Veena Vidya Shankar, Snigdha Das.
Background: The right and left renal veins open into the inferior vena cava at right angle. The left renal vein is 3 times longer as compared to right. The right gonadal vein (testicular in male or ovarian in female) drains directly into inferior vena cava and left gonadal vein into left renal vein. Method: During the routine dissection teaching of posterior abdominal wall for first year MBBS students in the Department of Anatomy, MSRMC, Bangalore, we found the presence of double right renal veins along with variation in the termination of right testicular vein in an adult male cadaver aged 65 years. All the structures were carefully dissected, measurements noted and photographed using a digital camera. Observation: In the present case, two right renal veins (superior and inferior) were found to be draining into inferior vena cava separately and right testicular vein into inferior right renal vein Conclusion: This type of variation will help the radiologists for planning radiographic procedures; the surgeons for planning surgery to avoid intra and post-operative complications and the clinicians in recognition and protection of the variation..


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AN EPIDEMIOLOGICAL STUDY OF ROAD TRAFFIC ACCIDENT CASES AT A TERTIARY CARE HOSPITAL IN UDAIPUR

2016-04-19T02-04-05Z
Source: International Journal of Current Research and Review
Solanki S.L., Mittal Hemlata.
Background: In present century, road traffic injuries represent a major epidemic of non-communicable diseases. Road traffic accidents cause considerable economic loss to nation, victims, and society. The price we pay in terms of hospitalization of victims for longer duration, incurring disability and death. If the cause is probed, it would be possible to reduce its number, severity of injury and even the prevention of RTAs. Objectives: To study the various epidemiological factors associated with road traffic accidentcases. Materials and Methods: 400 road traffic accident cases were studied, at emergency unit of RNT Government medical college, Udaipur, during the period of July 2010 to December 2010. Results: Among the 400 study subjects, majority (81.0%) were males, while (19%) females, most of them (33.25%) were in age group of (15-25) years. The motorcyclist comprised (42.5%) of RTA cases, followed by (20.25%) of occupants of car and jeep. Fatal injury (death) was more common(27.56%) in cases of motorized vehicle followed by the pedestrians (10.40%). Among 252 drivers majority (85.71%) were male and (32.94%) of them were not having driving licence. Highest RTAs (33.14%) occurred in drivers who had driving licence issued within two years. Nearly half (49.25%) of RTA cases took place between 5 PM to 9 PM and a good number of drivers(20.23%) reported that they were fatigued at the time of accident. Conclusion: Road traffic accident is a major public health problem which needs to accelerate the efforts of road safety preventive measures.


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EFFECT OF SUPPLEMENTATION OF KADIPATTA AND NEEM LEAF POWDER ON NUTRITIONAL QUALITY OF EGG

2016-04-19T02-04-05Z
Source: International Journal of Current Research and Review
Khushboo Rishishwar, Anshu Rahal.
Nowadays herbs are used in poultry diet as feed additive. In present trial the effect of supplementing tree leaves on egg quality was studied. One hundred twenty white leghorn layers were selected, divided randomly and subjected to six treatments. Eggs collected were analyzed for nutrient composition and quality. Egg protein content increased and significant differences were found in cholesterol and low density lipoprotein. Neem and/or Kadipatta leaves @0.5% can be used in poultry diet.


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EFFECTS OF VITAMIN-D AND SUNLIGHT ON THE HEMATO-BIOCHEMICAL PARAMETERS IN MICE

2016-04-19T02-04-05Z
Source: International Journal of Current Research and Review
Muhammad Rakibul Hasan, Md. Kamrul Islam, Md. Ziaul Haque.
Moderate exposure to sunlight increases vitamin-D status in the body and vitamin-D helps in absorption of calcium from intestine. This study was aimed to investigate the efficacy of vitamin-D and sunlight on blood parameters and serum biochemistry in mice. For this purpose, 50 adult Swiss albino mice were collected and randomly divided into five equal groups (Group A, B, C, D and E). Group A was considered as control and fed only on balanced normal feed. Group B was supplied with 15% butter in feed as a semi-synthetic source of vitamin-D, group C was exposed to direct sunlight (1.5 hours daily) and group D and E were supplied with oral synthetic form of vitamin-D @ 50 IU and 100 IU daily, respectively. After 120 days, blood and serum samples were collected for analysis. Our results showed that total erythrocytes count (TEC) and total leukocytes count (TLC) were found higher in group D but insignificant. Lymphocytes were significantly (P


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SIMULATING THE ACTIVITY OF VINCRISTIN (AN ANTICANCEROUS DRUG) WITH BIOGENIC NANOPARTICLES USING VIGNA RADIATASEEDS

2016-04-19T02-04-05Z
Source: International Journal of Current Research and Review
Himakshi Bhati Kushwaha, C. P. Malik.
Background: The present study reports the inhibitory effects of biogenic nanoparticles synthesized from Tridax procumbens stem (fresh and powder) aqueous extract on seed germination and seedling growth of Vigna radiata. These synthesized nanoparticles were well characterized by UV-visible spectroscopy; SEM; XRD and FTIR analysis. The constituents in the extract were also well characterized using FTIR analysis. The cytotoxic propertiesof the biogenic nanoparticles were then compared with the individual aqueous extract and vincristin (an anti-cancerous drug- used for ease in cancer.). The inhibition of seed germination and seedling growth was found to be dose-dependent and was suitable to quantify the bioactivity of biogenic nanoparticles preparations. Objective: The present investigation, emphasizes on simulating the activity of the synthesized biogenic nanoparticles from T. procumbens withan anticancerous drug vincristine using in vitro bioassay system (Kumar and Singhal, 2009). The growth promotion and/or retardation activity of crude plant extractis also described. Method:After reviewing number of peer-reviewed published articles the safest and eco-friendly method for the synthesis of the nanoparticles had been adopted. Biogenic nanoparticles were later well characterized by SEM, XRD, and FTIR analysis. Their activity against anticancerous drug vincristine, was tested using an in vitro bioassay on Vigna radiata. Results: Present study brings out the role of biogenic nanoparticles in inhibiting seed germination which was dose dependent. With vincristin comparable inhibition was observed. The plant extract, bionanoparticles and vincristin, promoted water imbibitions by the seeds though their higher concentrations inhibited this process. Reduction in water imbibitions, caused by these failed to trigger processes leading to reduced seed germination and radicle decay. The growth retardation following these treatments could be attributed to the inhibition of cell division and radicle protrusion brought about by osmotic stress (de Castro et al., 2000). From these observations it could be safely inferred that the plant extracts exhibited effective inhibitory activity, though biogenic nanoparticles and vincristin were most effective at 1.0 and 2.0 mg ml-1. Conclusion: Biogenic nanoparticles are eco-friendly, cost effective, and rapidly synthesized, and hence are more acceptable than the anti-cancerous drugs available in the market. The latter have side effects, cost issues, toxic chemicals involved in their synthesis, storage complexities, etc. The present study opens new avenue for medical sciences where plant extract synthesized nanoparticles via green route can be the safer alternative than synthetic anti-cancerous products.


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KNOWLEDGE OF QUALIFIED PARAMEDICAL STAFFS IN UNDERSTANDING THE SYMPTOMATOLOGY AND HORMONAL REPLACEMENT THERAPY IN MENOPAUSE

2016-04-19T02-04-05Z
Source: International Journal of Current Research and Review
Umakant Valvekar, S. Viswanathan.
Background: Menopause is a hormonal depletion state which may lead to psychosomatic condition where it needs psychological support by family members. Most menopausal women go untreated. It is better to have physicians advice in some cases for normal life style. The awareness of menopause and hormonal replacement therapy (HRT) was low among paramedical staff. Methodology: A survey was conducted in 34 women paramedical staff members of Karpaga Vinayaga Institute of Medical Sciences and Research Centre, Tamil Nadu, India. The survey was about the knowledge of women paramedical staff in understanding vasomotor, psychosocial, physical, sexual changes and hormonal replacement therapy (HRT) in menopausal women. The study subjects were divided into two groups as menopausal group (group A) and premenopausal group (group B) consists of 17 subjects in each group. Results: In the present study most menopausal group (group A) women answered that they had experienced hot flushes, insomnia, psychological disturbances, bloated feeling as major symptoms. In this survey most of the paramedical women staff members of menopausal group replied that there was a decrease in the sexual interest in them and they felt natural approaches are better than replacement therapy. Whereas majority of women from premenopausal group (group B) opinioned that sexual interest does not decrease even after menopause. However, they expressed similar opinion as that of menopausal women for the natural approach of menopause is better than hormonal replacement therapy. Conclusion: Awareness of the menopause and HRT is low even among the paramedical staffs. This clearly suggests that there is need to change the attitude of a common woman towards menopause. This can be done by conducting awareness programs on menopause and hormonal replacement therapy (HRT) to paramedical staffs and general public.


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DOES BODY MASS INDEX EFFECT NERVE CONDUCTION? A CROSS SECTIONAL STUDY

2016-04-19T02-04-05Z
Source: International Journal of Current Research and Review
Vineeta Chadha, Surendra S. Shivalkar.
Aim: Body mass index (BMI) is an important parameter in gauging adiposity and obesity. Many studies have shown higher incidence of cardiovascular diseases especially coronary artery diseases in population with BMI greater than 25. (1) Studies also reveal median and ulnar nerve compression associated with an increasing incidence of higher BMI. (2) This study is an attempt to establish a relationship between median nerve conduction parameters and BMI in a population group from a metropolitan city in urban India. Methodology: In the present study the effect of Body Mass Index (BMI) on Median nerve motor and sensory conduction latency, amplitude and velocity was analysed in 90 healthy people in the age group of 18-30 years. Standardized protocol was followed while performing nerve conduction study in all the subjects. Results: This study shows that sensory nerve conduction amplitude decreases significantly with increase in BMI whereas the effect on other parameters is non-significant. Conclusion: This could be attributed to attenuation in conduction current by thicker subcutaneous tissue in persons with higher BMI. Median nerve latency and conduction velocity do not show significant decrease. This could be due to the fact that speed of conduction is same in the fastest conducting fibres irrespective of the adiposity..


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Non-contact diagnostic system for sleep apnea–hypopnea syndrome based on amplitude and phase analysis of thoracic and abdominal Doppler radars

Abstract

Full-night polysomnography (PSG) has been recognized as the gold standard test for sleep apnea–hypopnea syndrome (SAHS). However, PSG examinees are physically restrained for the full night by many contact sensors and obtrusive connecting cables, inducing mental stress. We developed a non-contact SAHS diagnostic system that can detect apneic events without inducing stress in monitored individuals. Two Doppler radars were installed beneath the mattress to measure the vibrations of the chest and abdomen, respectively. Our system determines apnea and hypopnea events when the radar output amplitude decreases by <20 and 70 %, respectively, of the amplitude of a normal breath (without SAHS events). Additionally, we proposed a technique that detects paradoxical movements by focusing on phase differences between thoracic and abdominal movements, and were able to identify three types of sleep apnea: obstructive, central, and mixed. Respiratory disturbance indexes obtained showed a higher correlation (r = 94 %) with PSG than with pulse oximetry (r = 89 %). When predicting the severity of SAHS with an apnea–hypopnea index (AHI) of >15/h or >30/h using PSG as a reference, the radar system achieved a sensitivity of 96 and 90 %, and a specificity of 100 and 79 % with an AHI of >15/h and >30/h, respectively. The proposed radar system can be used as an alternative to the current airflow sensor, and to chest and abdomen belts for apnea–hypopnea evaluation.

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BARDET BEIDL SYNDROME - A RARE PLEIOTROPIC DISORDER

2016-04-19T02-04-05Z
Source: International Journal of Current Research and Review
Sonia Jaiswal, Navbir Pasricha, Prashant Bhargava.
Background: BardetBiedl Syndrome is a disorder with a pleiotropic gene action on multiple phenotypic traits and thus a wide range of clinical variability is seen within and between families. Bardet Beidl Syndrome is characterized by rod cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypo-gonadotrophic hypogonadism, complex female genitourinary malformations and renal abnormalities. Case Presentation: A one day old male child came to the Outpatient department of a private clinic. The case presented with polydactyly, absence of hard palate due to failure of fusion of bilateral premaxillary segments and macular grade corneal opacity as examined by an ophthalmologist. Conclusion: The diagnosis of Bardet Beidl syndrome (BBS) is established by clinical findings. According to studies by Beales et al in 1999 and 2001, diagnosis is confirmed with the presence of three primary features and two secondary features. An interpretation of the molecular pathogenesis with a thorough research into therapeutics may bring about new treatment options for the organ specific disorders of Bardet Beidl Syndrome.


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An alternative approach to approximate entropy threshold value ( r ) selection: application to heart rate variability and systolic blood pressure variability under postural challenge

Abstract

This study presents an alternative approach to approximate entropy (ApEn) threshold value (r) selection. There are two limitations of traditional ApEn algorithm: (1) the occurrence of undefined conditional probability (CP_u) where no template match is found and (2) use of a crisp tolerance (radius) threshold 'r'. To overcome these limitations, CP_u is substituted with optimum bias setting ɛ _opt which is found by varying ɛ from (1/N − m) to 1 in the increments of 0.05, where N is the length of the series and m is the embedding dimension. Furthermore, an alternative approach for selection of r based on binning the distance values obtained by template matching to calculate ApEn_bin is presented. It is observed that ApEn_max, ApEn_chon and ApEn_bin converge for ɛ _opt = 0.6 in 50 realizations (n = 50) of random number series of N = 300. Similar analysis suggests ɛ _opt = 0.65 and ɛ _opt = 0.45 for 50 realizations each of fractional Brownian motion and MIX(P) series (Lu et al. in J Clin Monit Comput 22(1):23–29, 2008). ɛ _opt = 0.5 is suggested for heart rate variability (HRV) and systolic blood pressure variability (SBPV) signals obtained from 50 young healthy subjects under supine and upright position. It is observed that (1) ApEn_bin of HRV is lower than SBPV, (2) ApEn_bin of HRV increases from supine to upright due to vagal inhibition and (3) ApEn_bin of BPV decreases from supine to upright due to sympathetic activation. Moreover, merit of ApEn_bin is that it provides an alternative to the cumbersome ApEn_max procedure.

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fMRat: an extension of SPM for a fully automatic analysis of rodent brain functional magnetic resonance series

Abstract

The purpose of this study was to develop a multi-platform automatic software tool for full processing of fMRI rodent studies. Existing tools require the usage of several different plug-ins, a significant user interaction and/or programming skills. Based on a user-friendly interface, the tool provides statistical parametric brain maps (t and Z) and percentage of signal change for user-provided regions of interest. The tool is coded in MATLAB (MathWorks^®) and implemented as a plug-in for SPM (Statistical Parametric Mapping, the Wellcome Trust Centre for Neuroimaging). The automatic pipeline loads default parameters that are appropriate for preclinical studies and processes multiple subjects in batch mode (from images in either Nifti or raw Bruker format). In advanced mode, all processing steps can be selected or deselected and executed independently. Processing parameters and workflow were optimized for rat studies and assessed using 460 male-rat fMRI series on which we tested five smoothing kernel sizes and three different hemodynamic models. A smoothing kernel of FWHM = 1.2 mm (four times the voxel size) yielded the highest t values at the somatosensorial primary cortex, and a boxcar response function provided the lowest residual variance after fitting. fMRat offers the features of a thorough SPM-based analysis combined with the functionality of several SPM extensions in a single automatic pipeline with a user-friendly interface. The code and sample images can be downloaded from http://ift.tt/1VA9sIR.

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Electrical resistance of human soft tissue sarcomas: an ex vivo study on surgical specimens

Abstract

This paper presents a study about electrical resistance, which using fixed electrode geometry could be correlated to the tissue resistivity, of different histological types of human soft tissue sarcomas measured during electroporation. The same voltage pulse sequence was applied to the tumor mass shortly after surgical resection by means of a voltage pulse generator currently used in clinical practice for electrochemotherapy that uses reversible electroporation. The voltage pulses were applied by means of a standard hexagonal electrode composed by seven, 20-mm-long equispaced needles. Irrespective of tumor size, the electrode applies electric pulses to the same volume of tissue. The resistance value was computed from the voltage and current recorded by the pulse generator, and it was correlated with the histological characteristics of the tumor tissue which was assessed by a dedicated pathologist. Some differences in resistance values, which could be correlated to a difference in tissue resistivity, were noticed according to sarcoma histotype. Lipomatous tumors (i.e., those rich in adipose tissue) displayed the highest resistance values (up to 1700 Ω), whereas in the other soft tissue sarcomas, such as those originating from muscle, nerve sheath, or fibrous tissue, the electrical resistance measured was between 40 and 110 Ω. A variability in resistance was found also within the same histotype. Among lipomatous tumors, the presence of myxoid tissue between adipocytes reduced the electrical resistance (e.g., 50–100 Ω). This work represents the first step in order to explore the difference in tissue electrical properties of STS. These results may be used to verify whether tuning electric field intensity according to the specific STS histotype could improve tissue electroporation and ultimately treatment efficacy.

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Biomechanical evaluation of the pathophysiologic developmental mechanisms of mitral valve prolapse: effect of valvular morphologic alteration

Abstract

Mitral valve prolapse (MVP) refers to an excessive billowing of the mitral valve (MV) leaflets across the mitral annular plane into the left atrium during the systolic portion of the cardiac cycle. The underlying mechanisms for the development of MVP and mitral regurgitation in association with MV tissue remodeling are still unclear. We performed computational MV simulations to investigate the pathophysiologic developmental mechanisms of MVP. A parametric MV geometry model was utilized for this study. Posterior leaflet enlargement and posterior chordal elongation models were created by adjusting the geometry of the posterior leaflet and chordae, respectively. Dynamic finite element simulations of MV function were performed over the complete cardiac cycle. Computational simulations demonstrated that enlarging posterior leaflet area increased large stress concentration in the posterior leaflets and chordae, and posterior chordal elongation decreased leaflet coaptation. When MVP was accompanied by both posterior leaflet enlargement and chordal elongation simultaneously, the posterior leaflet was exposed to extremely large prolapse with a substantial lack of leaflet coaptation. These data indicate that MVP development is closely related to tissue alterations of the leaflets and chordae. This biomechanical evaluation strategy can help us better understand the pathophysiologic developmental mechanisms of MVP.

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Computer-assisted liver tumor surgery using a novel semiautomatic and a hybrid semiautomatic segmentation algorithm

Abstract

We developed a medical image segmentation and preoperative planning application which implements a semiautomatic and a hybrid semiautomatic liver segmentation algorithm. The aim of this study was to evaluate the feasibility of computer-assisted liver tumor surgery using these algorithms which are based on thresholding by pixel intensity value from initial seed points. A random sample of 12 patients undergoing elective high-risk hepatectomies at our institution was prospectively selected to undergo computer-assisted surgery using our algorithms (June 2013–July 2014). Quantitative and qualitative evaluation was performed. The average computer analysis time (segmentation, resection planning, volumetry, visualization) was 45 min/dataset. The runtime for the semiautomatic algorithm was <0.2 s/slice. Liver volumetric segmentation using the hybrid method was achieved in 12.9 s/dataset (SD ± 6.14). Mean similarity index was 96.2 % (SD ± 1.6). The future liver remnant volume calculated by the application showed a correlation of 0.99 to that calculated using manual boundary tracing. The 3D liver models and the virtual liver resections had an acceptable coincidence with the real intraoperative findings. The patient-specific 3D models produced using our semiautomatic and hybrid semiautomatic segmentation algorithms proved to be accurate for the preoperative planning in liver tumor surgery and effectively enhanced the intraoperative medical image guidance.

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Biomechanical model of knee collateral ligament injury with six degrees of freedom

Abstract

Knee ligament injuries cannot be fully described using simplified joint models or by experimentation alone. The study objective was to model the contributions of the collateral ligaments over six degrees of freedom (DOF) of knee joint articulation to aid the diagnosis of knee ligament injuries. A kinematic model of the knee joint with six DOF was developed using the Musculoskeletal Joint Modeller software, and the effects of medial collateral ligament (MCL) and lateral collateral ligament (LCL) rupture were evaluated. The centres of mass of the tibia and femur were determined from their surface geometry, and the displacement of the moving tibia was determined by measuring the displacements of the attached ligaments with respect to its centre of mass. Compared to an intact knee, a tibia without the LCL had higher medial translation and lower valgus rotation, while a tibia without the MCL had higher lateral translation and higher valgus rotation. At 0°, 30° and 60° of flexion, the tibia without the LCL had more internal rotation than an intact knee. Understanding the complete kinematics of knee joints may improve the diagnosis of ligament injuries and guide tissue replacement surgery. Predicting joint behaviour in the clinic after treatment might benefit from a combined modelling approach that includes both clinicians and basic researchers.

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Estimation of dynamic metabolic activity in micro-tissue cultures from sensor recordings with an FEM model

Abstract

We estimated the dynamic cell metabolic activity and the distribution of the pH value and oxygen concentration in tissue samples cultured in vitro by using real-time sensor records and a numerical simulation of the underlying reaction–diffusion processes. As an experimental tissue model, we used chicken spleen slices. A finite element method model representing the biochemical processes and including the relevant sensor data was set up. By fitting the calculated results to the measured data, we derived the spatiotemporal values of the pH value, the oxygen concentration and the absolute metabolic activity (extracellular acidification and oxygen uptake rate) of the samples. Notably, the location of the samples in relation to the sensors has a great influence on the detectable metabolic rates. The long-term vitality of the tissue samples strongly depends on their size. We further discuss the benefits and limitations of the model.

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Finite element study on the anatomic transtibial technique for single-bundle anterior cruciate ligament reconstruction

Abstract

The anatomic transtibial (TT) technique is proposed as a new approach for single-bundle anterior cruciate ligament (ACL) reconstruction. Geometric models of the anatomic TT and anteromedial (AM) portal techniques were fabricated with a reconstructed knee joint model and virtual surgical operations. Grafts of 7 mm diameter were modeled and inserted into tunnels drilled in each model. In the models, the shape of the graft between the femur and the tibia, the lengths of the bone tunnels, and the femoral graft bending angles were evaluated. To evaluate the biomechanical effects of both techniques on the grafts, the contact pressures and maximum principal stresses in the grafts were calculated using the finite element method. The anatomic TT technique placed the femoral tunnel to the anatomic position of the native ACL femoral attachment site. In addition, it decreased the peak contact pressure and the maximum principal stress at the full extension position of the graft compared with the AM portal technique. The anatomic TT technique may be regarded as a superior surgical technique compared with the conventional TT and AM portal techniques. Because of the easy surgical operation involved, the technique decreases the operation time for ACL reconstruction and it provides a deformation behavior of grafts similar to that in the native ACL in a knee joint. With its few side effects, the anatomic TT technique may considerably help patients.

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Hybrid stent device of flow-diverting effect and stent-assisted coil embolization formed by fractal structure

Abstract

This paper presents a novel hybrid medical stent device. This hybrid stent device formed by fractal mesh structures provides a flow-diverting effect and stent-assisted coil embolization. Flow-diverter stents decrease blood flow into an aneurysm to prevent its rupture. In general, the mesh size of a flow-diverter stent needs to be small enough to prevent blood flow into the aneurysm. Conventional flow-diverter stents are not available for stent-assisted coil embolization, which is an effective method for aneurysm occlusion, because the mesh size is too small to insert a micro-catheter for coil embolization. The proposed hybrid stent device is capable of stent-assisted coil embolization while simultaneously providing a flow-diverting effect. The fractal stent device is composed of mesh structures with fine and rough mesh areas. The rough mesh area can be used to insert a micro-catheter for stent-assisted coil embolization. Flow-diverting effects of two fractal stent designs were composed to three commercially available stent designs. Flow-diverting effects were analyzed using computational fluid dynamics (CFD) analysis and particle image velocimetry (PIV) experiment. Based on the CFD and PIV results, the fractal stent devices reduce the flow velocity inside an aneurism just as much as the commercially available flow-diverting stents while allowing stent-assisted coil embolization.

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A new device combining mechanical stimulation of plantar sole and Achilles’ tendon to alleviate the consequences of muscle deconditioning

Abstract

Limb immobilization or confinement to bed results in a severe atrophy and weakness of lower leg muscles. Full recovery of muscle strength and physical function is rare and may impact the patient's outcome. Studies performed on rodents have demonstrated that the deleterious structural and functional adaptations which occur during muscle deconditioning can be counteracted through adequate physiological stimuli. Thus, based on this fundamental work, we developed a device that combines mechanical stimulation of proprioceptors located in the plantar sole and Achilles' tendon. The device is adapted to patients immobilized and confined to bed. Stimulations can be applied on muscle in passive state. The protocol is non-invasive and is well accepted by patients. This paper presents the technical features of the device, as well as preliminary results of the first clinical study. This device might allow considering new therapeutic strategies for prevention of atrophy in many pathologies.

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Acute effects of ethanol on action potential and intracellular Ca 2+ transient in cardiac ventricular cells: a simulation study

Abstract

Alcohol consumption may result in electrocardiographic changes and arrhythmias, at least partly due to effects of ethanol on cardiac ionic currents. Contractility and intracellular Ca²⁺ dynamics seem to be altered as well. In this study, we integrated the available (mostly animal) experimental data into previously published models of the rat and human ventricular myocytes to assess the share of ionic current components in ethanol-induced changes in AP configuration and cytosolic Ca²⁺ transient in ventricular cardiomyocytes. The rat model reproduced well the experimentally observed changes in AP duration (APD) under ethanol (slight prolongation at 0.8 mM and shortening at ≥8 mM). These changes were almost exclusively caused by the ethanol-induced alterations of I _K1. The cytosolic Ca²⁺ transient decreased gradually with the increasing ethanol concentration as a result of the ethanol-induced inhibition of I _Ca. In the human model, ethanol produced a dose-dependent APD lengthening, dominated by ethanol effect on I _Kr, the key repolarising current in human ventricles. This effect might contribute to the clinically observed proarrhythmic effects of ethanol in predisposed individuals.

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