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Τρίτη 12 Σεπτεμβρίου 2017

Friendship Selection and Influence Processes for Physical Aggression and Prosociality: Differences between Single-Sex and Mixed-Sex Contexts

Abstract

The present study examined to what extent selection and influence processes for physical aggression and prosociality in friendship networks differed between sex-specific contexts (i.e., all-male, all-female, and mixed-sex classrooms), while controlling for perceived popularity. Whereas selection processes reflect how behaviors shape friendships, influence processes reveal the reversed pattern by indicating how friends affect individual behaviors. Data were derived from a longitudinal sample of early adolescents from Chile. Four all-male classrooms (n = 150 male adolescents), four all-female classrooms (n = 190 female adolescents), and eight mixed-sex classrooms (n = 272 students) were followed one year from grades 5 to 6 (M age = 13). Analyses were conducted by means of stochastic-actor-based modeling as implemented in RSIENA. Although it was expected that selection and influence effects for physical aggression and prosociality would vary by context, these effects showed remarkably similar trends across all-male, all-female, and mixed-sex classrooms, with physical aggression reducing and with prosociality increasing the number of nominations received as best friend in all-male and particularly all-female classrooms. Further, perceived popularity increased the number of friendship nominations received in all contexts. Influence processes were only found for perceived popularity, but not for physical aggression and prosociality in any of the three contexts. Together, these findings highlight the importance of both behaviors for friendship selection independent of sex-specific contexts, attenuating the implications of these gendered behaviors for peer relations.



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Meet Our Editorial Board Member



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Editorial: Teratology and Reproductive Toxicology of Anticancer Agents



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Cytotoxic, Antiproliferative and Apoptotic Effects of Perillyl Alcohol and Its Biotransformation Metabolite on A549 and HepG2 Cancer Cell Lines

Background: A monoterpene, perillyl alcohol, has attracted attention in medicinal chemistry since it exhibited chemo-preventive and therapeutic properties against a variety of cancers. Objective: In the present work, it was aimed to obtain derivatives of perillyl alcohol through microbial biotransformation and investigate their anticancer activities against A549 and HepG2 cancer cell lines. Method: Biotransformation studies were carried out in a α-medium for 7 days at 25oC. XTT assay was performed to investigate the anticancer activities of perillyl alcohol and its biotransformation metabolite, dehydroperillic acid, against A549 and HepG2 cell lines and their selectivity using healthy cell line, NIH/3T3. Cell proliferation ELISA, BRDU (colorimetric) assay was used for measurement of proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analyses were also carried out for measuring apoptotic cell percentages, caspase 3 activation and mitochondrial membrane potential. Results: Biotransformation of perillyl alcohol with Fusarium culmorum yielded dehydroperillic acid in a yield of 20.4 %. In in vitro anticancer studies, perillyl alcohol was found to exert cytotoxicity against HepG2 cell line with an IC50 value of 409.2 μg/mL. However, this effect was not found to be selective because of its higher IC50 (250 μg/mL) value against NIH/3T3 cell line. On the other hand, dehydroperillic acid was found to be effective and also selective against A549 cell line with an IC50 value of 125 μg/mL and a selectivity index (SI) value of 400. Apoptosis inducing effects of dehydroperillic acid was better in A549 cell line. Conclusion: Dehydroperillic acid may be a good candidate for therapy of lung adenocarcinoma and may show this anticancer activity by inducing apoptosis.

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Regulatory Approaches to Nonclinical Reproductive Toxicity Testing of Anti-Cancer Drugs

This paper reviews the nonclinical reproductive toxicity testing of 15 drugs currently approved in the USA or Europe for the treatment of cancer. The list includes cytotoxic anti-tumour agents, small molecule inhibitors of pathways involved in neoplastic proliferation, monoclonal antibodies that target specific antigens expressed by neoplastic cells and supportive therapies used to counter the effects of chemotherapy. Most, but not all, drugs were tested for developmental or reproductive toxicity in animals prior to marketing and most were found to be embryotoxic or teratogenic. Because of the unmet need for comparative safety data on available cancer therapies for use by physicians when treating pregnant patients, at least embryofetal toxicity studies are now usually requested prior to marketing of new anti-cancer drugs, even when the pharmacological profile suggests likely side-effects on the embryo or fetus. Rats and rabbits are the preferred experimental species, but non-human primates have to be used for some biopharmaceuticals. Nonclinical study designs for anti-cancer drugs should be designed to allow the possibility of terminating the study once adverse effects have been demonstrated, without using the full number of animals specified in regulatory guidelines. All 15 drugs are currently labelled as being harmful to pregnancy, ether on the basis of animal data or documented hazards in humans. It is hoped that the forthcoming revision of the FDA drug labelling legislation will allow a better graduation of the relative risk between available anti-cancer therapies.

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Polo-Like Kinase 1 Pharmacological Inhibition as Monotherapy or in Combination: Comparative Effects of Polo-Like Kinase 1 Inhibition in Medulloblastoma Cells

Background: Medulloblastoma (MB) is one of most frequent malignant tumors that affect children. Despite the relatively good survival rate, long time sequels still represent a challenge for MB. Therefore, in an attempt to reduce treatment aftereffects, new therapeutic targets are constantly being explored. Polo like kinase 1 (PLK1) is a master cell cycle regulator that is increased in proliferative cells, while its depletion has been repeatedly proposed as an oncological therapeutic strategy. Objectives: Here, we evaluated and compared the effects of PLK1 inhibition alone and in combination with currently used radio- and chemotherapy in MB cells. Methods: UW402, UW473, ONS-76 and DAOY MB cell lines were treated with BI 2536, BI 6727, GW843682X, and GSK461364 PLK1 inhibitors and cell proliferation, apoptosis, clonogenicity, cell invasion, adhesion and cell cycle distribution were evaluated. In addition, the combinatorial effect with gamma irradiation or etoposide, cisplatin and temozolomide was evaluated. Results: We show that PLK1 inhibition causes a significant decrease on cell proliferation, clonogenic capacity, cell invasion and adhesion, with modest differences between inhibitors. Yet, the four drugs cause G2/M arrest followed by increased cell death. PLK1 inhibition proved to be efficient to sensitize MB cells to radiation irrespective of the inhibitor, even though it showed thrifty results when combined with chemotherapy. Conclusions: We proved that all PLK1 inhibitors have anti-mitotic effects on MB cells, supporting the idea of using them as radiosensitizers. Taken together, our results strengthen the potential of using PLK1 as a therapeutic target to improve treatment strategy for this tumor.

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Retinoic Acid Signaling in P19 Stem Cell Differentiation

Retinoic acid (RA), especially all-trans retinoic acid is the most potent natural metabolite of vitamin A. RA is involved in a variety of biological functions including embryogenesis, cell differentiation and apoptosis. RA acts through its nuclear receptors to induce transcription of specific target genes. Mouse P19 embryonic carcinoma (EC) stem cells (ES) are one of the most studied in vitro systems for RA-induced differentiation. P19 ES cells can differentiate to endodermal-like, mesodermal-like, and neuronal-like phenotypes in response to specific morphogens including RA and dimethyl sulfoxide (DMSO). At low concentrations, RA directs P19 ES cells to differentiate into cells displaying an endodermal phenotype, whereas at higher concentrations it induces differentiation to neuroectoderm. In the past, many RA-­‐regulated genes have been discovered in EC and ES cells and efforts are ongoing to elucidate the exact mechanisms of RA-induced ES cell differentiation and apoptosis. In the RA-triggered differentiation process of the P19 ES cells, several proteins belonging to different families participate, some being obligatory while others, dispensable. Revealing the mechanisms behind RA-induced effects on ES cells has a bearing on understanding how cells proliferate, differentiate and undergo apoptosis that can provide greater insight into cancer biology and therapy. In addition to summarizing the reports on gene/protein targets of RA in stem cells, the signaling pathways driven by some of the specific class of proteins in the presence or absence of RA in P19 ES cell differentiation, especially to an endodermal phenotype, are the focus of this review.

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15,16-dihydrotanshinone I Induces Apoptosis and Inhibits the Proliferation, Migration of Human Osteosarcoma Cell Line 143B in vitro

Background: 15,16-dihydrotanshinone I (DHTI), a lipophilic tanshinone extracted from Danshen root (Salvia miltiorrhiza Bunge), has been reported to function as an antitumor agent. However, its activity on osteosarcoma (OS), the most common primary malignant bone tumor, is unclear. Objective: This study aimed to determine the effects of DHTI treatment on proliferation, apoptosis and migration of human OS cell line 143B and investigate the possible underlying molecular mechanisms. Method: Human cell line 143B was used as a model for investigation of the inhibitory effects of DHTI on osteosarcoma. Cell proliferation was evaluated by MTT assays, while cell cycle progression, apoptosis and cell migration were analyzed by flow cytometer, caspase activity assays and scratch migration assays. qRT-PCR and western blot were carried out to detect the expression levels of representative genes and proteins during physiological processes examined above. Results: DHTI treatment inhibited the proliferation of 143B cells in a dose- and time-dependent manner through arresting cells in G1 phase by reducing the expression of cyclin D1, cyclin E1, CDK2, CDK4, CDK6, p-Rb, E2F1, SKP2 and increasing the expression of P53, P21cip1, P27kip1. In addition, DHTI induced apoptosis of 143B cells through caspase pathways to activate caspase-3, caspase-8, caspase-9, Bax, and PARP cleavage but reduce the expression of Bcl-2. Furthermore, DHTI treatment attenuated cell migration by down-regulating adhesion molecules VCAM-1 and ICAM-1. Conclusion: These findings suggest that DHTI could be a novel and efficient therapeutic candidate for OS treatment and further detailed investigation is warranted.

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Effects of Anticancer Drugs in Reproductive Parameters of Juvenile Male Animals and Role of Protective Agents

Nowadays, the advances in knowledge about oncologic treatment have led to an increase in survival rate for cancer patients and, consequently, a growing concern about the adverse effects of treatment in medium and long term, in order to ensure the future quality of life. For male patients in reproductive age or younger, one of the key concerns after cancer therapy is their ability to father children, since anticancer drugs exert cytotoxic effects on germ cells. Considering the incidence of cancer in children and adolescents and the vulnerability of these developmental phases to chemical injuries, this review is an attempt to highlight the importance of juvenile experimental models to test new anticancer drugs and agents with protective action. There is a relative scarcity of studies investigating the effects of chemotherapy in juvenile animals and an urgent need for further information. As far as this review was able to recover, available data about reproductive toxicology related to peripubertal treatment with anticancer drugs includes only the following pharmaceuticals: toposide, doxorrubicin, cisplatin, ciclophosphamide, cytarabine, flutamide and procarbazine. Together with the evaluation of adverse effects of anticancer drugs, is necessary to investigate possible protective agents to be pre-, co-, or post administrated with chemotherapy. Modern technologies and increasing knowledge about the cancer biology have allowed studies of new chemotherapy strategies, more effective and selective. Many of these compounds are derived from toxins and metabolites of microorganisms, plants, and animals, being a number of them isolated from marine sources, a relatively unexplored environment. Investment in research programs in bioprospecting, especially in marine environments, and pharmaceutical field, including toxicology risk evaluation, are crucial to discovery and improve new anticancer treatments.

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Congenital Malformations Attributed to Prenatal Exposure to Cyclophosphamide

Cyclophosphamide (CPA) remains one of the most widely prescribed anticancer drugs. It is also used in the treatment of rheumatoid arthritis, childhood nephrotic syndrome and systemic lupus erythematosus. It is a potent immunosuppressive agent. It is commonly used in blood and bone marrow transplantation. With the growing trend among women postponing childbearing, the number of women who are diagnosed with breast cancer is also increasing thus escalating the chances of exposure of the unborn child to antineoplastic drugs. A review of the literature provides strong evidence for the teratogenic effects on infants prenatally exposed to CPA. Both sporadic case reports and larger case series have demonstrated that babies with cyclophosphamide embryopathy are afflicted with intrauterine growth restriction, small for gestational age, and craniofacial malformations including eye anomalies, cleft/arched palate, hydrocephaly, micrognathia, low set microtia, hearing defects, craniosynostosis, and facial asymmetry. Also observed in these cases are limb defects such as radial, ulnar and tibial hypoplasia, club foot, digital defects of the hand and feet as well as vertebral fusion, brevicolis, and occasional Sprengel's deformity. These anomalies vary in consistency of occurrence and severity of the phenotype across cases and lack the specificity of thalidomide embryopathy or rubella embryopathy. However, they do occur is no longer in doubt. First trimester of pregnancy seems to be particularly susceptible to fetal malformations, although CPA effects on fetuses of later stages of gestation (hearing defects, growth restriction for example) are also reported occasionally. One of the major concerns from a mechanistic point of view is our inability to dissect the teratogenic effects of CPA from those of other drugs administered together with CPA as combination therapy. Animal experiments have been of particular value in that they are able to circumvent the numerous extraneous variables inherent to human case reports. They have also revealed the detrimental effects of CPA on gametes, preimplantation embryos, organogenesis as well as their potential teratogenic mechanisms. Of particular importance are the role of genetic polymorphisms, male mediated teratogenesis, ovarian failure, preimplantation embryo loss, epigenetic modifications, proxidant-antioxidant imbalance, autophagy, apoptosis, microRNAs and postclosure neural tube defects induced by CPA -all of which are areas for further research in CPA teratogenesis.

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Tocilizumab Labeling with 99mTechnetium via HYNIC as a Molecular Diagnostic Agent for Multiple Myeloma

Background: Multiple myeloma is the second most common hematological malignancy. Interleukin-6 (IL-6) is one of the key molecules related to growth, survival and proliferation of myeloma cells. Tocilizumab is a humanized monoclonal antibody directed against receptor of IL-6. Objective: To radiolabel Tocilizumab with 99mTechnetium as a potential imaging agents for MM. Methods: IL-6R expression was studied by laser confocal microscopy in MM cell lines (U266, NCI-H929 and MM1S). Tocilizumab was derivatized with NHS-HYNIC-Tfa and radiolabeling with 99mTc. Radiochemical stability was determined. In-vitro binding and immunoreactive fraction assays were performed. Biodistribution and SPECT/CT imaging were evaluated in healthy BALB/c and MM-bearing BALB/c nude mice. Results: LCM studies allowed us to demonstrate that U266, NCI-H929 and MM1S cells present high expression of IL-6R in cell membrane. Radiolabeling was carried out in a fast, reproducible, easy and stable way having high radiochemical purity and did not interfere with epitope recognition. The immunoreactive fraction of 99mTc- HYNIC-Tocilizumab was 86.35%. Biodistribution showed a high uptake in liver, spleen, gastrointestinal tract and kidneys. SPECT/CT imaging of MM-bearing BALB/c nude mice showed liver uptake and a high tumor selective uptake at 24 hours. Conclusions: Our results support the potential role of 99mTc-HYNIC-Tocilizumb as a novel MM radiotracer for targeting IL-6 expression in-vivo. We describe the development of a formulation kit to radiolabeling monoclonal antibodies in a clinical setting. We hope that these novel molecular imaging agents will open the path to new diagnostic and therapeutic strategies for MM disease.

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β-lactam Structured, 4-(4-(Methylsulfonyl)phenyl)-1-pentyl-3-phenoxyazetidin-2-one: Selectively Targets Cancerous B Lymphocyte Mitochondria

Background: β lactam-structured Cox-2 inhibitors, possesses anti-proliferative and anti-inflammatory effects. Objective: In this research, the actions of a synthetic β lactam-structured Cox-2 inhibitor with 4-(4- (Methylsulfonyl) phenyl)-1-pentyl-3-phenoxyazetidin-2-one on cellular viability of cancerous lymphoblast obtained from patients with acute lymphocytic leukemia (ALL) and normal lymphocytes obtained from healthy donors were compared. Methods: % the cell viability of cancerouslymphoblasts and normal lymphocytes treated with β lactam derivatives were assayed with MTT test. Early apoptosis and necrosis were detected by double staining of annexin V/ propidium iodide and activity of caspase 3 as the final mediator in apoptotic mode of cell death was evaluated by colorimetric assay. Results: Our results showed that β lactam derivatives inhibited the proliferation of cancerous lymphoblast but not normal lymphocytes in a concentration-dependent mode by inducing apoptosis. Treatment with β lactam derivatives resulted in a rapid loss of mitochondrial trans-membrane potential and induction of reactive oxygen species (ROS) formation, and cytochrome c release in cytosol of mitochondria resulted in activation of procaspase-9 and formation of active apoptosome. Conclusion: These findings suggest that 4-(4-(Methylsulfonyl)phenyl)-1-pentyl-3-phenoxyazetidin-2-one as a β lactam could induce ROS-mediated death signaling throughmitochondrial pathway that results in apoptosis in only cancerous lymphoblast cells. The stimulationof apoptosis by β lactams may provide a pivotal mechanismfor their anticancer effect in acute lymphocytic leukemia cells.

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Pembrolizumab in the treatment of advanced urothelial cancer

Future Oncology, Ahead of Print.


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Tumour-infiltrating lymphocytes (TILs)-related genomic signature predicts chemotherapy response in breast cancer

Abstract

Purpose

The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes.

Methods

We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies.

Results

Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P < 0.001). With the exception of HER2+, the TILs-GS had no prognostic value in subtypes of breast cancers. The Wilcoxon test revealed significantly different TILs-GS levels between the cases with pathological complete response (pCR) and residual disease after anthracycline and taxane-based neoadjuvant chemotherapy, with the exception of the luminal-low proliferation subtype. In the multivariate analysis, pCR was independently associated with smaller tumour size, higher histological grade, ER negativity, HER2 positivity and higher TILs-GS scores (OR 2.02, 95% CI 1.30–3.14, P = 0.025).

Conclusions

TILs-GS was associated with stromal and intra-tumour TILs levels, as evaluated using HE, which predicted prognosis and chemotherapy response in several breast cancer subtypes. Further studies are needed to perform stratification according to TILs-GS levels and the conventional breast cancer subtypes.



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Lasker Awards Honor Three Cancer Researchers [News in Brief]

Prestigious prizes recognize scientists whose work led to HPV vaccine, uncovered role of TOR.



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Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling [Research Briefs]

Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.



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A unified approach to targeting the lysosome's degradative and growth signaling roles. [Research Articles]

Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e. autophagy and macropinocytosis), while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQs) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.



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Bcl-3 induced by IL-22 via STAT3 activation acts as a potentiator of psoriasis-related gene expression in epidermal keratinocytes

IL-22 induces STAT3 phosphorylation and mediates psoriasis-related gene expression. However, the signaling mechanism leading from pSTAT3 to the expression of these genes remains unclear. We focused on Bcl-3, which is induced by STAT3 activation and mediates gene expression. In cultured human epidermal keratinocytes, IL-22 increased Bcl-3, which was translocated to the nucleus with p50 via STAT3 activation. The increases in CXCL8, S100As and human β-defensin 2 mRNA expression caused by IL-22 were abolished by siRNA against Bcl-3. Although CCL20 expression was also augmented by IL-22, the knockdown of Bcl-3 increased its level. Moreover, the combination of IL-22 and IL-17A enhanced Bcl-3 production, IL-22-induced gene expression, and the expression of other psoriasis-related genes, including those encoding IL-17C, IL-19, and IL-36γ. The expression of these genes (except for CCL20) was also suppressed by the knockdown of Bcl-3. Bcl-3 overexpression induced CXCL8 and HBD2 expression but not S100As expression. We also compared Bcl-3 expression between psoriatic skin lesions and normal skin. Immunostaining revealed strong signals for Bcl-3 and p50 in the nucleus of epidermal keratinocytes from psoriatic skin. The IL-22-STAT3-Bcl-3 pathway may be important in the pathogenesis of psoriasis.

This article is protected by copyright. All rights reserved



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Hyperin protects against cisplatin-induced liver injury in mice

Abstract Purpose: To evaluate the effect of hyperin in cisplatin-induced liver injury in mice. Methods: Mice were pretreated with hyperin at doses of 25 mg/kg and 50 mg/kg, respectively, for six days, and intraperitoneal injection of cisplatin (40 mg/kg) was administrated one hour after the final intragastrication of hyperin. Twenty-four hours later, blood and liver were collected for further research. Results: A single injection of cisplatin (40 mg/kg) for 24 h significantly increased serum alanine and aspartate aminotransferases (ALT/AST) and gamma glutamyl transferase (GGT) activities, whileas hyperin reversed cisplatin-induced such increases. Liver histopathological examination further demonstrated the protection of hyperin against cisplatin-induced liver injury. Further results showed hyperin reversed cisplatin-induced the increase in content of malondialdehyde (MDA) and the decrease in level of total antioxidant capacity (T-AOC) in liver. Moreover, hyperin increased the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), glutathione-s transferase (GST) in cisplatin-induced liver. Conclusion: Hyperin inhibits cisplatin-induced hepatic oxidative stress, which contributes greatly to the amelioration of cisplatin-induced liver injury in mice.

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Circulating Cell-free DNA for Metastatic Cervical Cancer Detection, Genotyping and Monitoring

Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA may serve as a unique tumor marker for HPV-associated malignancies, including cervical cancer. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for potential disease monitoring and treatment-related decision making. Patients and Methods: In this retrospective study, HPV ccfDNA was measured in serum samples from 19 metastatic cervical cancer patients by duplex digital droplet (dd) PCR. Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV genotype, drug treatment, and clinical outcome. Results: In blinded tests, HPV ccfDNA was detected in 19/19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87/87 (100%) sequential patient serum samples from 9 patients who received TIL immunotherapy. In three patients who experienced objective cancer regression after TIL treatment, a transient HPV ccfDNA peak was detected 2-3 days after TIL infusion. Furthermore, persistent clearance of HPV ccfDNA was only observed in two patients who experienced complete response (CR) after TIL immunotherapy. Conclusions: HPV ccfDNA represents a promising tumor marker for non-invasive HPV genotyping and may be used in selecting patients for HPV type-specific T cell based immunotherapies. It may also have value in detecting anti-tumor activity of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission.



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TMEM16A/ANO1 inhibits apoptosis via down-regulation of Bim expression

Purpose: TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCC), raising the possibility of an anti-apoptotic role in malignant cells. The present study investigated this using a multi-modal, translational investigation. Experimental Design: Combination of 1) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression 2) in vivo studies assessing similar outcomes, and 3) molecular and staining analysis of human HNSCC samples. Results: TMEM16A expression was found to correlate with greater tumor size, increased Erk 1/2 activity, less Bim expression, and less apoptotic activity overall in human HNSCC. These findings were corroborated in subsequent in vitro and in vivo studies and expanded to include a cisplatin-resistant phenotype with TMEM16A overexpression. A cohort of 41 patients with laryngeal cancer demonstrated that cases that recurred after chemoradiation failure were associated with a greater TMEM16A overexpression rate than HNSCC that did not recur. Conclusions: Ultimately, this study implicates TMEM16A as a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease.



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Facts and Hopes in Immunotherapy of Lymphoma and Myeloma

Immune checkpoint blockade has driven a revolution in modern oncology, and robust drug development of immune checkpoint inhibitors is underway in both solid tumors and hematologic malignancies. High response rates to programmed cell death 1 (PD-1) blockade using nivolumab or pembrolizumab in classical Hodgkin lymphoma (cHL) and several variants of non-Hodgkin lymphoma (NHL) revealed an intrinsic biologic sensitivity to this approach, and work is ongoing exploring combinations with immune checkpoint inhibitors in both cHL and NHL. There are also preliminary data suggesting antitumor efficacy of PD-1 inhibitors used in combination with immunomodulatory drugs in multiple myeloma (MM), and effects of novel monoclonal antibody therapies on the tumor microenvironment may lead to synergy with checkpoint blockade. Although immune checkpoint inhibitors are generally well-tolerated, clinicians must use caution and remain vigilant when treating patients with these agents in order to identify immune related toxicities and prevent treatment-related morbidity and mortality. Autologous stem cell transplant is a useful tool for treatment of hematologic malignancies and has potential as a platform for use of immune checkpoint inhibitors. An important safety signal has emerged surrounding the risk of graft-versus-host-disease (GVHD) associated with use of PD-1 inhibitors before and after allogeneic stem cell transplant. We aim to discuss the facts known to date in the use of immune checkpoint inhibitors for patients with lymphoid malignancies, and discuss our hopes for expanding the benefits of immunotherapy to patients in the future.



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Matrix screen identifies synergistic combination of PARP inhibitors and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in Ewing sarcoma

Purpose: While many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations. Experimental Design: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class. Comprehensive metabolomic and proteomic profiling was performed to better understand the mechanism underlying the synergy. Xenograft experiments were performed to determine efficacy and in vivo mechanism. Results: Several promising candidates emerged, including the combination of small molecule poly ADP-ribose polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, a rational combination as NAMPT inhibitors block the rate-limiting enzyme in the production of NAD+, a necessary substrate of PARP. Mechanistic drivers of the synergistic cell killing phenotype of these combined drugs included depletion of NMN and NAD+, diminished PAR activity, increased DNA damage, and apoptosis. Combination PARP and NAMPT inhibitors in vivo resulted in tumor regression, delayed disease progression and increased survival. Conclusions: These studies highlight the potential of these drugs as a possible therapeutic option in Ewing sarcoma.



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Targeting Prostate Cancer Subtype 1 by Forkhead box M1 Pathway Inhibition

Purpose: Prostate cancer was recently classified to three clinically relevant subtypes (PCS) demarcated by unique pathway activation and clinical aggressiveness. In this preclinical study, we investigated molecular targets and therapeutics for PCS1, the most aggressive and lethal subtype with no treatment options available in the clinic. Experimental Design: We utilized the PCS1 gene set and our model of enzalutamide (ENZR) castration-resistant prostate cancer (CRPC) to identify targetable pathways and inhibitors for PCS1. The findings were evaluated in vitro and ENZR CRPC xenograft model in vivo. Results: The results revealed that ENZR CRPC cells are enriched with PCS1 signature and that Forkhead box M1 (FOXM1) pathway is the central driver of this subtype. Notably, we identified Monensin as a novel FOXM1 binding agent that selectively targets FOXM1 to reverse the PCS1 signature and its associated stem-like features and reduces the growth of ENZR CRPC cells and xenograft tumors. Conclusions: Our preclinical data indicate FOXM1 pathway as a master regulator of PCS1 tumours, namely in ENZR CRPC, and targeting FOXM1 reduces cell growth and stemness in ENZR CRPC in vitro and in vivo. These preclinical results may guide clinical evaluation of targeting FOXM1 to eradicate highly aggressive and lethal PCS1 prostate cancer tumours.



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TOP2A and EZH2 provide early detection of an aggressive prostate cancer subgroup

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer (PCa). Aggressive PCa, defined by the progression from localized disease to metastasis, is responsible for the majority of PCa-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of PCa patients, however they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary PCa cohorts (N = 1,900), two metastatic castration resistant PCa datasets (N = 293) and one prospective cohort (N = 1,385) to assess the impact of TOP2A and EZH2 expression on PCa cellular program and patient outcomes. We also performed immunohistochemical staining for TOP2A and EZH2 in a cohort of primary PCa patients (N = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel PCa-derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic PCa datasets that concurrent TOP2A and EZH2 mRNA and protein up-regulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in PCa cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data supports further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neo-adjuvant targeted therapy approaches.



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Perconditioning combined with postconditioning on kidney ischemia and reperfusion

Abstract Purpose: To evaluate if combination of perconditioning and postconditioning provides improved renal protection compared to perconditioning alone in a model of renal reperfusion injury. Methods: Thirty rats were assigned into 6 groups: normality; sham; ischemia and reperfusion; postconditioning; perconditioning; perconditioning + postconditioning. Animals were subjected to right nephrectomy and left renal ischemia for 30 minutes. Postconditioning consisted of 3 cycles of 5 min renal perfusion followed by 5 min of renal ischemia after major ischemic period. Perconditioning consisted of 3 cycles of 5 min hindlimb ischemia followed by 5 min of hindlimb perfusion contemporaneously to renal major ischemic period. After 24 hours, kidney was harvested and blood collected to measure urea and creatinine. Results: Perconditioning obtained better values for creatinine and urea level than only postconditioning (p<0.01); performing both techniques contemporaneously had no increased results (p>0.05). Regarding tissue structure, perconditioning was the only technique to protect the glomerulus and tubules (p<0.05), while postconditioning protected only the glomerulus (p<0.05). Combination of both techniques shows no effect on glomerulus or tubules (p>0.05). Conclusions: Perconditioning had promising results on ischemia and reperfusion induced kidney injury, enhanced kidney function and protected glomerulus and tubules. There was no additive protection when postconditioning and perconditioning were combined.

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Evaluation of the effectiveness of sodium hyaluronate, sesame oil, honey, and silver nanoparticles in preventing postoperative surgical adhesion formation. An experimental study

Abstract Purpose: To evaluate the effectiveness of sodium hyaluronate, sesame oil, honey, and silver nanoparticles in preventing of postoperative surgical adhesion formation. Methods: Forty male Wistar rats were randomly assigned into five groups with eight rats in each group including control, hyaluronate, sesame, honey and silver groups. After two weeks the animals underwent laparotomy and were evaluated by two different blinded surgeons for severity of adhesions based on the two different classification scoring systems including Nair classification and cumulative adhesion scoring scale. Results: The scores of severity of adhesions in the hyaluronate and sesame groups were significantly lower than the control group based on the Nair classification (both P-values = 0.02), however based on the cumulative adhesion scoring scale just the score of severity of adhesions in the hyaluronate group was significantly lower than the control group (P-value = 0.02). In the hyaluronate group the severity of adhesions was decreased by 48% based on the cumulative adhesion scoring scale. Conclusions: Sodium hyaluronate and sesame oil may have a significant effect in preventing postoperative surgical adhesion formation.

http://ift.tt/2wZou44

Bacterial translocation and mortality on rat model of intestinal ischemia and obstruction

Abstract Purpose: To develop an experimental model of intestinal ischemia and obstruction followed by surgical resection of the damaged segment and reestablishment of intestinal transit, looking at bacterial translocation and survival. Methods: After anesthesia, Wistar rats was subject to laparotomy, intestinal ischemia and obstruction through an ileal ligature 1.5cm of ileum cecal valve; and the mesenteric vessels that irrigate upstream of the obstruction site to approximately 7 to 10 cm were ligated. Abdominal wall was closed. Three, six or twenty-four hours after, rats were subject to enterectomy followed by an end to end anastomosis. After 24h, mesenteric lymph nodes, liver, spleen and lung tissues were surgically removed. It was studied survival rate and bacterial translocation. GraphPadPrism statistical program was used. Results: Animals with intestinal ischemia and obstruction for 3 hours survived 24 hours after enterectomy; 6hx24h: survival was 70% at 24 hours; 24hx24h: survival was 70% and 40%, before and after enterectomy, respectively. Culture of tissues showed positivity on the 6hx24h and negativity on the 3hx24h. Conclusion: The model that best approached the clinic was the one of 6x24h of ischemia and intestinal obstruction, in which it was observed bacterial translocation and low mortality rate.

http://ift.tt/2wZZGcx

Intestinal inflammatory and redox responses to the perioperative administration of teduglutide in rats

Abstract Purpose: To investigate the inflammatory and redox responses to teduglutide on an animal model of laparotomy and intestinal anastomosis. Methods: Wistar rats (n=62) were allocated into four groups: "Ileal Resection and Anastomosis" vs. "Laparotomy", each one split into "Postoperative Teduglutide Administration" vs. "No Treatment"; and euthanized at the third or the seventh day. Ileal and blood samples were recovered at the baseline and at the euthanasia. Flow cytometry was used to study the inflammatory response (IL-1α, MCP-1, TNF-α, IFN-γ and IL-4 levels), oxidative stress (cytosolic peroxides, mitochondrial reactive species, intracellular glutathione and mitochondrial membrane potential) and cellular viability and death (annexin V/propidium iodide double staining). Results: Postoperative teduglutide treatment was associated with higher cellular viability index and lower early apoptosis ratio at the seventh day; higher cytosolic peroxides level at the third day and mitochondrial overgeneration of reactive species at the seventh day; higher tissue concentration of IL-4 and lower local pro-to-anti-inflammatory cytokines ratio at the seventh day. Conclusion: Those findings suggest an intestinal pro-oxidative and anti-inflammatory influence of teduglutide on the peri-operative context with a potential interference in the intestinal anastomotic healing.

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A study on reducing the absorption of lidocaine from the airway in cats

Abstract Purpose: To determine if the combination of lidocaine with epinephrine or gamma globulin would decrease the rate or reduce the amount of local absorption of lidocaine through the airway. Methods: Twenty adult male cats were randomly and evenly distributed into four groups: 1) Group LG: lidocaine administered with gamma globulin; 2) Group LS: lidocaine administered with physiological saline); 3) Group LE: lidocaine administered with epinephrine; 4) Group C: control group. Invasive blood pressure, heart rate, and concentration of lidocaine were recorded before and after administration. Results: The peak of plasma concentrations appeared difference (Group LG: 1.39 ± 0.23 mg/L; Group LS: 1.47 ± 0.29 mg/L and Group LE: 0.99 ± 0.08 mg/L). Compared to Group C, there were significant differences in the average heart rate of Groups LG, LS, and LE (P < 0.05). The average systolic blood pressures were significantly different when each group was compared to Group C (P < 0.05). The biological half-life, AUC0-120, peak time, and half-life of absorption among the three groups have not presented statistically significant differences (P > 0.05). Conclusion: Administering lidocaine in combination with gamma globulin through airway causes significant decrease the rate and reduce the amount of local absorption of lidocaine in cats.

http://ift.tt/2x04kar

Use of fibrinogen and thrombin sponge in pediatric split liver transplantation

Abstract Purpose: To analyze the use of this sponge in pediatric patients undergoing split-liver transplantation. Methods: Retrospective study, including 35 pediatric patients undergoing split-liver transplantation, divided into two groups according to the use of the sponge: 18 patients in Group A (no sponge) and 17 in Group B (with sponge). Results: The characteristics of recipients and donors were similar. We observed greater number of reoperation due to bleeding in the wound area in Group A (10 patients - 55.5%) than in Group B (3 patients - 17.6%); p = 0.035. The median volume of red blood cells transfused in Group A was significantly higher (73.4 ± 102.38 mL/kg) than that in Group B (35.1 ± 41.67 mL/kg); p = 0.048. Regarding bile leak there was no statistical difference. Conclusion: The use of the human fibrinogen and thrombin sponge, required lower volume of red blood cell transfusion and presented lower reoperation rates due to bleeding in the wound area.

http://ift.tt/2woqQpB

Fixation of the short-term central venous catheter. A comparison of two techniques

Abstract Purpose: To compare the fixation of the central venous catheter (CVC) using two suture techniques. Methods: A clinical, analytical, interventional, longitudinal, prospective, controlled, single-blind and randomized study in adult, intensive care unit (ICU) patients. After admission and indication of CVC use, the patients were allocated to the Wing group (n = 35, catheter fixation with clamping wings and retainers) or Shoelace group (n = 35, catheter fixation using shoelace cross-tied sutures around the device). Displacement, kinking, fixation failure, hyperemia at the insertion site, purulent secretion, loss of the device, psychomotor agitation, mental confusion, and bacterial growth at the insertion site were evaluated. Results: Compared with the Wing group, the Shoelace group had a lower occurrence of catheter displacement (n=0 versus n =4; p = 0.04), kinking (n=0 versus n=8; p=0.001), and fixation failure (n=2 versus n=8; p=0.018). No significant difference was found in bacterial growth (n=20 versus n=14; p=0.267) between groups. Conclusion: The Shoelace fixation technique presented fewer adverse events than the Wing fixation technique.

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On authorship in the BJCP



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Issue Information

No abstract is available for this article.



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Issue highlights



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Postoperative Delirium in Indian Patients Following Major Abdominal Surgery for Cancer: Risk Factors and Associations

Abstract

Postoperative delirium (POD) is not uncommon following major abdominal surgery with its incidence ranging between five and 51%. As cancer affects disproportionately, the population older than 65 years and as delirium is more common in the elderly, surgical oncology patients are at a higher risk of developing POD. The present study was undertaken to explore the impact and associations of POD in Indian patients undergoing oncological major abdominal surgery. A retrospective review of the electronic medical records in a tertiary cancer care institution of all postoperative patients who had undergone major gastrointestinal gynaecological and urological abdominal surgery for cancer and required psycho-oncology referral was performed. Patient, surgery and postoperative outcome-related data were collected. Statistical analysis was performed using univariate and multivariate logistic regression analysis. Out of 824 patients who underwent major abdominal surgery, 33 patients (4.0%) were diagnosed with POD. In univariate analysis, older age and history of addiction were found to be statistically significantly associated with POD (p < 0.001). Among the postoperative factors, respiratory complications (p < 0.001), sepsis (p < 0.05), ICU stay > 24 h (p < 0.05) and electrolyte impairment (p < 0.05) were the significant associations with the POD. Thirty-day mortality was higher in the POD group (p < 0.05). In multivariate logistic regression analysis, advanced age, addictions, respiratory complications and sepsis were found to be significant associations with POD, p < 0.001. Postoperative delirium is associated with higher mortality. Older age, postoperative respiratory complications and sepsis are common contributory factors of postoperative delirium.



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Response

We appreciate Dr. Kawada for your attention on our paper and thanks for your comments.

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Is There Ever a Role for the Unilateral Do Not Attempt Resuscitation Order in Pediatric Care?

Care for children as they near the end of life is difficult and very complex. More difficult still are the decisions regarding what interventions are and are not indicated during these trying times. Occasionally, families of children who are nearing the end of life disagree with the assessment of the medical team regarding these interventions. In rare cases, the medical team can be moved to enact a do not attempt resuscitation (DNAR) order against the wishes of the patient's parents. This manuscript presents one such illustrative case and discusses the ethical issues relevant to such challenging clinical scenarios.

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Utilization of hospice services in a population of patients with Huntington's Disease

Although the early and middle stages of Huntington's Disease (HD) and its complications have been well described, less is known about the course of late-stage illness. In particular, little is known about the population of patients who enroll in hospice.

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Characteristics of Older Adults in Primary Care Who May Benefit from Primary Palliative Care in the United States

Older adults with advanced illness and associated symptoms may benefit from primary palliative care, but limited data exist to identify older adults in U.S. primary care to benefit from this care.

http://ift.tt/2xv0bwo

Re: Association of inflammatory cytokines with the symptom cluster of pain, fatigue, depression, and sleep disturbance in Chinese patients with cancer

Ji et al examined the association between inflammatory cytokines and cluster symptoms on pain, fatigue, depression, and sleep disturbance in patients with cancer.1 Multiple logistic regression analysis was applied in 153 in-patients with cancer, composed of 125 patients with all low symptoms (subgroup 1) and 28 patients with moderate-to-high symptoms on 4 items (subgroup 3). Adjusted odds ratios (95% confidence intervals) of subgroup 3 against subgroup 1 for increased serum interleukin-6 level and poorer Eastern Cooperative Oncology Group (ECOG) physical performance status were 1.246 (1.114-1.394) and 31.831 (6.017-168.385), respectively.

http://ift.tt/2y3lFh9

Full Monte Carlo-based biological treatment plan optimization system for intensity modulated carbon ion therapy on GPU

One of the major benefits of carbon ion therapy is enhanced biological effectiveness at the Bragg peak region. For intensity modulated carbon ion therapy (IMCT), it is desirable to employ Monte Carlo (MC) methods to compute properties of each pencil-beam spot for treatment planning, because of their accuracy in modeling physics processes and estimating biological effects. We have previously developed goCMC, a graphics processing unit (GPU)-oriented MC engine for carbon ion therapy. The purpose of this study is to build a biological treatment plan optimization system based on goCMC.

http://ift.tt/2vSh5kp

Association between Exposure to Traffic-Related Air Pollution and Prevalence of Allergic Diseases in Children, Seoul, Korea

Although there has been suggestive evidence of the association between TRAP and ADs, findings remained inconsistent possibly due to limited population. We investigated the association between TRAP and ADs in a large population of children with rich spatial coverage and expanded age span in Seoul, Korea. TRAP exposures were estimated by categorized proximity to the nearest major road (≤150, 150–300, 300–500, and >500 m) and density of major roads within 300 meters from children's residences. We estimated the association between two TRAP exposures and three ADs using generalized mixed model after adjusting for individual characteristics. We also investigated whether the association varied by household and regional socioeconomic status. We found associations of atopic eczema with road density [OR = 1.08; 95% CI = 1.01–1.15] and road proximity [1.15, 1.01–1.32; 1.17, 1.03–1.34; and 1.16, 1.01–1.34 for ≤150, 150–300, and 300–500 m, resp., compared to >500 m]. There was no association with asthma and allergic rhinitis. Effect estimates were generally the highest in the low socioeconomic region. Children living in areas surrounded by large and busy roads were likely to be at greater risks for atopic eczema, with increased vulnerability when living in deprived areas.

http://ift.tt/2y3a5m9

Tapered, Double-Lead Threads Single Implants Placed in Fresh Extraction Sockets and Healed Sites of the Posterior Jaws: A Multicenter Randomized Controlled Trial with 1 to 3 Years of Follow-Up

Purpose. To evaluate the survival, success, and complication rates of tapered double-lead threads single implants, placed in fresh extraction sockets and healed sites of the posterior jaws. Methods. The enrolled patients were randomly divided into 2 groups: in the test group (TG), all implants were inserted at the time of tooth extraction; in the control group (CG), all implants were placed 3 months after extraction. The implants were followed for a period of 1 to 3 years after loading. The main outcomes were implant survival, complications, and implant-crown success. Results. Ninety-two patients had 97 installed implants (49 in the TG, 48 in the CG). Only two implants failed, in the TG; the survival rates were therefore 95.9% (47/49) and 100% (48/48) for TG and CG, respectively. In the surviving implants, no complications were reported, for an implant-crown success of 100%. Conclusions. Although a significant difference was found in the levels of primary stability between TG and CG, single implants placed in fresh extraction sockets and healed sites of the posterior jaws had similar survival and complication rates. Crestal bone levels and peri-implant bone resorption showed similar values. A longer follow-up period is however required, to confirm these positive outcomes.

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Role of diuretics in the harmful effects of beta blockers in patients with ascites



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Diabetes Infusion Sets by Medtronic: Recall - Vent Membrane May be Susceptible to Being Blocked by Fluid

[Posted 09/12/2017] AUDIENCE: Patient, Nursing, Risk Manager ISSUE: Medtronic is informing patients worldwide of a voluntary recall of specific lots of infusion sets used with all models of Medtronic insulin pumps. The recall is related to a...

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Diabetes Infusion Sets by Medtronic: Recall - Vent Membrane May be Susceptible to Being Blocked by Fluid

[Posted 09/12/2017] AUDIENCE: Patient, Nursing, Risk Manager ISSUE: Medtronic is informing patients worldwide of a voluntary recall of specific lots of infusion sets used with all models of Medtronic insulin pumps. The recall is related to a...

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BRAF mutation as a novel driver of eosinophilic cystitis

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A study on different therapies and prognosis-related factors for 101 patients with SCLC and brain metastases

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Clinicopathological characteristics and experience in the treatment of giant retroperitoneal liposarcoma: A case report and review of the literature

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Targeted Therapy and Local Control: The Dynamic Duo



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Usefulness of Mapping Biopsy in the Treatment of Penoscrotal Extramammary Paget’s Disease

Abstract

Background

Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy; however, the standard treatment of EMPD has not been established. In this study, we applied mapping biopsy to penoscrotal EMPD and evaluated its effects.

Methods

A retrospective chart review was performed to determine the outcomes of patients with primary penoscrotal EMPD who underwent surgery at our institution between 2007 and 2014. Patients were divided into two groups (one group underwent mapping biopsy, while the other group did not), and the difference between the two groups was analyzed. The 5-year tumor-free rate was estimated using the Kaplan–Meier method, and the risk factors for local recurrence were also estimated.

Results

A total of 44 patients were analyzed, and the mean follow-up of patients was 50.27 months. Patients who underwent mapping biopsy showed significantly lower tumor involvement at permanent and frozen biopsies and a lower local recurrence rate than those who did not undergo mapping biopsy. The 5-year tumor-free rate was significantly higher in the mapping biopsy group than in the non-mapping biopsy group. Multivariable analysis demonstrated that age at operation, mapping biopsy, and false-negative results at frozen biopsy were associated with local recurrence.

Conclusions

Mapping biopsy is beneficial to reduce local recurrence in penoscrotal EMPD.



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Impact of Sustained Virological Response to Interferon Therapy on Recurrence of Hepatitis C Virus-Related Hepatocellular Carcinoma

Abstract

Background

Although achieving a sustained virological response (SVR) in hepatitis C virus (HCV) infection is recognized as improving liver function and reducing hepatocellular carcinoma (HCC) development, its impact on HCC recurrence is unclear. This study investigated how preoperative SVR achievement by interferon treatment affects HCC recurrence in patients undergoing hepatic resection.

Methods

The study subjects were 521 patients with HCV infection who underwent initial and curative hepatic resection for HCC. To adjust for confounding factors between the SVR and non-SVR groups, propensity score-matching analysis was performed.

Results

After propensity score matching, 45 of the 49 patients in the SVR group, and an equal number of the 472 patients in the non-SVR group, were matched. The two groups had similar distributions of clinicopathological characteristics. In the matched cohort, the 3-, 5-, and 7-year recurrence-free survival rates after surgery were 56, 45, and 37%, respectively, in the SVR group, and 34, 23, and 7.2%, respectively, in the non-SVR group (p = 0.033). Additionally, the 3-, 5-, and 7-year overall survival rates after surgery were 82, 80, and 75%, respectively, in the SVR group, and 78, 64, and 44%, respectively, in the non-SVR group (p = 0.065). The 1- and 2-year cumulative recurrence rates in the early phase showed no significant difference between the SVR and non-SVR groups (p = 0.27). however, the 3-, 5-, and 7-year cumulative recurrence rates in the late phase were 14, 32, and 43%, respectively, in the SVR group, and 33, 55, and 86%, respectively, in the non-SVR group (p = 0.037).

Conclusion

Achievement of SVR may reduce postoperative recurrence after hepatic resection.



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Impact of Patient Age on the Postoperative Survival in Pancreatic Head Cancer

Abstract

Background

Some reports have stated that pancreatoduodenectomy for elderly patients have comparable morbidity and mortality to that of young patients. However, the long-term outcomes of these patients have not been fully evaluated, especially for pancreatic head cancer.

Methods

A total of 227 patients who underwent pancreatoduodenectomy for pancreatic head cancer between 2007 and 2014 were included. They were stratified according to age: young (<70 years), elderly (70 to <80 years), and very elderly (≥80 years). The short- and long-term outcomes were evaluated.

Results

There were no significant differences in terms of morbidity among the three groups. The median disease-free survival times were 15 months in the young, 11 months in the elderly, and 7 months in the very elderly. The disease-free survival of the young patients was significantly better than that in both the elderly and the very elderly (p = 0.012 and p = 0.016). The median overall survival times were 30 months in the young, 20 months in the elderly, and 14 months in the very elderly. The overall survival of the young patients was significantly better than that in both the elderly and the very elderly (p = 0.007 and p < 0.001). The difference was marginal between the elderly and the very elderly (p = 0.053). Multivariate analysis revealed that lymph node metastasis (p < 0.001), age ≥80 years (p = 0.013), lack of adjuvant chemotherapy (p = 0.003), blood transfusion (p = 0.015), and CA 19-9 ≥300 U/ml (p = 0.040) were significant prognostic factors.

Conclusions

Patient age influenced the survival after pancreatoduodenectomy for pancreatic cancer.



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2017 Update on the Querleu–Morrow Classification of Radical Hysterectomy

Abstract

Background

One of the most important principles in modern cervical cancer surgery is the concept of tailoring surgical radicality. In practice, this means abandoning the "one-fits-all" concept in favor of tailored operations. The term "radical hysterectomy" is used to describe many different procedures, each with a different degree of radicality. Anatomic structures are subjected to artificial dissection artifacts, as well as different interpretations and nomenclatures. This study aimed to refine and standardize the principles and descriptions of the different classes of radical hysterectomy as defined in the Querleu–Morrow classification and to propose its universal applicability.

Methods

All three authors independently examined the current literature and undertook a critical assessment of the original classification. Images and pathologic slides demonstrating different types of radical hysterectomy were examined to document a consensual vision of the anatomy. The Cibula 3-D concept also was included in this update.

Results

The Querleu–Morrow classification is based on the lateral extent of resection. Four types of radical hysterectomy are described, including a limited number of subtypes when necessary. Two major objectives remain constant: excision of central tumor with clear margins and removal of any potential sites of nodal metastasis.

Conclusion

Studies evaluating radicality in the surgical management of cervical cancer should be based on precise, universally accepted descriptions. The authors' updated classification presents standardized, universally applicable descriptions of different types of hysterectomies performed worldwide, categorized according to degree of radicality, independently of theoretical considerations.



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Sustained Growth of a University-Based Endocrine Surgery Program Over 10 Years

Abstract

Background

Endocrine surgery continues to mature as a subspecialty field. We describe the clinical performance of an academic endocrine surgery program (ESP) over its first 10 years.

Methods

We examined all endocrine procedures performed during the 10-year period (2006–2015) following the inception of the ESP. Institutional and state-level data on case volume, patient geographic origin, and hospital-side costs were obtained.

Results

Endocrine case volume increased by approximately ninefold over the study period (from 102 cases in 2006 to 919 cases in 2015). The rate of growth remained approximately linear, and was driven by geographic expansion of referral regions coupled with transitioning low- to moderate-acuity operations to venues outside of the main tertiary care hospital. Market share across the eight-county Southern California region grew by more than twofold over the study period. Increased utilization of outpatient surgery led to cost reductions, averaging 11.1% per case by 2015.

Conclusions

Establishment of an academic ESP can lead to sustained clinical growth and a fundamental shift in regional referral patterns. The nation's continued need for skilled high-volume endocrine surgeons represents opportunities for medical centers to institute their own dedicated endocrine surgery programs.



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Usefulness of Mapping Biopsy in the Treatment of Penoscrotal Extramammary Paget’s Disease



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Optimal Lymphadenectomy for Duodenal Adenocarcinoma: Does the Number Alone Matter?

Abstract

Background

Duodenal adenocarcinoma (DA) is a rare disease, and the optimal extent of lymphadenectomy and the role of limited resection remain controversial.

Objective

The aim of our study was to assess the pattern of regional lymph node spread of DA and to determine the optimal extent of resection.

Methods

A total of 65 patients who underwent curative resection for DA at our institution from 1989 through 2015 were included in this study. Clinicopathologic factors associated with long-term outcomes and the patterns of regional node spread per primary tumor location were evaluated.

Results

Fifty-one patients (78%) underwent pancreaticoduodenectomy (PD), with the remainder undergoing limited resection. The median number of retrieved lymph nodes was 24 (range 1–63) and 48% of patients had regional node metastasis. The 5-year overall survival (OS) rate was 67%. In the multivariate analysis, regional node and para-aortic lymph node metastasis were risk factors associated with poorer OS (hazard ratio [HR] 12.1 [p = 0.025], and HR 3.2 [p = 0.045], respectively). While pancreaticoduodenal (#13) and superior mesenteric (#14) lymph node stations were commonly involved by both distal and proximal DA (33 vs. 39% for #13, p = 0.39; and 33 vs. 22% for #14, p = 0.27), the pyloric lymph node station was much less involved by distal DA than proximal DA (0 vs. 37%, p = 0.036).

Conclusion

The pancreaticoduodenal lymph node station was the most commonly involved lymph node in DA, and PD should be the standard operation for DA. Segmental resection should only be reserved for patients with distal DA who are physically unfit for PD.



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Survival Rates for Patients with Resected Gastric Adenocarcinoma Finally have Increased in the United States

Abstract

Background

In the United States, the overall survival rates for gastric adenocarcinoma have remained low, with surgical resection as the only therapy for many patients. Given the advances in multimodality treatment and the development of guidelines recommending adequate lymph node evaluation, the authors determined whether overall survival rates for patients with gastric adenocarcinoma have increased in the United States.

Methods

The study used the Surveillance Epidemiology and End Results (SEER) database to examine overall survival for patients with the diagnosis of gastric adenocarcinoma between 1988 and 2013. The study cohort was divided into five periods: 1988–1992, 1993–1997, 1998–2002, 2003–2007, and 2008–2013. Kaplan–Meier methods and Cox proportional hazards modeling were used to determine the effect that year of diagnosis had on overall survival.

Results

The diagnosis was determined for 13,470 patients between 1988 and 2013. The use of radiation therapy and the proportion of patients who had at least 15 lymph nodes evaluated significantly increased during the study period. Unadjusted Kaplan–Meier estimates demonstrated significantly better survival rates for the patients with a diagnosis of gastric cancer in the later periods (2003–2007 and 2008–2013) than for those in the three earlier periods. In our Cox proportional hazards model, recent period was associated with a significantly lower hazard of 5-year mortality.

Conclusion

This analysis demonstrated for the first time that gastric cancer survival rates have significantly improved in the United States during the past 2 decades. This observation likely reflects improved adherence to cancer treatment guidelines, including adequate lymph node evaluation and delivery of adjuvant treatment more consistently.



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Hybrid cell-centred/vertex model for multicellular systems with equilibrium-preserving remodelling

Abstract

We present a hybrid vertex/cell-centred model for mechanically simulating planar cellular monolayers undergoing cell reorganisation. Cell centres are represented by a triangular nodal network, while the cell boundaries are formed by an associated vertex network. The two networks are coupled through a kinematic constraint which we allow to relax progressively. Special attention is paid to the change of cell-cell connectivity due to cell reorganisation or remodelling events. We handle these situations by using a variable resting length and applying an Equilibrium-Preserving Mapping (EPM) on the new connectivity, which computes a new set of resting lengths that preserve nodal and vertex equilibrium. We illustrate the properties of the model by simulating monolayers subjected to imposed extension and during a wound healing process. The evolution of forces and the EPM are analysed during the remodelling events. As a by-product, the proposed technique enables to recover fully vertex or fully cell-centred models in a seamless manner by modifying a numerical parameter of the model. This article is protected by copyright. All rights reserved.



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HU content and dynamics in E. coli during the cell cycle and at different growth rates

Abstract
DNA binding proteins play an important role in maintaining bacterial chromosome structure and functions. HU histone-like protein is one of the most abundant of these proteins and participates in all major chromosome-related activities. Owing to its low sequence specificity, HU fusions with fluorescent proteins were used for general staining of the nucleoid, aiming to reveal its morphology and dynamics. We have exploited a single chromosomal copy of hupA-egfp fusion under the native promoter and used quantitative microscopy imaging to investigate the amount and dynamics of HUα in E. coli cells. We found that in steady-state growing populations the cellular HUα content is proportional to the cell size, whereas its concentration is size independent. Single-cell live microscopy imaging confirmed that the amount of HUα exponentially increases during the cell cycle, but that its concentration is maintained constant. This supports the existence of an auto-regulatory mechanism underlying the HUα cellular level, in addition to reflecting the gene copy number. Both the HUα amount and concentration strongly increase with the cell growth rate in different culture media. Unexpectedly, the HU/DNA stoichiometry also remarkably increases with the growth rate. This last finding may be attributed to a higher requirement for maintaining the chromosome structure in nucleoids with higher complexity.

http://ift.tt/2f3pONd

HM2-phage resistant solventogenic Clostridium saccharoperbutylacetonicum N1-4 shows increased exopolysaccharide production

Abstract
During the history of the solventogenic clostridia fermentation industry, bacteriophages have been a recurrent problem. This study reports that HM2, a lytic bacteriophage for the solventogenic Clostridium saccharoperbutylacetonicum N1–4 (N1–4), has a genome size of 17,470 bps with 22 ORFs, including replication, lysis, integration and structural modules. To understand the HM2 infection and resistance in N1–4, bacteriophage insensitive mutants (BIMs) were isolated and characterized. These 8 independent BIMs included 4 adsorption-mediated and 4 non-adsorption types. Adsorption-mediated BIMs had increased EPS production and decreased attachment of HM2 to the cell surface. Non-adsorption mediated BIMs had a moderate increase in EPS production, which did not impact HM2 attachment. Absorption-mediated BIMs had reduced fermentation performance whereas the non-absorption mediated BIMs were indistinguishable from N1–4. Consequently, non-adsorption mediated BIMs would be more useful in a fermentation since they couple good fermentation performance with phage resistance.

http://ift.tt/2wYLDSG

Bioactive and biocontrol potential of endophytic fungi associated with Brugmansia aurea Lagerh.

Abstract
The present study describes 32 fungal endophytes isolated from different tissues of Brugmansia aurea Lagerh. Each fungal strain was authenticated based on ITS rDNA sequence. Phylogenetic analysis showed that these fungi are distributed in 3 classes, 7 orders and 12 genera. The dichloromethane extracts of endophytic strains were screened for anticancer and antimicrobial activity. Anticancer activity of extracts against human cancer cell lines revealed that fifty % strains are active with IC50 < 10 μg/mL. While analysing antimicrobial potential against both gram positive and gram negative bacteria, 56.25% endophytic strains displayed activity at least against one of the tested human pathogenic bacteria with minimum inhibitory concentration of 12.5–100 μg/mL. In vitro antagonistic activity of endophytes was analysed against Sclerotinia sp., Aspergillus fumigatus, Fusarium solani, Aspergillus flavus and Fusarium oxysporum pathogen. The broad spectrum anti-phytopathogenic activity was shown by R2BA. Presence of KS domain of PKS gene and high degree of bioactivity shown by endophytic fungi suggested that they have potential to produce therapeutic compounds and to serve as biocontrol agent.

http://ift.tt/2f3pIVR

Prognostic value of systemic immune-inflammation index in patients with gastric cancer

Inflammation-based indexes have been used to predict survival and recurrence in cancer patients. Systemic immune-inflammation index (SII) was reported to be associated with prognosis in some malignant tumors. ...

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A patient with mitochondrial disorder due to a novel mutation in MRPS22

Abstract

MRPS22 gene defect is a very rare newly discovered mitochondrial disorder. We report a 4-month-old severely affected male infant with MRPS22 mutation. Whole exome sequencing revealed a novel homozygous splicing mutation c.339 + 5 G > A in MRPS22 gene. He has mild dysmorphism, hypotonia, developmental delay but not hypertrophic cardiomyopathy and tubulopathy which differ from other majority of reported patients. Therefore, hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22. With this case report, we also present first symmetrical bilateral brainstem and medial thalamic lesions, and cerebellar and cerebral atrophy on a brain MR imaging follow-up of ten months.



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Neuropilin-2 rs849563 gene variations and susceptibility to autism in Iranian population: A case-control study

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disruptions usually diagnosed in the first three years of child's life that characterized by some impairments in verbal and nonverbal communication, problems in social interactions and repetitive behaviors. The neuropilin-2 (NRP2) gene has been shown to both guide axons and control neuronal migration in the central nervous system (CNS). In this study the association between the NRP2 gene and autism using a cohort of 120 Iranian children (50 cases with autism and 70 control cases) was analyzed. Single nucleotide polymorphism (SNP) was genotyped by the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analyses. There was significant difference between the genotype and allele frequency between control and patient groups (P = 0.003 and P = 0.01, respectively). The prevalence of genotype frequencies of TT and TG in autistic children were 40% and 60%, respectively, while in controls were 68.5% and 31.5%, respectively. The heterozyote TG was associated with an increased risk of autism compared with TT genotype (OR = 3.72, 95%CI = 1.53–6.95, P = 0.02). The allele frequencies of T and G in autistic children were 78.5% and 21.4%, respectively and in controls were 84.2% and 15.7%, respectively. The NRP2 G allele conferred a 2.29-fold increased risk to autism relative to the T allele (OR = 2.29, 95%CI = 1.23–4.29, P = 0.009). The results of this study showed that there is a significant association between rs849563 polymorphism and autism in the studied population. However in order to obtain a definitive conclusion larger studies with more samples are required to confirm the results of this study.



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DRα1-MOG-35-55 treatment reduces lesion volumes and improves neurological deficits after traumatic brain injury

Abstract

Traumatic brain injury (TBI) results in severe neurological impairments without effective treatments. Inflammation appears to be an important contributor to key pathogenic events such as secondary brain injury following TBI and therefore serves as a promising target for novel therapies. We have recently demonstrated the ability of a molecular construct comprised of the human leukocyte antigen (HLA)-DRα1 domain linked covalently to mouse (m)MOG-35-55 peptide (DRα1-MOG-35-55 construct) to reduce CNS inflammation and tissue injury in animal models of multiple sclerosis and ischemic stroke. The aim of the current study was to determine if DRα1-MOG-35-55 treatment of a fluid percussion injury (FPI) mouse model of TBI could reduce the lesion size and improve disease outcome measures. Neurodeficits, lesion size, and immune responses were determined to evaluate the therapeutic potential and mechanisms of neuroprotection induced by DRα1-MOG-35-55 treatment. The results demonstrated that daily injections of DRα1-MOG-35-55 given after FPI significantly reduced numbers of infiltrating CD74+ and CD86+ macrophages and increased numbers of CD206+ microglia in the brain concomitant with smaller lesion sizes and improvement in neurodeficits. Conversely, DRα1-MOG-35-55 treatment of TBI increased numbers of circulating CD11b+ monocytes and their expression of CD74 but had no detectable effect on cell numbers or marker expression in the spleen. These results demonstrate that DRα1-MOG-35-55 therapy can reduce CNS inflammation and significantly improve histological and clinical outcomes after TBI. Future studies will further examine the potential of DRα1-MOG-35-55 for treatment of TBI.



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Coenzyme Q10 and niacin mitigate streptozotocin- induced diabetic encephalopathy in a rat model

Abstract

Diabetic encephalopathy is an important complication of diabetes characterized by cognitive impairment, neurochemical and structural abnormalities. This study aimed to investigate the effect of coenzyme Q10 (CoQ10) and niacin as well as their combination in the treatment of encephalopathy associated with streptozotocin (STZ)- induced diabetes in rats. Glibenclamide (reference diabetic drug) and donepezil hydrochloride (acetylcholinesterase inhibitor) were also evaluated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). One month after STZ injection, diabetic rats were treated with the aforementioned drugs for two weeks. The evaluation was done through measuring glucose level, total antioxidant capacity (TAC), interleukin 6 (IL6), DNA degradation as well as serotonin and noradrenaline as neurotransmitters. The present data illustrated that combining CoQ10 and niacin exhibiting the most potent effect in improving the measured parameters and ameliorating some of diabetes complications.



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Intervention Mapping Approach in the Design of an Interactive Mobile Health Application to Improve Self-care in Heart Failure.

Heart failure is a complex syndrome among older adults who may experience and interpret symptoms differently. These differences in symptom interpretation may influence decision-making in symptom management. A well-informed and motivated person may develop the knowledge and skills needed to successfully manage symptoms. Therefore, the patient-centered mobile health application HeartMapp was designed to engage patients with heart failure in self-care management by offering tailored alerts and feedback using mobile phones. The main objective of this article is to describe the six-step intervention mapping approach including (1) the initial needs assessment, (2) proximal program objective, (3) selection of theory-based methods, (4) the translation of objectives into an actual program plan for mobile health intervention, (5) adaptation and implementation plan, and (6) evaluation plan that assisted the team in the development of a conceptual framework and intervention program matrix during the development of HeartMapp. The HeartMapp intervention takes the information, motivation, and behavioral skills model as the theoretical underpinning, with "patient engagement" as the key mediator in achieving targeted and persistent self-care behavioral changes in patients with heart failure. The HeartMapp intervention is proposed to improve self-care management and long-term outcomes. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Nucleolar and spindle associated protein 1 promotes the aggressiveness of astrocytoma by activating the Hedgehog signaling pathway

Abstract

Background

The prognosis of human astrocytoma is poor, and the molecular alterations underlying its pathogenesis still needed to be elucidated. Nucleolar and spindle associated protein 1 (NUSAP1) was observed in several types of cancers, but its role in astrocytoma remained unknown.

Methods

The expression of NUSAP1 in astrocytoma cell lines and tissues were measured with western blotting and Real-Time PCR. Two hundred and twenty-one astrocytoma tissue samples were analyzed by immunochemistry to demonstrate the correlation between the NUSAP1 expression and clinicopathological characteristics. 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, colony formation, transwell matrix penetration assay, wound healing assay and anchorage-independent growth assay were used to investigate the biological effect of NUSAP1 in astrocytoma. An intracranial brain xenograft tumor model was used to confirm the oncogenic role of NUSAP1 in human astrocytoma. Luciferase reporter assay was used to investigate the effect of NUSAP1 on Hedgehog signaling pathway.

Results

NUSAP1 was markedly overexpressed in astrocytoma cell lines and tissues compared with normal astrocytes and brain tissues. NUSAP1 was found to be overexpressed in 152 of 221 (68.78%) astrocytoma tissues, and was significantly correlated to poor survival. Further, ectopic expression or knockdown of NUSAP1 significantly promoted or inhibited, respectively, the invasive ability of astrocytoma cells. Moreover, intracranial xenografts of astrocytoma cells engineered to express NUSAP1 were highly invasive compared with the parental cells. With regard to its molecular mechanism, upregulation of NUSAP1 in astrocytoma cells promoted the nuclear translocation of GLI family zinc finger 1 (GLI1) and upregulated the downstream genes of the Hedgehog pathway.

Conclusion

These findings indicate that NUSAP1 contributes to the progression of astrocytoma by enhancing tumor cell invasiveness via activation of the Hedgehog signaling pathway, and that NUSAP1 might be a potential prognostic biomarker as well as a target in astrocytoma.



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Integrator complex subunit 6 (INTS6) inhibits hepatocellular carcinoma growth by Wnt pathway and serve as a prognostic marker

Abstract

Background

Integrator complex subunit 6 (INTS6) was found to play a tumour suppressing role in certain types of solid tumours. In this study, we wanted to determine the expression level of INTS6 in hepatocellular carcinoma (HCC) and evaluate its clinical characteristics and mechanisms in HCC patients (Lui and Lu, European Journal of Cancer, 51:S94, 2015).

Methods

First, we used a microarray analysis to explore the mRNA expression levels in HCC and paired normal liver tissues; second, we used qRT-PCR to measure the INTS6 mRNA levels in a cohort of 50 HCC tissues and adjacent normal liver tissues; third, we used Western blot analyses to detect the INTS6 protein levels in 20 paired HCC and normal liver tissues; fourth, we used immunohistochemistry to determine the INTS6 expression levels in 70 archived paraffin-embedded HCC samples. Finally, we investigated the suppressive function of INTS6 in the Wnt pathway.

Results

Herein, according to the microarray data analysis, the expression levels of INTS6 were dramatically down-regulated in HCC tissues vs. those in normal liver tissues (p<0.05). qRT-PCR and Western blot analyses showed that the INTS6 mRNA and protein expression was significantly down-regulated in tumour tissues compared to the adjacent normal liver tissues (p<0.05). Immunohistochemical assays revealed that decreased INTS6 expression was present in 62.9% (44/70) of HCC patients. Correlation analyses showed that INTS6 expression was significantly correlated with serum alpha-fetoprotein levels (AFP, p =0.004), pathology grade (p =0.005), and tumour recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had shorter overall and disease-free survival rates than patients with high INTS6 expression levels (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor of overall survival and disease-free survival rates. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/β-catenin signalling pathway.

Conclusion

The results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients.



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Haptic simulation of tissue tearing during surgery

Summary

We present a method for the real-time, interactive simulation of tissue tearing during laparoscopic surgery. The method is designed to work at haptic feedback rates (i.e., around 1kHz). Tissue tearing is simulated under the general framework of continuum damage mechanics. The problem is stated as a general, multidimensional parametric problem, which is solved by means of Proper Generalized Decomposition (PGD) methods. One of the main novelties is the reduction of history-dependent problems, such as damage mechanics, by resorting to an approach in which a reduced-order field of initial damage values is considered as a parameter of the formulation. We focus on the laparoscopic cholecystectomy procedure as a general example of the performance of the method. This article is protected by copyright. All rights reserved.



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Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients



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Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer



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Albumin, bilirubin, uric acid and cancer risk: results from a prospective population-based study



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Estimating the impact of a cancer diagnosis on life expectancy by socio-economic group for a range of cancer types in England



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Circulating cytokines and small molecules follow distinct expression patterns in acute myeloid leukaemia



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P 97 Individualized MRI are a valid alternative to individual MRI in navigated TMS studies

Navigated transcranial magnetic stimulation (nTMS) provides significant benefits over non-navigated TMS such as control for non-physiological TMS parameters and intracerebral electric field distribution (Ruohonen and Karhu, 2010; Schmidt et al., 2015). These benefits come at the cost of an often time consuming, expensive and not in all subjects feasible acquisition of individual structural magnetic resonance images (MRI). Spatial transformation is a well-established method that is used in functional neuroimaging to align individual MRI with template MRI (Friston, 1999).

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P 106 Functional magnetic resonance imaging of appetitive aggression in martial artists

The direct execution as well as the visual perception of violence can have a hedonistic aspect and elicit positive arousal. (Elbert et al., 2010) So far, neurobiological correlates of this "appetitive" form of aggression have not been investigated in healthy subjects.Using functional magnetic resonance imaging (fMRI), we tested if subjects who act violently (martial artists) showed greater brain responses to violent images compared to controls in the subcortical reward-associated areas of the mesolimbic dopaminergic system.

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P 111 Clinical trials in neurological disorders causing vertigo

The German Center for Vertigo and Balance Disorders (DSGZ) is an interdisciplinary center for research and treatment of vertigo, balance and ocular motor disorders. The long-term aim is to establish a patient-oriented research institution that is networked with all involved disciplines and methods. This includes also the establishment of a study infrastructure for prospective multicenter clinical trials. With this abstract we would like to give an overview over the current clinical trials conducted in collaborations with other investigational sites throughout Germany.

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P 120 A machine learning approach to detecting sleep and sleep disorders in acceleration sensor data

The major diagnostic sleep laboratory tool for assessing excessive daytime sleepiness (EDS), the multiple sleep latency test (MSLT), is increasingly criticized for poor precision in the differentiation of idiopathic hypersomnia (IH) and narcolepsy (Trotti et al., 2013; Johns, 2000). Recent evidence suggests that actigraphy can supplement the diagnostic process by providing information about the sleep-wake rhythm (Kretzschmar et al., 2016; Filardi et al., 2015; Bruck et al., 2005). An actigraphy analysis tool is introduced that processes actigraphy recordings with machine learning methods.

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P 101 Quantitative Chemical Shift Spectroscopy (CSI) with respect to B0- and B1-inhomogeneities

CSI is a method to visualize brain metabolism of, which may be important in the diagnosis of diseases like Alzheimer, dementia, brain tumors etc. Despite the fact that signal strength increases linearly with higher B0-fields, there exist many confounding variables, which diminish the accuracy of quantitative measurements of a 3T-device in relation to 1.5T.Susceptibility artifacts caused by inhomogeneities in the B0- and B1-fields as well as digitalization artifacts represent a challenging obstacle to measure accurate quantitative values of metabolite concentrations in CSI.

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P 122 Stimulus-responsive myoclonic jerks of both levator palpebrae muscles in a comatose survivor of cardiopulmonary resuscitation may pretended awareness

Comatose survivors of cardiopulmonary resuscitation (CPR), who develop myoclonus within 1–2days after CPR, usually have a poor prognosis. Typically, such myoclonus occurs or increases on sensory stimuli like touching the patient or acoustic stimuli. Myclonic jerks mainly occur in the muscles of the face, shoulder girdle and diaphragm. Sometimes, such jerks may be restricted to one muscle like the diaphragm leading to hiccups. We report one comatose survivor of CPR with stimulus-sensitive myoclonus, which was restricted to both levator palpebrae muscles leading to eye opening on acoustic stimulation and by doing so pretending awareness.

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P 118 Unilateral polyradicular deficit from C4 to C6 as a symptom of a spontaneous extracranial vertebral artery dissection.

A 47-year old man with shoulder and neck pain of the right side presented sensory deficits and peripheral paresis of the proximal arm. The rare cause was a spontaneous extracranial vertebral artery dissection affecting C4 to C6 nerve roots diagnosed by cervical magnetic resonance imaging (MRI) and angiography. The treatment based on anticoagulation and physical therapy.

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P 113 The dynamics of human REM sleep investigated by the analysis of time dependent transition probabilities

Sleep can be conceptualized as a sequence of discernable vigilance states (sleep stages). When the polysomnogram is decomposed into bouts of subsequent epochs of the same sleep stage it can be shown from sufficiently large data bases that bout lengths follow a stochastic process characterized e.g. by exponential of power law distributions. A complementary method of analysis calculates the probability of transition to another stage dependent on the time spent in the initial stage (time dependent transition probabilities).

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P 108 Modified motor threshold criterion for intraoperative corticobulbar MEPs for prediction of postoperative facial nerve outcome

Intraoperatively, facial nerve (FN) function can be assessed with corticobulbar Motor Evoked Potentials (FN-coMEP). MEP-amplitude decrement and increase in motor threshold (MT) serve as warning criteria. A novel threshold criterion for extremity MEP additionally compared MT-increments to the non-operated side (bilateral final-to-baseline motor threshold level, BFB-MT). We applied BFB-MT for FN-coMEP with regard to postoperative FN-function.

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P 103 Aggressiveness of martial artists correlates with reduced temporal pole gray matter concentration

Perception and practice of violence have, aside from reactive components, also hedonistic aspects that are associated with positive arousal (appetitive aggression). Earlier studies have predominantly investigated the etiology of aggressive behavior in forensic and psychiatric patients. The present study examined structural brain abnormalities in healthy people inclined to violence (martial artists) compared to healthy controls not showing violent behavior.

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P 99 Additional diagnostic benefit of high resolution ultrasound of the peripheral nerv in addition to classical ENG 2 case reports of posttraumatic nerve injury from an interdisciplinary consultancy

Posttraumatic/post-surgery nerve injury is a frequent problem in surgical departments and has a grave impact on patients recovery and functionality.Exact diagnosis of nerve function and severity of the injury is often a demanding task for electrophysiology laboratories. Classical neurophysiological exams like EMG and ENG occasionally have limited only value in establishing the location and etiology of nerve injury. High resolution ultrasound is a valuable additional tool to plan further treatment.

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What’s new in chemotherapy for non-small cell lung cancer?

Summary

The last few years have seen an explosion of novel treatment options for patients diagnosed with lung cancer, mostly for those with stage IV non-small cell lung cancer. On the one hand, this was due to the development of modern diagnostic tools permitting accurate molecular diagnoses leading to the identification of several oncogenic driver mutations which can be therapeutically targeted. On the other hand, the advent of immunotherapy in medical oncology in general, but in thoracic oncology in particular, has changed the treatment landscape first in second-line systemic treatment, but recently also in first-line treatment in patients with programmed death ligand-1 (PD-L1) expression in their tumors of >50%. Despite those advances, the majority of patients we treat in our daily routine will still receive chemotherapy: a so-called druggable aberration is only found in approximately 20% of cases. Some 25% present with an activating KRAS mutation, which despite decades of research still cannot be directly targeted. In the remainder, no genomic aberration of direct clinical consequences has been identified. On the other hand, the rate of PD-L1 positivity >50% at diagnosis has been reported to be between 24.9 and 30.2%. Overall, this leaves the majority of patients without any of those options in first-line therapy and they will receive standard of care chemotherapy. This minireview discusses the latest developments in the field of chemotherapy for non-small cell lung cancer.



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Assessment of acute bowel function after radiotherapy for prostate cancer: Is it accurate enough?

Abstract

Background and purpose

Pelvic radiotherapy for prostate cancer can be associated with bowel toxicity, which may have a significant impact on quality of life. Our aim was to assess the adequacy of the tools currently used to assess bowel symptoms after radiotherapy, including physician and patient reported outcomes. This sub-study on acute toxicity was part of a prospective trial assessing long-term bowel dysfunction.

Materials and methods

Between February 2013 and July 2015, 75 patients with prostate cancer who received radiotherapy completed the LENT/SOMA and the EPIC questionnaires baseline and 2 weeks after the treatment. The Bristol stool scale and two additional questions on faecal urgency were added. Physicians assessed toxicity using Common Terminology Criteria for Adverse Events v.4.0. Agreement between patients and clinicians was assessed using the Cohen's κ coefficient.

Results

Acute toxicity during radiotherapy was very low. The pattern of overall bowel bother was similar before and after treatment. Faecal urgency significantly increased after radiotherapy compared to baseline but was only detected by the additional questions and not by the physicians or the patient-reported outcomes (PRO) questionnaires. Correlation between physician and PRO was poor for most symptoms.

Conclusion

Bowel symptoms such as urgency may remain undetected by usual tools to assess toxicity after radiotherapy. Assessment of bowel toxicity should be reappraised in order to identify those patients who may have symptoms with an impact on their quality of life.



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Associations of two-pore domain potassium channels and triple negative breast cancer subtype in The Cancer Genome Atlas: systematic evaluation of gene expression and methylation

It is unclear whether 2-pore domain potassium channels are novel molecular markers with differential expression related to biologically aggressive triple-negative type breast tumors. Our objective was to syste...

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Prevalence and associations of microalbuminuria in proteinuria-negative patients with type 2 diabetes in two regional hospitals in Cameroon: a cross-sectional study

Microalbuminuria (MA) is the earliest clinical evidence of diabetic nephropathy, but most patients in sub-Saharan Africa (SSA) only have access to much cheaper dipstick proteinuria as a means to screen for dia...

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Eye–hand coordination during visuomotor adaptation: effects of hemispace and joint coordination

Abstract

We previously examined adaptive changes of eye–hand coordination during learning of a visuomotor rotation. Gazes during reaching movements were initially directed to a feedback cursor in early practice, but were gradually shifted toward the target with more practice, indicating an emerging gaze anchoring behavior. This adaptive pattern reflected a functional change of gaze control from exploring the cursor–hand relation to guiding the hand to the task goal. The present study further examined the effects of hemispace and joint coordination associated with target directions on this behavior. Young adults performed center-out reaching movements to four targets with their right hand on a horizontal digitizer, while looking at a rotated visual feedback cursor on a computer monitor. To examine the effect of hemispace related to visual stimuli, two out of the four targets were located in the ipsilateral workspace relative to the hand used, the other two in the contralateral workspace. To examine the effect of hemispace related to manual actions, two among the four targets were related to reaches made in the ipsilateral workspace, the other two to reaches made in the contralateral workspace. Furthermore, to examine the effect of the complexity of joint coordination, two among the four targets were reaches involving a direct path from the start to the target involving elbow movements (simple), whereas the other two targets were reaches involving both shoulder and elbow movements (complex). The results showed that the gaze anchoring behavior gradually emerged during practice for reaches made in all target directions. The speed of this change was affected mainly by the hemispace related to manual actions, whereas the other two effects were minimal. The gaze anchoring occurred faster for the ipsilateral reaches than for the contralateral reaches; gazes prior to the gaze anchoring were also directed less at the cursor vicinity but more at the mid-area between the starting point and the target. These results suggest that ipsilateral reaches result in a better predictability of the cursor–hand relation under the visuomotor rotation, thereby prompting an earlier functional change of gaze control through practice from a reactive to a predictive control.



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An Automated Rapid Iterative Negative Geotaxis Assay for Analyzing Adult Climbing Behavior in a Drosophila Model of Neurodegeneration

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This step-by-step protocol analyzes Drosophila negative geotaxis behavior using an automated multi-cylinder system that hosts hundreds of flies and synchronizes their action by an electric motor. Upon synchronization, fly negative geotaxis behavior is assayed, digitally recorded, and analyzed using the self-designed RflyDetection software.

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Measuring In Vivo Changes in Extracellular Neurotransmitters During Naturally Rewarding Behaviors in Female Syrian Hamsters

This paper details the use of fixed-potential amperometric recordings using carbon fiber electrodes and enzymatic biosensor technology to measure the release of dopamine and glutamate with high temporal resolution during natural rewarding behavior in the female hamster.

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Counterarguments Are Critical to Debunking Misinformation

It's no use simply telling people they have their facts wrong. To be more effective at correcting misinformation in news accounts and intentionally misleading "fake news," you need to provide a detailed counter-message with new information – and get your audience to help develop a new narrative. Those are some takeaways from an extensive new meta-analysis of debunking studies published in the journal Psychological Science, a journal of the Association for Psychological Science.

The analysis, the first conducted with this collection of debunking data, finds that a detailed counter-message is better at persuading people to change their minds than merely labeling misinformation as wrong. But even after a detailed debunking, misinformation still can be hard to eliminate, the study finds.

"The effect of misinformation is very strong," said co-author Dolores Albarracín, professor of psychology at the University of Illinois at Urbana-Champaign. "When you present it, people buy it. But we also asked whether we are able to correct for misinformation. Generally, some degree of correction is possible but it's very difficult to completely correct."

The study was conducted by researchers at the Social Action Lab at the University of Illinois at Urbana-Champaign and at the Annenberg Public Policy Center of the University of Pennsylvania. In total, they examined 20 experiments in eight research reports involving 6,878 participants and 52 independent samples.

The analyzed studies, published from 1994 to 2015, focused on false social and political news accounts, including misinformation in reports of robberies; investigations of a warehouse fire and traffic accident; the supposed existence of "death panels" in the 2010 Affordable Care Act; positions of political candidates on Medicaid; and a report on whether a candidate had received donations from a convicted felon.

The researchers coded and analyzed the results of the experiments across the different studies and measured the effect of presenting misinformation, the effect of debunking, and the persistence of misinformation.

"This analysis provides evidence of the value of the extended correction of misinformation," said co-author Kathleen Hall Jamieson, director of the Annenberg Public Policy Center (APPC) and co-founder of its project FactCheck.org, which aims to reduce the level of deception in politics and science. "Simply stating that something is false or providing a brief explanation is largely ineffective."

The lead author, Man-pui Sally Chan, a research assistant professor in psychology at the University of Illinois at Urbana-Champaign, said the study found that "the more detailed the debunking message, the higher the debunking effect. But misinformation can't easily be undone by debunking. The formula that undercuts the persistence of misinformation seems to be in the audience."

As the researchers reported: "A detailed debunking message correlated positively with the debunking effect. Surprisingly, however, a detailed debunking message also correlated positively with the misinformation-persistence effect."

However, Albarracín said the analysis also showed that debunking is more effective – and misinformation is less persistent – when an audience develops an explanation for the corrected information.

"What is successful is eliciting ways for the audience to counterargue and think of reasons why the initial information was incorrect," she said.

For news outlets, involving an audience in correcting information could mean encouraging commentary, asking questions, or offering moderated reader chats – in short, mechanisms to promote thoughtful participation.

The researchers made three recommendations for debunking misinformation:

  • Reduce arguments that support misinformation: News accounts about misinformation should not inadvertently repeat or belabor "detailed thoughts in support of the misinformation."
  • Engage audiences in scrutiny and counterarguing of information: Educational institutions should promote a state of healthy skepticism. When trying to correct misinformation, it is beneficial to have the audience involved in generating counterarguments.
  • Introduce new information as part of the debunking message: People are less likely to accept debunking when the initial message is just labeled as wrong rather than countered with new evidence.

The authors also included Christopher R. Jones, a former postdoctoral fellow at APPC and at the University of Illinois.

All data have been made publicly available via the Open Science Framework. The complete Open Practices Disclosure for this article is available online. This article has received the badge for Open Data.

Research reported in this article was supported by the National Cancer Institute of the National Institutes of Health (NIH) and Food and Drug Administration (FDA) Center for Tobacco Products (Award No. P50CA179546). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH or the FDA.



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