A possible link between KCNQ2- and STXBP1-related encephalopathies: STXBP1 reduces the inhibitory impact of syntaxin-1A on M current

Summary

Objective

Kv7 channels mediate the voltage-gated M-type potassium current. Reduction of M current due to KCNQ2 mutations causes early onset epileptic encephalopathies (EOEEs). Mutations in STXBP1 encoding the syntaxin binding protein 1 can produce a phenotype similar to that of KCNQ2 mutations, suggesting a possible link between STXBP1 and Kv7 channels. These channels are known to be modulated by syntaxin-1A (Syn-1A) that binds to the C-terminal domain of the Kv7.2 subunit and strongly inhibits M current. Here, we investigated whether STXBP1could prevent this inhibitory effect of Syn-1A and analyzed the consequences of two mutations in STXBP1 associated with EOEEs.

Methods

Electrophysiologic analysis of M currents mediated by homomeric Kv7.2 or heteromeric Kv7.2/Kv7.3 channels in Chinese hamster ovary (CHO) cells coexpressing Syn-1A and/or STXBP1 or mutants STXBP1 p.W28* and p.P480L. Expression and interaction of these different proteins have been investigated using biochemical and co-immunoprecipitation experiments.

Results

Syn-1A decreased M currents mediated by Kv7.2 or Kv7.2/Kv7.3 channels. STXBP1 had no direct effects on M current but dampened the inhibition produced by Syn-1A by abrogating Syn-1A binding to Kv7 channels. The mutation p.W28*, but not p.P480L, failed to rescue M current from Syn-1A inhibition. Biochemical analysis showed that unlike the mutation p.W28*, the mutation p.P480L did not affect STXBP1 expression and reduced the interaction of Syn-1A with Kv7 channels.

Significance

These data indicate that there is a functional link between STXBP1 and Kv7 channels via Syn-1A, which may be important for regulating M-channel activity and neuronal excitability. They suggest also that a defect in Kv7 channel activity or regulation could be one of the consequences of some STXBP1 mutations associated with EOEEs. Furthermore, our data reveal that STXBP1 mutations associated with the Ohtahara syndrome do not necessarily result in protein haploinsufficiency.

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Treatment of hemorrhagic head and neck lesions by direct puncture and nBCA embolization

Life-threatening bleeding in the head and neck region requires urgent management. These hemorrhagic lesions, for example, a ruptured pseudoaneurysm, are often treated by transarterial embolization (TAE), but prior intervention or surgery, inflammation, anatomic variants, and vessel tortuosity may render an endovascular approach challenging, time-consuming, and sometimes impossible. We report two cases of severe head and neck hemorrhages successfully embolized with n-butyl cyanoacrylate via direct puncture, and propose this approach as a fast, safe, and effective alternative to TAE.

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BioEssays 11∕2017

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BioEssays 11∕2017

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BioEssays 11∕2017

The ability to survive desiccation is a rare, but widespread trait found in at least some organisms within every kingdom of life. An enigmatic group of proteins, intrinsically disordered proteins (IDPs), have emerged as hallmarks of desiccation tolerance. As discussed by Boothby and Pielak in article number 1700119, how IDPs mediate survival during drying is unknown, but uncovering their mechanism(s) of protection is essential for understanding this enigmatic phenomenon.

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BioEssays 11d∕2017

The Golgi ribbon Structure regulates a range of cellular networks: The cover shows a super-resolution microscopic image of a HeLa cell stained with markers for the trans-Golgi network (green) and cis-Golgi (red) and nucleus (blue) which demonstrates the Golgi apparatus as a continuous ribbon structure in interphase cells. In article 1700063, Prajakta Gosavi and Paul Gleeson discuss recent studies which recognize a role for the Golgi ribbon structure in regulating a range of higher order cellular process and that fragmentation of this Golgi ribbon structure, which is associated with a number of pathological conditions, perturbs these processes.

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BioEssays – Next Issue

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Correlation of Circulating CD64 + /CD163 + Monocyte Ratio and stroma/peri-tumoral CD163 + Monocyte Density with Human Papillomavirus Infected Cervical Lesion Severity

Abstract

HPV infected cervical cells secrete mediators that are gradually changed and have influence on infiltrating M2 phenotypic monocytes in cervical lesions. However, profiles of circulating immune cells in women with cervical lesions and M2 phenotypic monocyte activity in HPV infected cervical lesions are limited. This study aimed to investigate circulating monocyte populations correlated with M2 phenotype density and its activity in HPV infected cervical lesions. HPV DNA was investigated in cervical tissues using PCR. High risk HPV E6/E7 mRNA was detected using in situ hybridization. CD163 immunohistochemical staining was performed for M2 macrophage. CD163 and Arg1 mRNA expression were detected using real-time PCR. Circulating monocyte subpopulations were analyzed using flow cytometry. CD163 and Arg1 mRNA expression were increased according to cervical lesion severity and corresponding with density of M2 macrophage in HSIL and SCC in stroma and peri-tumoral areas. Additionally, the relationship between M2 macrophage infiltration and high risk HPV E6/E7 mRNA expression was found and corresponded with cervical lesion severity. Circulating CD14⁺CD16⁺ and CD14⁺CD163⁺ monocytes were elevated in No-SIL and cervical lesions. Interestingly, CD14⁺CD64⁺ monocyte was greatly elevated in HSIL and SCC, whereas intracellular IL-10⁺ monocytes were not significantly different between cervical lesions. The correlation between increasing ratio of circulating CD64⁺/CD163⁺ monocyte and density of infiltrating CD163⁺ monocytes was associated with severity of HPV infected cervical lesions. The elevated circulating CD64⁺/CD163⁺ monocyte ratio correlates to severity of HPV infected cervical lesions and might be a prognostic marker in cervical cancer progression.

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RELA fusion-positive anaplastic ependymoma: molecular characterization and advanced MR imaging

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Simple, mild, one-step labelling of proteins with gallium-68 using a tris(hydroxypyridinone) bifunctional chelator: a 68 Ga-THP-scFv targeting the prostate-specific membrane antigen

Abstract

Background

Labelling proteins with gallium-68 using bifunctional chelators is often problematic because of unsuitably harsh labelling conditions such as low pH or high temperature and may entail post-labelling purification. To determine whether tris(hydroxypyridinone) (THP) bifunctional chelators offer a potential solution to this problem, we have evaluated the labelling and biodistribution of a THP conjugate with a new single-chain antibody against the prostate-specific membrane antigen (PSMA), an attractive target for staging prostate cancer (PCa). A single-chain variable fragment (scFv) of J591, a monoclonal antibody that recognises an external epitope of PSMA, was prepared in order to achieve biokinetics matched to the half-life of gallium-68. The scFv, J591c-scFv, was engineered with a C-terminal cysteine.

Results

J591c-scFv was produced in HEK293T cells and purified by size-exclusion chromatography. A maleimide THP derivative (THP-mal) was coupled site-specifically to the C-terminal cysteine residue. The THP-mal-J591c-scFv conjugate was labelled with ammonium acetate-buffered gallium-68 from a ⁶⁸Ge/⁶⁸Ga generator at room temperature and neutral pH. The labelled conjugate was evaluated in the PCa cell line DU145 and its PSMA-overexpressing variant in vitro and xenografted in SCID mice.

J591c-scFv was produced in yields of 4–6 mg/l culture supernatant and efficiently coupled with the THP-mal bifunctional chelator. Labelling yields > 95% were achieved at room temperature following incubation of 5 μg conjugate with gallium-68 for 5 min without post-labelling purification. ⁶⁸Ga-THP-mal-J591c-scFv was stable in serum and showed selective binding to the DU145-PSMA cell line, allowing an IC50 value of 31.5 nM to be determined for unmodified J591c-scFv. Serial PET/CT imaging showed rapid, specific tumour uptake and clearance via renal elimination. Accumulation in DU145-PSMA xenografts at 90 min post-injection was 5.4 ± 0.5%ID/g compared with 0.5 ± 0.2%ID/g in DU145 tumours (n = 4).

Conclusions

The bifunctional chelator THP-mal enabled simple, rapid, quantitative, one-step room temperature radiolabelling of a protein with gallium-68 at neutral pH without a need for post-labelling purification. The resultant gallium-68 complex shows high affinity for PSMA and favourable in vivo targeting properties in a xenograft model of PCa.

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Repression of Middle Sporulation Genes in Saccharomyces cerevisiae by the Sum1-Rfm1-Hst1 Complex Is Maintained by Set1 and H3K4 Methylation

The conserved yeast histone methyltransferase Set1 targets H3 lysine 4 (H3K4) for mono-, di- and tri-methylation and is linked to active transcription due to the euchromatic distribution of these methyl marks and the recruitment of Set1 during transcription. However, loss of Set1 results in increased expression of multiple classes of genes, including genes adjacent to telomeres and middle sporulation genes, which are repressed under normal growth conditions because they function in meiotic progression and spore formation. The mechanisms underlying Set1-mediated gene repression are varied and still unclear in some cases, although repression has been linked to both direct and indirect action of Set1, associated with noncoding transcription and often dependent on the H3K4me2 mark. We show that Set1, and particularly the H3K4me2 mark, are implicated in repression of a subset of middle sporulation genes during vegetative growth. In the absence of Set1, there is loss of the DNA-binding transcriptional regulator Sum1 and the associated histone deacetylase Hst1 from chromatin in a locus-specific manner. This is linked to increased H4K5ac at these loci and aberrant middle gene expression. These data indicate that, in addition to DNA sequence, histone modification status also contributes to proper localization of Sum1. In addition, our results show that the role for Set1 in middle gene expression control diverges as cells receive signals to undergo meiosis. Overall, this work dissects an unexplored role for Set1 in gene-specific repression and provides important insights into a new mechanism associated with the control of gene expression linked to meiotic differentiation.

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Mapping Second Chromosome Mutations to Defined Genomic Regions in Drosophila melanogaster

Hundreds of Drosophila melanogaster stocks are currently maintained at the Bloomington Drosophila Stock Center with mutations that have not been associated with sequence-defined genes. They have been preserved because they have interesting loss-of-function phenotypes. The experimental value of these mutations would be increased by tying them to specific genomic intervals so that geneticists can more easily associate them with annotated genes. Here we report the mapping of 86 second chromosome complementation groups in the Bloomington collection to specific, small clusters of contiguous genes or individual genes in the sequenced genome. This information should prove valuable to Drosophila geneticists interested in processes associated with particular phenotypes and those searching for mutations affecting specific sequence-defined genes.

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The immunoproteasome subunit LMP7 is required in the murine thymus for filling up a hole in the T cell repertoire

Abstract

Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine-inducible variant of the proteasome which has been implicated in regulating inflammatory responses and antigen presentation. In the thymus, medullary thymic epithelial cells (mTECs) and cortical thymic epithelial cells (cTECs) do express different proteasome subunits exerting chymotrypsin-like activities suggesting distinct functions in thymic T cell selection. Employing the lymphocytic choriomeningitis virus (LCMV) infection model, we could show that the immunoproteasome subunit LMP7 was absolutely required for the generation of LCMV GP_118-125-specific T cells although the class I mediated presentation of GP_118-125 was not dependent on LMP7. Using bone marrow chimeras and adoptive transfer of LMP7-deficient CD8⁺ T cells into RAG1-deficient mice we show that LMP7-deficient mice lacked GP_118-125-specific T cell precursors and that LMP7 was required in radioresistant cells – most likely thymic epithelial cells - to enable their selection. Since LMP7 is strongly expressed in negatively selecting mTECs but barely in positively selecting cTECs our data suggest that LMP7 was required to avoid excessive negative selection of GP_118-125-specific T cell precursors. Taken together, this study demonstrates that the immunoproteasome is a crucial factor for filling up holes within the cytotoxic T cell repertoire.

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Myc binding protein 2 suppresses M2-like phenotypes in macrophages during zymosan-induced inflammation in mice

Abstract

MYCBP2 is an E3 ubiquitin ligase, which is well characterized as a key element in the inhibition of neuronal growth, synapse formation and synaptic strength by regulating several signaling pathways. Although MYCBP2 was suspected to be expressed also in immune cells, to date nothing is known about its role in inflammation. We used Multi-epitope ligand cartography (MELC), a method for multiple sequential immunohistology, to show that MYCBP2 is strongly expressed in monocyte-derived macrophages during zymosan-induced inflammation. We generated a myeloid-specific knockout mouse and found that loss of MYCBP2 in myeloid cells reduced nociceptive (painful) behavior during the resolution phase (1-3 days after zymosan injection). Quantitative MELC analyses and flow cytometric analysis showed an increased number of CD206-expressing macrophages in the inflamed paw tissue. Fittingly, CD206 and arginase 1 expression was upregulated in MYCBP2-deficient bone marrow-derived macrophages after polarization with IL10 or IL4. The regulation of protein expression in these macrophages by MYCBP2 varied depending on the polarization signal. The increased IL10-induced CD206 expression in MYCBP2-deficient macrophages was mediated by p38 MAPK, while IL4-induced CD206 expression in MYCBP2-deficient macrophages was mediated by protein kinase A.

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Chemical profiling of primary mesothelioma cultures defines subtypes with different expression profiles and clinical responses

Finding new treatment options for patients with malignant pleural mesothelioma is challenging due to the rarity and heterogeneity of this cancer type. The absence of druggable targets further complicates the development of new therapies. Current treatment options are therefore limited and prognosis remains poor. Experimental Design: We performed drug screening on primary mesothelioma cultures to guide treatment decisions of corresponding patients that were progressive after first or second line treatment. Results: We observed a high concordance between in vitro results and clinical outcomes. We defined three subgroups responding differently to the anti-cancer drugs tested. In addition, gene expression profiling yielded distinct signatures that segregated the differently responding subgroups. These genes signatures involved various pathways, most prominently the fibroblast growth factor pathway. Conclusions: Our primary mesothelioma culture system has proved to be suitable to test novel drugs. Chemical profiling of primary mesothelioma cultures allows personalizing treatment for a group of patients with a rare tumor type, where clinical trials are notoriously difficult. This personalized treatment strategy is expected to improve the poor prospects of mesothelioma patients.

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Tumor microvessel density as a prognostic marker in high-risk renal cell carcinoma patients treated on ECOG-ACRIN E2805

Purpose: Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis, however its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC. Methods: We obtained pre-treatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence we measured tumor MVD as the area of CD34-expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm and clinicopathologic variables. Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (p=0.021) and for patients treated with placebo (p=0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p=0.060). MVD was not associated with DFS (p=1.00). On multivariable analysis, MVD remained independently associated with improved OS (p=0.013). High MVD correlated with Fuhrman grade 1-2 (p<0.001), clear cell histology (p<0.001), and absence of necrosis (p<0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size. Conclusions:High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high risk patients for adjuvant therapy trials.

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PQR309 is a novel dual PI3K/mTOR inhibitor with pre-clinical antitumor activity in lymphomas as a single agent and in combination therapy

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types and pharmacological inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models. Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene expression profiling and comparison with other signaling inhibitors. Results: PQR309 had in vitro anti-lymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib and rituximab. Sensitivity to PQR309 was associated with specific baseline gene expression features, such as high expression of transcripts coding for BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene expression signatures induced by PQR309 and of other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib. Conclusions: Based on these results, PQR309 appeared as a novel and promising compound being worthwhile developing in the lymphoma setting.

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Molecular subtypes of pulmonary large cell neuroendocrine carcinoma predict chemotherapy treatment outcome

Purpose: Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the RB1 mutated (mostly co-mutated with TP53) and the RB1 wild-type groups. We assessed if these subtypes have a predictive value on chemotherapy outcome. Experimental Design: Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for TP53, RB1, STK11, and KEAP1 genes, as well as immunohistochemistry (IHC) for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression free survival (PFS), stratifying for non-small cell lung cancertype chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE). Results: RB1 mutation and protein loss were detected in 47% (n=37) and 72% (n=78) of the cases, respectively. RB1 wild-type LCNEC patients treated with NSCLC-GEM/TAX had a significantly longer OS (9.6 [95% CI 7.7-11.6] months) than those treated with SCLC-PE (5.8 [5.5-6.1]; P=0.026). Similar results were obtained for patients expressing RB1 in their tumors P=0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an RB1 mutation or lost RB1 protein. Conclusions: Patients with LCNEC tumors that carry a wild-type RB1 gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for RB1 mutated or with lost protein expression.

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Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Letter

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Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Response

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CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells

The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL-2 and expression of co-inhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNγ production by responder CD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within non-invaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNγ, TNF, IL-2 and high expression of co-inhibitory receptors. Although T cell receptor engagement was sufficient to induce CD39 on human CD8+ T cells, exposure to IL-6 and IL-27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8+ T cells, with implications for defining a biomarker of T cell dysfunction and a target for immunotherapeutic intervention.

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CBX8 exhibits oncogenic activity via AKT/{beta}-Catenin activation in hepatocellular carcinoma

Deregulation of Polycomb proteins influences the development and progression of hepatocellular carcinoma (HCC). Here we show that chromobox 8 (CBX8) expression is increased in HCC and correlates with poor outcome in two independent cohorts containing a total of 879 cases. Ectopic expression of CBX8 facilitated tumor growth and metastasis, whereas CBX8 silencing suppressed these effects. CBX8 efficiently activated AKT/β-catenin signaling via upregulation of the transcription factor EGR1 and miR-365-3p in a non-canonical manner: CBX8 directly bound the EGR1 promoter to enhance its activity. In the nucleus, CBX8 also interacted with EGR1 to prevent its degradation. Furthermore, CBX8 increased the transcription of miR-365a-3p, which promoted the nuclear localization of β-catenin by targeting the 3'-UTR ZNRF1. Inhibiting either EGR1 or miR-365a-3p partially rescued CBX8-mediated malignant phenotypes. In clinical samples, CBX8 expression closely correlated with EGR1, miR-365a-3p and nuclear β-catenin. Collectively, our results show that CBX8 functions as an oncogene to upregulate EGR1 and miR-365-3p to stimulate the AKT/β-catenin pathway. This newly identified signaling axis may suggest new therapeutic strategies against HCC.

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Comparative transcriptome analysis quantifies immune cell transcript levels, metastatic progression and survival in osteosarcoma

Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of inter-tumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103) and dogs (n=34) were generated using RNA-sequencing. Conserved inter-tumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) to quantify inter-tumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA). Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients.

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A subpopulation of stromal cells controls cancer cell homing to the bone marrow

Breast and prostate cancer cells home to the bone marrow where they presumably hijack the hematopoietic stem cell niche. We characterize here the elusive premetastatic niche by examining the role of mesenchymal stromal cells (MSC) in cancer cell homing. Decreasing the number of MSC pharmacologically enhanced cancer cell homing to the bone marrow in mice. In contrast, increasing the number of these MSC by various interventions including G-CSF administration diminished cancer cell homing. The MSC subpopulation that correlated best with cancer cells expressed stem, endothelial, and pericytic cell markers suggesting these cells represent an undifferentiated component of the niche with vascular commitment. In humans, a MSC subpopulation carrying markers for endothelial and pericytic cells was lower in the presence of cytokeratin+ cells in bone marrow. Taken together, our data show that a subpopulation of MSC with both endothelial and pericytic cell surface markers suppresses the homing of cancer cells to the bone marrow. Similar to the presence of cytokeratin+ cells in the bone marrow, this mesenchymal stromal cell subpopulation could prove useful in determining the risk of metastatic disease, and its manipulation might offer a new possibility for diminishing bone metastasis formation.

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Evidence for Kaposi's Sarcoma originating from Mesenchymal Stem Cell through KSHV-induced Mesenchymal-to-Endothelial Transition

The major transmission route for Kaposi's sarcoma-associated herpesvirus (KSHV) infection is the oral cavity through saliva. Kaposi's sarcoma (KS) frequently occurs in the oral cavity in HIV-positive individuals and is often the first presenting sign of AIDS. However, the oral target cells for KSHV infection and the cellular origin of KS remain unknown. Here we present clinical and experimental evidences that KS spindle cells may originate from virally modified oral mesenchymal stem cells (MSC). AIDS-KS spindle cells expressed neuroectodermal stem cell marker (Nestin) and oral MSC marker CD29, suggesting an oral/craniofacial MSC lineage of AIDS-associated KS. Furthermore, oral MSC were highly susceptible to KSHV infection, and infection promoted multi-lineage differentiation and mesenchymal-to-endothelial transition (MEndT). KSHV infection of oral MSCs resulted in expression of a large number of cytokines, a characteristic of KS, and upregulation of KS signature and MEndT-associated genes. These results suggest that KS may originate from pluripotent MSC and KSHV infection transforms MSC to KS-like cells through MEndT.

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Geographical distance and local environmental conditions drive the genetic population structure of a freshwater microalga (Bathycoccaceae; Chlorophyta) in Patagonian lakes

Abstract

The patterns and mechanisms underlying the genetic structure of microbial populations remain unresolved. Herein we investigated the role played by two non-mutually exclusive models (i.e. isolation by distance and isolation by environment) in shaping the genetic structure of lacustrine populations of a microalga (a freshwater Bathycoccaceae) in the Argentinean Patagonia. To our knowledge, this was the first study to investigate the genetic population structure in a South American microorganism. Population-level analyses based on ITS1–5.8S-ITS2 sequences revealed high levels of nucleotide and haplotype diversity within and among populations. Fixation index and a spatially explicit Bayesian analysis confirmed the occurrence of genetically distinct microalga populations in Patagonia. Isolation by distance and isolation by environment accounted for 38.5% and 17.7% of the genetic structure observed, respectively, whereas together these models accounted for 41% of the genetic differentiation. While our results highlighted isolation by distance and isolation by environment as important mechanisms in driving the genetic population structure of the microalga studied, none of these models (either alone or together) could explain the entire genetic differentiation observed. The unexplained variation in the genetic differentiation observed could be the result of founder events combined with rapid local adaptations, as proposed by the monopolisation hypothesis.

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Obinutuzumab Effective in Follicular Lymphoma, but at a Cost [News in Brief]

Anti-CD20 antibody outperforms rituximab—although side effects more frequent, serious.

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Making Bryostatin 1 through Smart Chemistry [News in Brief]

Scientists devise scalable synthesis of a difficult-to-harvest natural compound, paving the way for further clinical studies.

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In Vitro Antibacterial Activity of Pomegranate Juice and Peel Extracts on Cariogenic Bacteria

Aim. To evaluate the antimicrobial activity of hydroalcoholic extracts of pomegranate (Punica granatum L.) peel and juice, against the microorganisms considered the main etiologic agents of dental caries. Methods. The values of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined against Streptococcus mutans Clarke ATCC® 25175™ strain and Rothia dentocariosa clinical isolate. Results. Peel extracts inhibit effectively the growth and survival of S. mutans ATCC 25175 strain and R. dentocariosa clinical isolate with MIC and MBC values of 10 μg/μl and 15 μg/μl, respectively. Furthermore, the pomegranate juice extract showed high inhibitory activity against S. mutans ATCC 25175 strain with a MIC value of 25 μg/μl and a MBC value of 40 μg/μl, whereas, against R. dentocariosa, it has displayed a moderate inhibitory activity, with MIC and MBC values of 20 μg/μl and 140 μg/μl, respectively. Conclusions. In vitro microbiological tests demonstrate that the hydroalcoholic extracts of pomegranate juice and peel are able to contrast the main cariogenic bacteria involved in tooth decay. Although being preliminary data, our results suggest that pomegranate polyphenolic compounds could represent a good adjuvant for the prevention and treatment of dental caries.

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Neovascular Prostate-Specific Membrane Antigen Expression Is Associated with Improved Overall Survival under Palliative Chemotherapy in Patients with Pancreatic Ductal Adenocarcinoma

Aims. Expression of PSMA (prostate-specific membrane antigen) has been demonstrated in various cancers, including pancreatic ductal adenocarcinoma (PDAC). However, PSMA expression in PDAC-associated neovasculature has so far not been systematically analyzed. Methods and Results. We analyzed PSMA expression in 81 PDAC tissue samples from 61 patients. Microvessel density (MVD) was assessed by software-based image analysis and showed a mean MVD of 63.7 microvessels/0.785 mm2. PSMA was practically absent in tumor tissue (5.3%) and PDAC cell lines (0/7) but could be detected in tumor-associated neovasculature in 53.2% of cases. There was no association between neovascular PSMA expression and clinicopathological tumor characteristics. Samples with PSMA+ neovasculature showed increased MVD; however, this result was not statistically significant (). Presence of PSMA+ neovessels correlated with overall survival under palliative chemotherapy (894 versus 400 days; HR 0.42; 95% CI: 0.12 to 0.87; ). Conclusion. PSMA expression in tumor-associated neovasculature is a common feature and associated with improved overall survival under palliative chemotherapy in PDAC. Our results point towards a possible association between PSMA expression and response to therapy which might be based on enhanced intratumoral bioavailability of systemic chemotherapy.

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Barriers to Physical Activity in Low Back Pain Patients following Rehabilitation: A Secondary Analysis of a Randomized Controlled Trial

Background. Promoting health-enhancing physical activity following rehabilitation is a well-known challenge. This study analysed the barriers to leisure time activity among low back pain patients. Methods. A subset of 192 low back pain patients who participated in a randomized controlled trial promoting physical activity was analysed. Physical activity, barriers, and sociodemographic and indication-related variables were assessed by a questionnaire. Differences in barriers between active and inactive participants were tested by Pearson's chi squared test. A logistic regression model was fitted to identify influencing factors on physical activity at six months following rehabilitation. Results. Inactive and active participants differed significantly in nine of the 19 barriers assessed. The adjusted regression model showed associations of level of education (OR = 5.366 [1.563; 18.425]; value = 0.008) and fear of pain (OR = 0.612 [0.421; 0.889]; value = 0.010) with physical activity. The barriers included in the model failed to show any statistically significant association after adjustment for sociodemographic factors. Conclusions. Low back pain patients especially with a low level of education and fear of pain seem to need tailored support in overcoming barriers to physical activity. This study is registered at German Clinical Trials Register (DRKS00004878).

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Effect of incubation duration, growth temperature, and abiotic surface type on cell surface properties, adhesion and pathogenicity of biofilm-detached Staphylococcus aureus cells

The goal of this study was to investigate the effect of growth conditions such as the temperature (20, 30 and 37 °C), incubation duration (24 and 48 h) and surface type (stainless steel and polycarbonate) on t...

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Responses of zinc recovery to temperature and mineral composition during sphalerite bioleaching process

Temperature and energy resources (e.g., iron, sulfur and organic matter) usually undergo dynamic changes, and play important roles during industrial bioleaching process. Thus, it is essential to investigate th...

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Global sagittal alignment

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Magnetic resonance cinematography of the fingers: a 3.0 Tesla feasibility study with comparison of incremental and continuous dynamic protocols

Abstract

Objective

To study the feasibility of magnetic resonance cinematography of the fingers (MRCF) with comparison of image quality of different protocols for depicting the finger anatomy during motion.

Materials and methods

MRCF was performed during a full flexion and extension movement in 14 healthy volunteers using a finger-gating device. Three real-time sequences (frame rates 17–59 images/min) and one proton density (PD) sequence (3 images/min) were acquired during incremental and continuous motion. Analyses were performed independently by three readers. Qualitative image analysis included Likert-scale grading from 0 (useless) to 5 (excellent) and specific visual analog scale (VAS) grading from 0 (insufficient) to 100 (excellent). Signal-to-noise calculation was performed. Overall percentage agreement and mean absolute disagreement were calculated.

Results

Within the real-time sequences a high frame-rate true fast imaging with steady-state free precession (TRUFI) yielded the best image quality with Likert and overall VAS scores of 3.0 ± 0.2 and 60.4 ± 25.3, respectively. The best sequence regarding image quality was an incremental PD with mean values of 4.8 ± 0.2 and 91.2 ± 9.4, respectively. Overall percentage agreement and mean absolute disagreement were 47.9 and 0.7, respectively. No statistically significant SNR differences were found between continuous and incremental motion for the real-time protocols.

Conclusion

MRCF is feasible with appropriate image quality during continuous motion using a finger-gating device. Almost perfect image quality is achievable with incremental PD imaging, which represents a compromise for MRCF with the drawback of prolonged scanning time.

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Browser’s notes

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Intermetatarsal bursa primary synovial chondromatosis: case report and review of the literature

Abstract

Primary synovial chondromatosis is a benign neoplastic process, occurring mostly in large joints, more rarely in tendon sheaths, and extremely uncommonly in bursae. We describe a patient with primary synovial chondromatosis arising in the fourth intermetatarsal bursa. Knowledge of the bursal anatomy of the forefoot, and of characteristic imaging findings and the pathogenesis of synovial chondromatosis, is essential in including this uncommon entity in the differential when occurring in unusual locations.

http://ift.tt/2yMygru

Magnetic resonance imaging patterns of mononeuropathic denervation in muscles with dual innervation

Abstract

Magnetic resonance imaging (MRI) of mononeuropathy in muscles with dual innervation depicts geographic denervation corresponding to the affected nerve. Knowledge of the normal distribution of a muscle's neural supply is clinically relevant as partial muscle denervation represents a potential imaging pitfall that can be confused with other pathology, such as muscle strain. This article reviews the normal innervation pattern of extremity muscles with dual supply, providing illustrative examples of mononeuropathy affecting such muscles.

http://ift.tt/2y5kkVO

Scaphoid fracture: Bone marrow edema detected with dual-energy CT virtual non-calcium images and confirmed with MRI

Abstract

We aimed to determine whether bone marrow edema (BME) in acute traumatic scaphoid fracture could be demonstrated with dual-energy CT (DECT) using MRI as the gold standard. In recent years, virtual non-calcium (VNCa) images have been used to demonstrate BME in trauma cases, for example, in vertebral compression fractures, hip trauma to detect occult fractures and knee fractures. We present three cases of acute scaphoid trauma. Two patients had subtle or invisible fractures on x-ray and conventional CT images, while DECT VNCa images clearly visualized the BME, which was confirmed by MRI. One patient had negative findings on both VNCa and MRI images. The DECT VNCa algorithm is a promising technique to demonstrate BME in scaphoid fractures, with potential for increasing the diagnostic value of CT in this type of injury.

http://ift.tt/2yMfQa4

High-resolution 3-T MRI of the triangular fibrocartilage complex in the wrist: injury pattern and MR features

Abstract

Objectives

To investigate if using high-resolution 3-T MRI can identify additional injuries of the triangular fibrocartilage complex (TFCC) beyond the Palmer classification.

Materials and methods

Eighty-six patients with surgically proven TFCC injury were included in this study. All patients underwent high-resolution 3-T MRI of the injured wrist. The MR imaging features of TFCC were analyzed according to the Palmer classification.

Results

According to the Palmer classification, 69 patients could be classified as having Palmer injuries (52 had traumatic tears and 17 had degenerative tears). There were 17 patients whose injuries could not be classified according to the Palmer classification: 13 had volar or dorsal capsular TFC detachment and 4 had a horizontal tear of the articular disk.

Conclusion

Using high-resolution 3-T MRI, we have not only found all the TFCC injuries described in the Palmer classification, additional injury types were found in this study, including horizontal tear of the TFC and capsular TFC detachment. We propose the modified Palmer classification and add the injury types that were not included in the original Palmer classification.

http://ift.tt/2y4g6xv

Bilateral multifocal lower extremity localized soft tissue amyloidomas: case report with ultrasonographic characterization

Abstract

Amyloidosis may be acquired or hereditary and consists of multiple disease processes characterized by the abnormal deposition of extracellular fibrillary protein aggregates. The presentation of amyloidosis is varied, ranging from an isolated, focal deposition to systemic disease. While systemic involvement is common, a rare entity known as amyloidoma or tumor amyloidosis may also occur. The 75-year-old female in this case presented with slowly growing multifocal bilateral lower extremity masses and was ultimately diagnosed with localized amyloidomas in the absence of chronic illness or systemic disease. This case report includes a description of the sonographic features of localized extremity amyloidoma that, to the best of our knowledge, have not yet been described in the literature. Awareness of the sonographic features, and this unique presentation of multifocal soft tissue extremity amyloidomas will allow for this rare diagnosis to be included in a limited differential diagnosis.

http://ift.tt/2yM3Nd1

Isolated atrophy of the abductor digiti quinti in patients with rheumatoid arthritis

Abstract

Objective

We aim to discuss the association of isolated atrophy of the abductor digiti quinti muscle in patients with rheumatoid arthritis as well as review the anatomy and imaging findings of this condition on MRI.

Materials and methods

A consecutive series of 55 patients diagnosed with rheumatoid arthritis according to the 2010 ACR/EULAR classification criteria were recruited. MRI of the clinically dominant feet was performed using a 1.5-T scanner.

Results

The study population was predominantly female (94.5%), and the age range was 31–79 years (mean 57.5 ± 11). A total of 55 ankles were examined by MRI, and 20 patients (36.3%), all females, showed abductor digiti quinti denervation signs. Seven patients demonstrated severe fatty atrophy of the abductor digiti quinti, corresponding to Goutallier grade 4, 2 patients showed moderate fatty atrophy (Goutallier grade 3), and the remaining 11 patients showed less than 50% fatty atrophy, corresponding to a Goutallier grade 2. Substantial agreement was found for both intra- and interobserver agreement regarding the Goutallier grading system.

Conclusion

Prevalence of signs of abductor digiti quinti denervation on MRI was high in the studied population, suggesting that rheumatoid arthritis may be associated with inferior calcaneal nerve compression.

http://ift.tt/2y4g0pU

Case report of a novel nonsyndromic unilateral syndactyly of the hand

Abstract

Syndactyly is a cutaneous and/or bony digital malformation with possible webbing of adjacent fingers or toes and uni- or bilateral occurrence. We report an 84-year old woman with a novel non-syndromic congenital malformation of her left hand. Clinical examination showed that she only had four digits. Radiograph of the hand revealed synostosis of the second and third proximal phalanx, resulting in a triangular shaped bone with relatively normal articulations at both ends. The phalangeal base of the fused finger tapers distally and is broader than the middle phalangeal bases of the ring and little finger. This malformation does not fit in any of the known types of syndromic or non-syndromic syndactylies. Our case report highlights that radiological imaging is crucial for identification of bony syndactyly and correct classification of a given syndactyly. Knowledge of the different types of syndactylies is important because certain malformations may occur as a defining part of a syndromic disease.

http://ift.tt/2y4OJ6z

Association of lunate morphology, sex, and lunotriquetral interosseous ligament injury with radiologic measurement of the capitate-triquetrum joint

Abstract

Objective

Radiologic presentation of carpal instability at the radial side of the carpus, e.g. scapholunate diastasis following scapholunate interosseous ligament injury, has been studied extensively. By comparison, presentation at the ulnar-sided carpus has not. The purpose of this study was to assess the effects of lunate morphology, sex, and lunotriquetral interosseous ligament (LTIL) status on the radiologic measurement of the capitate-triquetrum joint (C-T distance). Further, we sought to evaluate the diagnostic accuracy of C-T distance for assessing LTIL injuries.

Materials and methods

We retrospectively identified 223 wrists with wrist radiographs and MR arthrograms with contrast injection. Data collected included sex, lunate morphology and LTIL status from MR arthrography, and C-T distance from radiography. The effects of lunate morphology, sex, and LTIL injury status on C-T distance were evaluated using generalized linear models. Diagnostic performance of C-T distance was assessed by the area under receiver-operator characteristic curve (AUROC).

Results and conclusion

Lunate morphology, sex, and LTIL injury status all had significant effects on C-T distance; wrists with type II lunates, men, and wrists with LTIL injuries had greater C-T distances than wrists with type I lunates, women, and wrists without LTIL injuries, respectively (p < 0.01). The diagnostic value of the C-T distance for identifying patients with full-thickness LTIL tears was sufficient for women with type I (AUROC = 0.67) and type II lunates (0.60) and good for men with type I (0.72) and type II lunates (0.77). The demonstrated influence of LTIL status on C-T distance supports the use of C-T distance as a tool in assessing for full-thickness LTIL tears.

http://ift.tt/2yMv1QN

Cystic degeneration of the tibial nerve: magnetic resonance neurography and sonography appearances of an intraneural ganglion cyst

Abstract

Extra- and intraneural ganglion cysts have been described in the literature. The tibial nerve ganglion is uncommon and its occurrence without intra-articular extension is atypical. The pathogenesis of cystic degeneration localized to connective and perineural tissue secondary to chronic mechanical irritation or idiopathic mucoid degeneration is hypothesized. Since the above pathology is extremely rare and the magnetic resonance imaging examination detects the defining characteristics of the intrinsic alterations of the tibial nerve, the authors illustrate such a case of tibial intaneural ganglion cyst with its magnetic resonance neurography and sonography appearances.

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The glenoid track: a review of the clinical relevance, method of calculation and current evidence behind this method

Abstract

In the setting of bipolar bone injury, orthopedic surgeons are currently making use of the glenoid track method to guide surgical management. Using preoperative CT or MR imaging, this method allows the identification of patients who are more likely to fail a primary capsuloligamentous Bankart repair. As the glenoid track method becomes increasingly used in preoperative planning, it is important for the radiologist to become familiar with its concept and method of calculation. This review article aims to concisely summarize the current literature and the clinical implications of the glenoid track method.

http://ift.tt/2yM6s6d

Negative magnetic resonance imaging in three cases of anterior tibial cortex stress fractures

Abstract

Anterior mid-tibial cortex stress fractures (ATCSF) are uncommon and notoriously challenging to treat. They are termed high risk due to their predilection to prolonged recovery, nonunion and complete fracture. Early diagnosis is essential to avoid progression and reduce fracture complications. Imaging plays a key role in confirming the diagnosis. Magnetic resonance imaging (MRI) is accepted as the gold standard modality due to its high accuracy and nonionizing properties. This report describes three cases of ATCSFs in recreational athletes who had positive radiographic findings with no significant MRI changes. Two athletes had multiple striations within their tibias. Despite the radiographic findings, their severity of symptoms were low with mild or no tenderness on examination. Clinicians should be mindful that the ATCSFs may not present with typical acute stress fracture symptoms. We recommend that plain radiographs should be used as the first line investigation when suspecting ATCSFs. Clinicians should be aware that despite MRI being considered the gold standard imaging modality, we report three cases where the MRI was unremarkable, whilst radiographs and computed tomography confirmed the diagnosis. We urge clinicians to continue to use radiographs as the first line imaging modality for ATCSFs and not to directly rely on MRI. Those who opt directly for MRI may be falsely reassured causing a delay in diagnosis.

http://ift.tt/2y4gjRo

The influence of epidural catheter on the incidence of intravascular injection during caudal block

Abstract

Objective

The aim of this study was to analyze the influence of epidural catheters on the incidence of intravascular injection and to identify possible predictors of intravascular injection in patients undergoing a caudal block using fluoroscopy.

Methods

A total of 154 patients scheduled to receive a caudal block were randomized into group N (those without epidural catheter) or group C (those with epidural catheter). Demographic and clinical data were recorded and analyzed.

Results

The incidence of intravascular injection was 15.6% in group N, 6.5% in group C, and 11.0% overall, without statistical differences between the two groups (P = 0.105). Univariate analysis revealed that blood at hub (P = 0.047) and positive aspiration test (P = 0.045) were more frequently observed in group N than in group C. Quality of analgesia was significantly higher in group C than in group N (P = 0.029). Multivariate analysis identified older age (P = 0.024), blood at hub (P = 0.003), and positive aspiration test (P = 0.001) as predictors of intravascular injection.

Conclusions

In this study, while the incidence of intravascular injection during caudal blocks was less frequent with epidural catheter use, it was not statistically significant. However, a caudal block using an epidural catheter provided a lower incidence of blood at hub, fewer positive aspiration tests, and superiority in pain improvement.

http://ift.tt/2yMpSrQ

Surgical considerations when reporting MRI studies of soft tissue sarcoma of the limbs

Abstract

Soft tissue sarcomas (STS) are rare tumours that require prompt diagnosis and treatment at a specialist centre. Magnetic resonance imaging (MRI) has become the modality of choice for identification, characterisation, biopsy planning and staging of soft tissue masses. MRI enables both the operating surgeon and patient to be optimally prepared prior to surgery for the likelihood of margin-negative resection and to anticipate possible sacrifice of adjacent structures and consequent loss of function. The aim of this review is to aid the radiologist in performing and reporting MRI studies of soft tissue sarcomas, with particular reference to the requirements of the surgical oncologist.

http://ift.tt/2yMhTLu

Magnetic resonance imaging at primary diagnosis cannot predict subsequent contralateral slip in slipped capital femoral epiphysis

Abstract

Objective

Prophylactic fixation of the contralateral hip in slipped capital femoral epiphysis (SCFE) is controversial, and no reliable method has been established to predict subsequent contralateral slip. The main purpose of this study was to evaluate if magnetic resonance imaging (MRI) performed at primary diagnosis could predict future contralateral slip.

Materials and methods

Twenty-two patients with unilateral SCFE were included, all had MRI of both hips taken before operative fixation. Six different parameters were measured on the MRI: the MRI slip angle, the greatest focal widening of the physis, the global widening of the physis measured at three locations (the midpoint of the physis and 1 cm lateral and medial to the midpoint), periphyseal (epiphyseal and metaphyseal) bone marrow edema, the presence of pathological joint effusion, and the amount of joint effusion measured from the lateral edge of the greater trochanter. Mean follow-up was 33 months (range, 16–63 months). Six patients were treated for contralateral slip during the follow-up time and a comparison of the MRI parameters of the contralateral hip in these six patients and in the 16 patients that remained unilateral was done to see if subsequent contralateral slip was possible to predict at primary diagnosis.

Results

All MRI parameters were significantly altered in hips with established SCFE compared with the contralateral hips. However, none of the MRI parameters showed any significant difference between patients who had a subsequent contralateral slip and those that remained unilateral.

Conclusions

MRI taken at primary diagnosis could not predict future contralateral slip.

http://ift.tt/2y4OHeX

An intracortical chondromyxoid fibroma in the diaphysis of the metatarsal

Abstract

Chondromyxoid fibromas (CMFs) are rare, benign, primary tumors of bones, and occur in the metaphyses of the medullary canals of the long bones. The occurrence of intracortical CMFs is extremely rare. Very few cases of intracortical CMFs located in the long tubular bones have been reported to date. Moreover, even though the feet are the second most common site for CMF (after the knees), intracortical metatarsal CMF has not been reported previously, to our knowledge. We report an intracortical CMF occurring in the diaphysis of the metatarsal in a 17-year-old man. It showed the same imaging findings as usual intramedullary CMFs, except for its cortical location. The development and serial increase in this tumor over time are also demonstrated in this report. Additionally, we present a review of current literature on intracortical CMFs.

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What's up in the ALPS

Frédéric Rieux-Laucat

http://ift.tt/2i1WRi9

Anemia at pediatric intensive care unit discharge: prevalence and risk markers

Anemia is prevalent at pediatric intensive care unit (PICU) admission and incident during PICU stay, but little is known about anemia at PICU discharge . Anemia after critical illness is an important issue bec...

http://ift.tt/2yJgs0Q

Beware of the force of the horse: mechanisms and severity of equestrian-related injuries.

Background: Equestrian-related injuries (ERIs) are relatively severe compared with injuries in other popular sports. Previous studies on epidemiology of ERIs vary widely and mainly focus on incidence instead of severity of the injury. Purpose: The aim of this study was to determine incidence, mechanisms and severity of ERIs in two Dutch hospitals (level 1 and level 2 trauma centers) over a 5-year period. Patients and methods: All patients with ERIs who visited the emergency departments of VieCuri Medical Centre in Venlo and Maastricht University Medical Centre+ in Maastricht, The Netherlands, between July 2010 and June 2015 were retrospectively included. Clinical data were extracted from medical records. Results: Most ERIs occurred in mounted riders (646 events; 68%); 94.9% of which involved a fall. Being kicked (42.5%) or trapped (30.1%) was the most common cause of injury in unmounted riders. Most frequently injured body parts were the upper extremities (43.8%) in mounted riders and lower extremities (40.5%) in the unmounted group. A relatively high percentage of facial injuries (9.7%) were found in the unmounted group. Seventeen per cent of all ERIs required admission. The median Injury Severity Score was 5 in the admitted population and 1 in the total population. Conclusion: Horseback riding is a risky activity. Prior studies particularly studied admitted patients in level 1 trauma centers outside of Europe and demonstrated a high risk of significant injury. However, our study demonstrates that these studies in selected groups might have overestimated the severity of ERIs in the general population. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2yQJziN

Big Ass Light creates the world’s toughest portable work light

LEXINGTON, Ky. — Big Ass Light, a division of Big Ass Fans, announces the release of the world's toughest and brightest battery-powered LED work light: the Big Ass Light Bar. Big Ass Light Bar was built to uncompromising quality standards. Its durable design and ability to survive being doused and dropped make it ideal for use on the toughest jobs. Big Ass Light Bar's features include: ...

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Photo roundup: EMS World Expo 2017

Did you attend this year's conference? Add your photos in the comments

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Sp17 Protein Expression and Major Histocompatibility Class I and II Epitope Presentation in Diffuse Large B Cell Lymphoma Patients

Improved therapies are urgently needed for patients with diffuse large B cell lymphoma (DLBCL). Success using immune checkpoint inhibitors and chimeric antigen receptor T cell technology has fuelled demand for validated cancer epitopes. Immunogenic cancer testis antigens (CTAs), with their widespread expression in many tumours but highly restricted normal tissue distribution, represent attractive immunotherapeutic targets that may improve treatment options for DLBCL and other malignancies. Sperm protein 17 (Sp17), a CTA reported to be immunogenic in ovarian cancer and myeloma patients, is expressed in DLBCL. The aim of the present study was to investigate Sp17 epitope presentation via the presence of a cytotoxic T cell (CTL) and a CD4 T-helper (Th) response in DLBCL patients. A significant γ-interferon CTL response was detected in peripheral blood mononuclear cells of 13/31 DLBCL patients following short-term cell stimulation with two novel HLA-0201 peptides and one previously reported HLA-0101-restricted nine-mer Sp17 peptide. No significant responses were detected in the HLA-0201-negative DLBCL patients or four healthy subjects. A novel immunogenic 20-mer CD4 Th Sp17 peptide was detected in 8/17 DLBCL patients. This is the first report of a CTL and a CD4 Th response to Sp17 in DLBCL and supports Sp17 as a potential immunotherapeutic target for DLBCL.

http://ift.tt/2zAKyk5

MagneGrip exhaust removal systems firehouse installations have cleaner air for firefighters

MagneGrip Exhaust Removal Systems and AirHAWK Air Purification Systems remove vehicle exhaust emissions and other contaminants in firehouses to reduce firefighter risk for cancer, respiratory and cardiovascular diseases while keeping spaces clean and tidy. At Mount Pleasant Fire Department (Mount Pleasant, SC), a combination of MagneGrip Sliding Balancer Track (SBT), Straight Suction Rail (SSR) and ...

http://ift.tt/2h57dxY

Spatio-temporal pattern analysis for evaluation of the spread of human infections with avian influenza A(H7N9) virus in China, 2013–2014

A large number (n = 460) of A(H7N9) human infections have been reported in China from March 2013 through December 2014, and H7N9 outbreaks in humans became an emerging issue for China health, which have caused nu...

http://ift.tt/2zBltp5

Scale-up Chemical Synthesis of Thermally-activated Delayed Fluorescence Emitters Based on the Dibenzothiophene-S,S-Dioxide Core

Scale-up synthesis of highly efficient thermally activated delayed fluorescence emitters is described in the presented article.

http://ift.tt/2y1RDhe

Inhibitors of apoptosis: clinical implications in cancer

Abstract

Inhibitor of apoptosis (IAP) family comprises a group of endogenous proteins that function as main regulators of caspase activity and cell death. They are considered the main culprits in evasion of apoptosis, which is a fundamental hallmark of carcinogenesis. Overexpression of IAP proteins has been documented in various solid and hematological malignancies, rendering them resistant to standard chemotherapeutics and radiation therapy and conferring poor prognosis. This observation has urged their exploitation as therapeutic targets in cancer with promising pre-clinical outcomes. This review describes the structural and functional features of IAP proteins to elucidate the mechanism of their anti-apoptotic activity. We also provide an update on patterns of IAP expression in different tumors, their impact on treatment response and prognosis, as well as the emerging investigational drugs targeting them. This aims at shedding the light on the advances in IAP targeting achieved to date, and encourage further development of clinically applicable therapeutic approaches.

http://ift.tt/2lezNS7

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice

Abstract

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART^®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

http://ift.tt/2yLLQv1

Surgical Management of Primary Retroperitoneal Sarcomas: Rationale for Selective Organ Resection

Abstract

Background

Recently, some have argued for routine resection of adjacent but uninvolved organs in patients with retroperitoneal sarcoma (RPS) without stipulating the rationale for such organ resection (beyond the need to achieve a macroscopically complete resection) or examining histopathologic organ invasion (HOI). This study reviewed the authors' experience with primary RPS to investigate the rate and rationale for individual organ resection and the rate of HOI.

Methods

Operative and pathology reports for patients with primary RPS who underwent resection at our institution were retrospectively reviewed. Histopathologic organ invasion was confirmed by a dedicated sarcoma pathologist.

Results

From 2002 through 2011, 118 patients underwent resection of a primary RPS, and 99 of these patients (84%) had at least one organ resected. Kidney (n = 57), colon (n = 51), and adrenal (n = 41) were the most commonly resected organs. For the 302 organs removed, the perioperative clinical rationale for the resection was suspected invasion or tumor origin (n = 52, 17%), involved end-organ vasculature (n = 39, 13%), organ encasement (n = 42, 14%), tumor adherence (n = 127, 42%), resection required for R0/R1 resection (n = 25, 8%), or other (n = 17, 6%). The presence of HOI was found in 77 (25%) of the 302 organs resected. In the reviewed studies, HOI was identified in 34 (65%) of 52 organs suspected of invasion or tumor origin, in 19% of organs resected due to tumor encasement, and in 26% of organs with adherent tumor, even when not suspected intraoperatively, but was never identified in organs resected purely as part of a liberal en bloc resection of adjacent organs. When invasion was suspected intraoperatively, HOI was confirmed in 50, 78, and 100% of resected organs respectively for well-dedifferentiated liposarcoma, dedifferentiated liposarcoma (DDLPS), and leiomyosarcoma (LMS).

Conclusions

Histologic organ invasion was observed more commonly in organs resected with suspicion of invasion than in organs resected simply to achieve a negative margin, although this reflects a degree of subjectivity and selection bias. In more than one-fourth of adherent organs, HOI was present even when not suspected intraoperatively. Histologic subtype may predict HOI because DDLPS and LMS are associated with high rates of HOI when invasion is suspected intraoperatively. Development of a data-driven, histology-specific rationale for adjacent organ resection is critical.

http://ift.tt/2h57ilC

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice

Abstract

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART^®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

http://ift.tt/2yLLQv1

On the security of compressed encryption with partial unitary sensing matrices embedding a secret keystream

The principle of compressed sensing (CS) can be applied in a cryptosystem by providing the notion of security. In this paper, we study the computational security of a CS-based cryptosystem that encrypts a plai...

http://ift.tt/2gGbPho

Phase Behavior of Charged Vesicles Under Symmetric and Asymmetric Solution Conditions Monitored with Fluorescence Microscopy

Experiments on phase separated giant unilamellar vesicles (GUVs) frequently neglect physiological solution conditions. This work presents approaches to study the effect of high-salinity buffer on liquid-liquid phase separation in charged multicomponent GUVs as a function of trans-membrane solution asymmetry and temperature.

http://ift.tt/2gFrk9f

Correction to: Development and validation of a risk score to assist screening for acute HIV-1 infection among men who have sex with men

http://ift.tt/2gAt53O

Fundamentals of Laser-Based Hydrogel Degradation and Applications in Cell and Tissue Engineering

Abstract

The cell and tissue engineering fields have profited immensely through the implementation of highly structured biomaterials. The development and implementation of advanced biofabrication techniques have established new avenues for generating biomimetic scaffolds for a multitude of cell and tissue engineering applications. Among these, laser-based degradation of biomaterials is implemented to achieve user-directed features and functionalities within biomimetic scaffolds. This review offers an overview of the physical mechanisms that govern laser–material interactions and specifically, laser–hydrogel interactions. The influences of both laser and material properties on efficient, high-resolution hydrogel degradation are discussed and the current application space in cell and tissue engineering is reviewed. This review aims to acquaint readers with the capability and uses of laser-based degradation of biomaterials, so that it may be easily and widely adopted.

The fundamental mechanisms, based on laser and hydrogel properties that mediate laser-based hydrogel degradation are discussed here, and the current application space in cell and tissue engineering is presented. The aim is to acquaint readers with the capabilities and limitations of laser-based hydrogel degradation so that it may be easily and widely adopted for biofabrication and other applications.

http://ift.tt/2xjM3Cz

A Novel Use of Three-dimensional High-frequency Ultrasonography for Early Pregnancy Characterization in the Mouse

Mice are widely used to study gestational biology. However, pregnancy termination is required for such studies which precludes longitudinal investigations and necessitates the use of large numbers of animals. Therefore, we describe a non-invasive technique of high-frequency ultrasonography for early detection and monitoring of post-implantation events in the pregnant mouse.

http://ift.tt/2yI9JEI

Enrichment of Detergent-insoluble Protein Aggregates from Human Postmortem Brain

An abbreviated fractionation protocol for the enrichment of detergent-insoluble protein aggregates from human postmortem brain is described.

http://ift.tt/2gJohwF

Inkjet-Printed Nanocavities on a Photonic Crystal Template

Abstract

The last decade has witnessed the rapid development of inkjet printing as an attractive bottom-up microfabrication technology due to its simplicity and potentially low cost. The wealth of printable materials has been key to its widespread adoption in organic optoelectronics and biotechnology. However, its implementation in nanophotonics has so far been limited by the coarse resolution of conventional inkjet-printing methods. In addition, the low refractive index of organic materials prevents the use of "soft-photonics" in applications where strong light confinement is required. This study introduces a hybrid approach for creating and fine tuning high-Q nanocavities, involving the local deposition of an organic ink on the surface of an inorganic 2D photonic crystal template using a commercially available high-resolution inkjet printer. The controllability of this approach is demonstrated by tuning the resonance of the printed nanocavities by the number of printer passes and by the fabrication of photonic crystal molecules with controllable splitting. The versatility of this method is evidenced by the realization of nanocavities obtained by surface deposition on a blank photonic crystal. A new method for a free-form, high-density, material-independent, and high-throughput fabrication technique is thus established with a manifold of opportunities in photonic applications.

Reproducible and structurally tunable high-Q cavities with small modal volumes are fabricated by a new method via femtoliter inkjet printing on a photonic crystal template. The versatility of the method enables the realization of nanocavities through surface deposition on a defect-free photonic crystal. This thus establishes a free-form, high-density, material-independent, and high-throughput fabrication technique, with manifold opportunities in photonic applications.

http://ift.tt/2zAjoty

Partial Verification Distorts Estimates of Sensitivity in Diagnostic Accuracy Studies for Fine-Needle Aspiration Cytology

http://ift.tt/2gFZKJ8

Reduced Port Laparoscopic Distal Gastrectomy with D2 Lymphadenectomy

Abstract

Background

Reduced port laparoscopic surgery (RPLS), as a more minimally invasive treatment alternative to conventional laparoscopic surgery (CLS), has been increasing in recent years.¹ With the accumulation of surgical experience and improvements in surgical techniques, the indication of RPLS has been gradually extended from benign diseases to malignant tumors, including gastric cancer.^2–4 However, due to the lack of counteraction and triangulation, lymphadenectomy during reduced port laparoscopic gastrectomy (RPLG) for gastric cancer was considered challenging. In this study, we report our experience performing RPLG with D2 lymphadenectomy for distal gastric cancer.

Methods

A disposable, single-incision, multiport, laparoscopic surgery trocar was used through a 3-cm incision at the umbilicus for the laparoscopist and surgeon's right hand. One 12-mm trocar was inserted at the upper-right quadrant for the surgeon's left hand. Distal gastrectomy with D2 lymphadenectomy was performed in the same manner with CLS.⁵ After extracting the resected specimen through the umbilicus incision, intracorporeal Roux-en-Y or B-II gastrojejunostomy was used for reconstruction.

Results

RPLG with D2 lymphadenectomy was performed on five patients from April 2017 to June 2017. No intraoperative event requiring conversion to CLS or open surgery occurred. No postoperative complication was observed. The median operating time and blood loss was 166 min and 50 ml. The mean number of retrieved lymph nodes was 32.7. Postoperatively, the mean time to first flatus, soft intake, and hospital stay was 2.6, 3.5, and 6.7 days respectively.

Conclusions

RPLG with D2 lymphadenectomy might be safe and feasible in selected patients.

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Do Lumpectomy Cavity Shaved Margins Really Not Impact Re-excision Rates in Breast Cancer?

http://ift.tt/2gGRZ5s

Prediction of Non-sentinel Node Status in Patients with Melanoma and Positive Sentinel Node Biopsy: An Italian Melanoma Intergroup (IMI) Study

Abstract

Background and Purpose

Approximately 20% of melanoma patients harbor metastases in non-sentinel nodes (NSNs) after a positive sentinel node biopsy (SNB), and recent evidence questions the therapeutic benefit of completion lymph node dissection (CLND). We built a nomogram for prediction of NSN status in melanoma patients with positive SNB.

Methods

Data on anthropometric and clinicopathological features of patients with cutaneous melanoma who underwent CLND after a positive SNB were collected from nine Italian centers. Multivariate logistic regression was utilized to identify predictors of NSN status in a training set, while model efficiency was validated in a validation set.

Results

Data were available for 1220 patients treated from 2000 through 2016. In the training set (n = 810), the risk of NSN involvement was higher when (1) the primary melanoma is thicker or (2) sited in the trunk/head and neck; (3) fewer nodes are excised and (4) more nodes are involved; and (5) the lymph node metastasis is larger or (6) is deeply located. The model showed high discrimination (area under the receiver operating characteristic curve 0.74, 95% confidence interval [CI] 0.70–0.79) and calibration (Brier score 0.16, 95% CI 0.15–0.17) performance in the validation set (n = 410). The nomogram including these six clinicopathological variables performed significantly better than five other previously published models in terms of both discrimination and calibration.

Conclusions

Our nomogram could be useful for follow-up personalization in clinical practice, and for patient risk stratification while conducting clinical trials or analyzing their results.

http://ift.tt/2yFUUlP

Prophylactic Cholecystectomy at Time of Surgery for Small Bowel Neuroendocrine Tumor Does Not Increase Postoperative Morbidity

Abstract

Background

Prophylactic cholecystectomy at time of surgery for small bowel neuroendocrine tumor (SBNET) has been advocated, as these patients often go on to require somatostatin analogue therapy, which is known to increase risk of cholestasis and associated complications. Little is known regarding patterns of adoption of this practice or its associated morbidity.

Methods

The American College of Surgeons National Surgical Quality Improvement Program database (2008–2014) was queried to identify patients who underwent SBNET resection. The risk differences of morbidity and mortality associated with performance of concurrent cholecystectomy were determined with multivariable adjustment for confounders.

Results

Among 1300 patients who underwent SBNET resection, 144 (11.1%) underwent concurrent cholecystectomy. Median age of patients undergoing cholecystectomy was 62 years [interquartile range (IQR) 52–69 years], and 75 were male. They more commonly had disseminated cancer (36.1 vs. 11.6%, p < 0.001) or SBNET located in duodenum (10.4 vs. 4.9%, p = 0.045) without difference in other baseline characteristics. Operative time was significantly longer in the cholecystectomy group (median 172 vs. 123 min, p < 0.001). Rate of postoperative morbidity was not significantly different between cholecystectomy and no-cholecystectomy groups (11.8 vs. 11.1%, p = 0.79). After adjustment for confounding, the risk difference of morbidity attributable to cholecystectomy was + 0.4% [95% confidence interval (CI) − 4.9 to + 5.6%]. Mortality within 30 days was not significantly different between cholecystectomy and no-cholecystectomy groups (1.4 vs. 0.6%, p = 0.29).

Conclusions

Concurrent cholecystectomy at time of resection of SBNET is not associated with higher morbidity or mortality yet is performed in a minority of patients. Prospective study can identify which patients may derive benefit from this approach.

http://ift.tt/2gEcLTk

CDK20 inhibition and immune checkpoint blockade: bringing cancer biology and tumour immunology together to develop novel treatment options for HCC

On 22 September 2017 the Food and Drug Administration granted accelerated approval to nivolumab for the treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib. Approval was based on a 154-patient subgroup of a multicentre, open-label trial conducted in patients with HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib.1 With an overall response rate of close to 15%, which lasted in more than 90% of the patients 6 months or longer, immune checkpoint blockade has become a treatment option for patients with HCC after many years of failures in drug development. However, these data also call for future combination studies, which will increase the number of patients responding to immunotherapy. But what is the best combination partner for an immune checkpoint inhibitor in HCC?

While immune checkpoint inhibitors successfully lead to activation of T cells in patients with HCC,

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Low eukaryotic viral richness is associated with faecal microbiota transplantation success in patients with UC

We read with interest the recent Gut study by Zuo and colleagues showing that a good outcome of faecal microbiota transplantation (FMT) in Clostridium difficile infection (CDI) was associated with bacteriophage transfer.1 FMT is an established treatment to restore a balance in disturbed intestinal microbiotas of patients with CDI,2 3 and recent multicentre randomised, double-blind, placebo-controlled trials showed its effectiveness in inducing clinical and endoscopic remission in patients with UC.4 We examined the gut virome dynamics of nine patients with UC who were undergoing FMT (64 patient and 8 healthy donor samples).5 Two patients with UC achieved long-lasting complete remission with mucosal healing (>2 years; figure 1: patient 1 and 3), and one patient reported temporary remission for 6 weeks (figure 1; patient 4).5 The remaining six patients did not respond to treatment. Using...

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Real-time differentiation of adenomatous and hyperplastic diminutive colorectal polyps during analysis of unaltered videos of standard colonoscopy using a deep learning model

Background

In general, academic but not community endoscopists have demonstrated adequate endoscopic differentiation accuracy to make the 'resect and discard' paradigm for diminutive colorectal polyps workable. Computer analysis of video could potentially eliminate the obstacle of interobserver variability in endoscopic polyp interpretation and enable widespread acceptance of 'resect and discard'.

Study design and methods

We developed an artificial intelligence (AI) model for real-time assessment of endoscopic video images of colorectal polyps. A deep convolutional neural network model was used. Only narrow band imaging video frames were used, split equally between relevant multiclasses. Unaltered videos from routine exams not specifically designed or adapted for AI classification were used to train and validate the model. The model was tested on a separate series of 125 videos of consecutively encountered diminutive polyps that were proven to be adenomas or hyperplastic polyps.

Results

The AI model works with a confidence mechanism and did not generate sufficient confidence to predict the histology of 19 polyps in the test set, representing 15% of the polyps. For the remaining 106 diminutive polyps, the accuracy of the model was 94% (95% CI 86% to 97%), the sensitivity for identification of adenomas was 98% (95% CI 92% to 100%), specificity was 83% (95% CI 67% to 93%), negative predictive value 97% and positive predictive value 90%.

Conclusions

An AI model trained on endoscopic video can differentiate diminutive adenomas from hyperplastic polyps with high accuracy. Additional study of this programme in a live patient clinical trial setting to address resect and discard is planned.

http://ift.tt/2lf8h7k

Prevalence of Co-existing Autoimmune Disease in Rheumatoid Arthritis: A Cross-Sectional Study

Abstract

Introduction

Many autoimmune diseases, including rheumatoid arthritis (RA), share common mechanisms; however, population-based studies of the magnitude of multiple autoimmune diseases in patients with RA have not been performed.

Methods

We conducted a cross-sectional study using a US administrative healthcare thcare claims database to screen for prevalence of multiple autoimmune diseases in patients with RA and osteoarthritis (OA). Each patient diagnosed with RA between January 1, 2006 and September 30, 2014 was age- and sex-matched with five patients with OA. The prevalence of 37 pre-specified autoimmune diseases during the 24-month period before and after RA or OA diagnosis was compared.

Results

Overall, 286,601 patients with RA and 992,838 matched patients (from 1,421,624 records) with OA were evaluated. During the baseline period, at least one and more than one autoimmune diseases were identified in 24.3% and 6.0% of patients with RA compared with 10.5% and 1.4% of patients with OA, respectively. Highest prevalence rates for patients with RA were for systemic lupus erythematosus (3.8% versus 0.7% for OA) and psoriatic arthritis (3.2% versus 0.4%). Highest odds ratios (ORs) comparing RA with OA were for the prevalence of ankylosing spondylitis (OR 8.0; 95% CI 7.6, 8.5) and psoriatic arthritis (OR 7.8; 95% CI 7.6, 8.1).

Conclusion

Patients with RA have more concurrent autoimmune diseases than patients with OA. These data suggest that the interrelationship between RA and other autoimmune diseases, and outcomes associated with the occurrence of multiple autoimmune diseases, may play an important role in disease understanding, management, and treatment decisions.

Funding

Bristol-Myers Squibb.

http://ift.tt/2xkwPNs

Paroxysmal atrial fibrillation recognition based on multi-scale wavelet α-entropy

This study proposed an effective method based on the wavelet multi-scale α-entropy features of heart rate variability (HRV) for the recognition of paroxysmal atrial fibrillation (PAF). This new algorithm combines...

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Psychophysiological Response and Fine Motor Skills in High-Altitude Parachute Jumps

High Altitude Medicine & Biology , Vol. 0, No. 0.


http://ift.tt/2zztQBM

Impact of surgical resection extension on outcome for primary well-differentiated thyroid cancer—a retrospective analysis

Abstract

Background

The surgical resection extension in well-differentiated thyroid cancer is controversially discussed with the possibility of an overtreatment on the one hand against the risk of local disease recurrence. The aim of this study is to evaluate how the surgical resection extension with the adjunction of radioiodine therapy affects postoperative morbidity and the oncologic outcome of patients primarily treated for well-differentiated thyroid cancer.

Methods

All patients undergoing primary surgery for a well-differentiated, non-recurrent thyroid cancer from January 2005 to April 2013 at Tuebingen University Hospital were retrospectively analyzed.

Results

Papillary thyroid cancer (PTC) was present in 73 patients (including 27 papillary microcarinoma) and follicular thyroid cancer in 14 patients. Fifty-six of 87 patients (64%) underwent one-stage surgery, of which 26 patients (30%) received simultaneous lymph node dissection (LND). The remaining 31 patients (36%) underwent a two-stage completion surgery (29 patients with LND). Only in three patients a single lymph node metastasis was newly detected during two-stage completion surgery. Patients with LND at either one-stage and two-stage completion surgery had a significant higher rate of transient postoperative hypocalcemia.

Postoperative adjuvant radioiodine therapy was performed in 68 of 87 patients (78%). After a median follow-up of 69 months [range 9–104], one local recurrence was documented in a patient suffering from PTC 23 months after surgery.

Conclusion

No prophylactic two-stage lymphadenectomy should be performed in case of well-differentiated thyroid cancer to avoid unnecessary complication without any proven oncologic benefit.

http://ift.tt/2xkxvCB

Postoperative C-reactive protein/albumin ratio as a novel predictor for short-term complications following gastrectomy of gastric cancer

Abstract

Background

Postoperative complications following gastric cancer resection remain a clinical problem. Early detection of postoperative complications is needed before critical illness develops. The purpose of this study was to evaluate the prognostic value of C-reactive protein/albumin ratio in patients with gastric cancer.

Methods

A total of 322 patients undergoing curative (R0) gastrectomy between 2015 and 2017 were retrospectively analyzed. Univariate and multivariate analyses were performed to identify clinical factors predicting postoperative complications. The cutoff values and diagnostic accuracy of C-reactive protein/albumin ratio and C-reactive protein were determined by receiver-operating characteristic curves.

Results

Among all of the patients, 85 (26.4%) developed postoperative complications. The optimal cutoff of C-reactive protein/albumin ratio was set at 3.04 based on the ROC analysis. Multivariate analysis identified C-reactive protein/albumin ratio was an independent risk factors for complications after gastrectomy (OR 3.037; 95% CI 1.248–7.392; P = 0.014). Additionally, C-reactive protein/albumin ratio showed a higher diagnostic accuracy than C-reactive protein on postoperative day 3 (AUC: 0.685 vs 0.660; sensitivity: 0.624 vs 0.471; specificity: 0.722 vs 0.835).

Conclusions

Elevated C-reactive protein/albumin ratio was an independent predictor for postoperative complications following gastrectomy of gastric cancer, and the diagnostic accuracy was higher than C-reactive protein alone. Overall, postoperative C-reactive protein/albumin ratio may help to identify patients with high probability of postoperative complications.

http://ift.tt/2zN2WXN

Antiobesity and Anti-Inflammatory Effects of Orally Administered Bonito Extracts on Mice Fed a High-Fat Diet

Background. The condensed fermentative extract of bonito (BoE), skipjack tuna (Katsuwonus pelamis), has claimed its health conditioning effects against lifestyle-related diseases such as hypertension and type 2 diabetes. Methods. We evaluated the antiobesity and anti-inflammatory effects of BoE on mice fed a high-fat diet (HFD). Mice (9 weeks of age) were maintained for 11 weeks on HFD with or without BoE (50 mg or 500 mg/kg). Results. Compared with untreated mice, BoE50 or BoE500 mice achieved maximum weight reductions of 7.4% (males) and 11.4% (females), and visceral fat in male BoE500 mice was more decreased among all mice ( = 0.00459). Furthermore, an antiobesity gene uncoupling protein-1 was significantly induced in the visceral fat tissues of male BoE500 ( = 0.0110) and female BoE50 and BoE500 mice ( = 0.0110 and = 0.0110, resp.). Finally, we detected reduced amount of granulocyte-colony stimulating factor ( = 0.0250) in the sera of female BoE50 and interleukin- (IL-) 5 ( = 0.0120), IL-6 ( = 0.0118), and IL-13 ( = 0.0243) in female BoE500 mice. Conclusion. The antiobesity and anti-inflammatory effects of BoE were demonstrated with our examination system and any toxic adverse effects were not observed in mice during the 3-month investigation.

http://ift.tt/2yOmUn9

Targeting Anaplastic Lymphoma Kinase (ALK) in Rhabdomyosarcoma (RMS) with the Second-Generation ALK Inhibitor Ceritinib

Abstract

Background

The receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) has been implicated in the tumorigenesis of rhabdomyosarcoma (RMS). However, the exact role of ALK in RMS is debatable and remains to be elucidated.

Objective

To determine the in vitro and in vivo effects and mechanism of action of the second-generation ALK inhibitor ceritinib on RMS cell growth.

Methods

Effects of ceritinib on cell proliferation, wound healing, cell cycle, and RTK signaling were determined in alveolar and embryonal rhabdomyosarcoma (ARMS, ERMS). In addition, possible synergistic effects of combined treatment with ceritinib and the Abl/Src family kinase inhibitor dasatinib were determined.

Results

Ceritinib treatment led to decreased cell proliferation, cell cycle arrest, apoptosis, and decreased in vivo tumor growth for the ARMS subtype. ERMS cell lines were less affected and showed no cell cycle arrest or apoptosis. Both subtypes lacked intrinsic ALK phosphorylation, and ceritinib was shown to affect the IGF1R signaling pathway. High levels of phosphorylated Src (Tyr416) were present following ceritinib treatment, making combined treatment with a Src inhibitor a potential treatment option. Combined treatment of ceritinib and dasatinib showed synergistic effects in both ERMS and ARMS cell lines.

Conclusion

This study shows that monotherapy with an ALK inhibitor, such as ceritinib, in RMS, has no effect on ALK signaling. However, the synergistic effects of ceritinib and dasatinib are promising, most probably due to targeting of IGF1R and Src.

http://ift.tt/2yFiu2h

A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer

Abstract

Background

This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors.

Objectives

Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity.

Patients and Methods

Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D.

Results

The PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m² was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations.

Conclusions

Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies.

http://ift.tt/2yFz3Lx

The dawn of “immune-revolution” in children: early experiences with checkpoint inhibitors in childhood malignancies

Abstract

Modern immunotherapy with checkpoint inhibitors has changed clinical practice of adult patients with advanced cancer. Blockade of CTLA-4 and PD-1 pathways have shown survival benefits in different diseases. In children, combination of surgery, radiotherapy and chemotherapy have improved survival rates of solid tumors. However, the outcomes for subsets of patients such as those with high-grade, refractory, or metastatic disease remain extremely poor. Currently, the treatment of these patients is almost exclusively based on standard chemotherapy. The significant proportion of pediatric cancers with high number of mutations and subsequent high expression of neoantigens, together with the potential prognostic role of the immunosuppressive checkpoint molecules (CTLA-4, PD-L1) can represent a promising rationale that support the use of checkpoint inhibitors. We made a revision about emerging data regarding safety and activity of checkpoint inhibitors in children with solid tumors.

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Extended spectrum and metalo beta-lactamase producing airborne Pseudomonas aeruginosa and Acinetobacter baumanii in restricted settings of a referral hospital: a neglected condition

Frequently encountered multidrug-resistant bacterial isolates of P. aeruginosa and A. baumannii are common and prevalent in a hospital environment. The aim of this study was to determine the prevalence and patter...

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School district partners with ambulance service in career program

By Teresa Stepzinski The Florida Times-Union GREEN COVE SPRINGS, Fla. — Clay County career academy students soon will have an opportunity for hands-on training and clinical hours necessary to complete industry certifications through a partnership between the school district and Liberty Ambulance Service Inc. Students in the Emergency Medical Response (EMR) program in the Academy of Health Science ...

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Nanoemulsions from unsaturated fatty acids concentrates of carp oil using chitosan, gelatin and their blends as wall materials

Abstract

This work aimed to study the development of food-grade nanoemulsions containing unsaturated fatty acids concentrates from carp oil, using chitosan and gelatin as wall materials. The effects of chitosan:gelatin ratio, polymer concentration and homogenization time on the nanoemulsions characteristics were evaluated. Phase separation occurred when the chitosan:gelatin ratio was higher than 50:50. Nanoemulsions using proportion of chitosan over than 70% remained visually stable, with no phase separation, for more of 7 days. The highest homogenization time (20 min) and the lowest biopolymers concentration (1% w/v) resulted in smaller particle sizes for the ratios of 100:0, 90:10 and 70:30 (respectively, 292.0 nm, 52.3 nm and 34.8 nm). The zeta potential increased with the amount of chitosan (from 26.5 to 31.0 mV), while pH and refractive index were not affected by the biopolymers ratio. After 7 days of storage, the nanoemulsion with 90:10 of chitosan:gelatin ratio was in the acceptable range of the legislation, showing peroxide value of 4.8 meq kg⁻¹, p–anisidine value of 9.8 meq kg⁻¹ and ToTox value of 19.4 meq kg⁻¹. Chitosan and gelatin provided high stability to the emulsions and also behaved as good wall materials, demonstrating the importance of studying its combination to form food–grade nanoemulsions.

Practical applications: Carp viscera are by-products of the fishery industry, rich in unsaturated fatty acids, which are associated to human health benefits. However, its low solubility in water and oxidative instability difficult the foods enrichment with these unsaturated fatty acids. Nanoemulsions delivery systems can be used to protect and increase its solubility. Edible biopolymers, such as chitosan and gelatin, can increase the physical and oxidative stability of these lipids in food systems through the formation of nanoemulsions, to facilitate the addition these lipophilic active ingredients in aqueous-based foods or beverages.

http://ift.tt/2y3EEGR

Fruit pits recovered from fourteen genotypes of apricot (Prunus armeniaca L.) as potential biodiesel feedstock

Abstract

Kernels recovered from fruit pits of fourteen apricot (Prunus armeniaca L.) genotypes were tested for future application as feedstock for biodiesel production. The difference between the lowest and the highest oil yield between studied samples was over two-fold and reached between 27.1 and 58.7% (w/w) dw. The oleic and linoleic acids were the two dominant fatty acids in apricot kernel oils; however, their content was affected meaningfully by the variety and amounted to 38.5–67.2% and 26.4-54.8%, respectively. Two significant correlations (p < 0.000005) were found between oil yield in kernels of different apricot genotypes and two fatty acids, oleic and linoleic (r = 0.947 and r = -0.927, respectively). The biodiesel parameters of fourteen apricot genotypes were calculated empirically according to previously developed equations based on the fatty acid methyl esters composition of the potential feedstock. The European biodiesel standards of kinematic viscosity, cetane number, density and iodine value were met for thirteen investigated samples. The exception was noted for genotype HL PSŠ 5. The recorded differences between minimum and maximum value of individual biodiesel parameters calculated empirically for various apricot genotypes differed as follows: 0.20 mm²/s (kinematic viscosity), 4.9 (cetane number), 0.06 MJ/kg (higher heating value), 0.0028 g/cm³ (density), 15.6 I₂/100 g (iodine value), 1.67 °C (CFPP) and 2.15 h (induction period). The logarithmic regression model in comparison to linear regression model, better expressed the relationship between physicochemical properties of biofuel and the ΣPUFA/(ΣSFA+ΣMUFA) ratio. To confirm the usefulness of the applied empirical equations for biodiesel parameters prediction of the apricot feedstock, five cold-pressed apricot kernel oils of different origin and with a varied composition of fatty acids were tested experimentally and compared with the values calculated empirically.

Practical applications: Apricot kernels have limited use in food industry due to a high content of the amygdalin. Therefore, application of apricot kernels as potential feedstock for the biodiesel production seems to be reasonable, especially due rich oil yield (up to even 60%). This paper describes the impact of the apricot genotype on the potential application in the biodiesel industry as well as the relationship between the oil yield and apricot biodiesel quality. Obtained biodiesel parameters of fourteen apricot (Prunus armeniaca L.) genotype oils can help estimate the economic perspectives of utilization as a potential energy source. The present study may contribute to the more targeted use of the apricot (Prunus armeniaca L.) kernels and promotes the efficient management of the plant material and environmental sustainability.

http://ift.tt/2yLgl4o

Impact of exon 19 versus exon 21 EGFR-activating mutation on outcomes with upfront pemetrexed–carboplatin chemotherapy

Vanita Noronha, Vijay Patil, Amit Joshi, Anuradha Chougule, Atanu Bhattacharjee, Rajiv Kumar, Sucheta More, Supriya Goud, Ashay Karpe, Anant Ramaswamy, Nikhil Pande, Arun Chandrasekharan, Alok Goel, Vikas Talreja, Abhishek Mahajan, Amit Janu, Nilendu Purandare and Kumar Prabhash

http://ift.tt/2zMQFT9

Laparoscopic liver resection in metastatic colorectal cancer treatment: comparison with long-term results using the conventional approach

Rafael José Maurette, Marcos García Ejarque, Matías Mihura, Mariano Bregante, Diego Bogetti and Daniel Pirchi

http://ift.tt/2xj6PC9

Standards for use of drones by public safety agencies released

The new standards will provide guidance on the tactical, legal and ethical use of unmanned aircraft systems

http://ift.tt/2y2YlPl

GRcalculator: an online tool for calculating and mining dose–response data

Abstract

Background

Quantifying the response of cell lines to drugs or other perturbagens is the cornerstone of pre-clinical drug development and pharmacogenomics as well as a means to study factors that contribute to sensitivity and resistance. In dividing cells, traditional metrics derived from dose–response curves such as IC ₅₀ , AUC, and E _max , are confounded by the number of cell divisions taking place during the assay, which varies widely for biological and experimental reasons. Hafner et al. (Nat Meth 13:521–627, 2016) recently proposed an alternative way to quantify drug response, normalized growth rate (GR) inhibition, that is robust to such confounders. Adoption of the GR method is expected to improve the reproducibility of dose–response assays and the reliability of pharmacogenomic associations (Hafner et al. 500–502, 2017).

Results

We describe here an interactive website (www.grcalculator.org) for calculation, analysis, and visualization of dose–response data using the GR approach and for comparison of GR and traditional metrics. Data can be user-supplied or derived from published datasets. The web tools are implemented in the form of three integrated Shiny applications (grcalculator, grbrowser, and grtutorial) deployed through a Shiny server. Intuitive graphical user interfaces (GUIs) allow for interactive analysis and visualization of data. The Shiny applications make use of two R packages (shinyLi and GRmetrics) specifically developed for this purpose. The GRmetrics R package is also available via Bioconductor and can be used for offline data analysis and visualization. Source code for the Shiny applications and associated packages (shinyLi and GRmetrics) can be accessed at http://ift.tt/2i1KjHL and http://ift.tt/2gA4zQn.

Conclusions

GRcalculator is a powerful, user-friendly, and free tool to facilitate analysis of dose–response data. It generates publication-ready figures and provides a unified platform for investigators to analyze dose–response data across diverse cell types and perturbagens (including drugs, biological ligands, RNAi, etc.). GRcalculator also provides access to data collected by the NIH LINCS Program (http://ift.tt/1LdKiq5/) and other public domain datasets. The GRmetrics Bioconductor package provides computationally trained users with a platform for offline analysis of dose–response data and facilitates inclusion of GR metrics calculations within existing R analysis pipelines. These tools are therefore well suited to users in academia as well as industry.

http://ift.tt/2gyybxv