Miriam’s Journey to Sound

"It was one of the best days of my life," says Miriam Green in an emotionally charged voice. "I wish...

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Save the Date: Dr. Steven Zeitels to Speak at ORL Frontiers Next Month

Steven Marc Zeitels, MD, is the invited speaker for ORL Frontiers 2018, which will be held Saturday, June 23, at...

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Amber Luong, MD, PhD Recognized as Trailblazer

Amber Luong, MD, PhD, associate professor of otorhinolaryngology, has been recognized with the 2017 Helen F. Krause, MD Memorial Trailblazer...

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Anticancer Properties of a New Hybrid Analog AD-013 Combining a Coumarin Scaffold with an α-methylene-δ-lactone Motif

Background: Coumarin is a natural phytochemical but as such has no medical uses. However, various natural and synthetic coumarin analogs attract attention due to their interesting biological properties.

Objective: Here, we evaluated and compared anticancer properties of a new synthetic hybrid compound AD- 013, which integrates a coumarin moiety and an α-methylene-δ-lactone motif, with novobiocin, a natural antibiotic bearing a coumarin scaffold.

Methods: Cytotoxic activities of compound AD-013 and novobiocin were assessed by the MTT assay. In order to explore the mechanism of anticancer activity of analog AD-013, we performed quantitative real-time PCR analysis of apoptosis- and cell cycle-related genes. The ability of AD-013 and novobiocin to induce apoptosis and DNA damage was studied by flow cytometry.

Results: The cytotoxic activity of this new compound was compared with the activity of a coumarin-based antibiotic novobiocin against two cancer cell lines, MCF-7 and HL-60 and also against normal human cells, MCF- 10A and HUVEC. AD-013 was much more cytotoxic than novobiocin in both cancer cell lines and showed some selectivity against MCF-7 cancer cells as compared with MCF-10A healthy cells. Expression levels of the pro-apoptotic genes significantly increased while the anti-apoptotic genes, were down-regulated for both compounds in both cancer cell lines.

AD-013 was able to inhibit cell proliferation, generate DNA damage and induce apoptosis. The obtained data showed that this compound caused the cell cycle arrest in subG0/G1 in both cancer cell lines.

Conclusion: The new hybrid analog was a much stronger apoptosis inducer than novobiocin and activated the intrinsic pathway of apoptosis.

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Genistein Induces Alterations of Epigenetic Modulatory Signatures in Human Cervical Cancer Cells

Introduction: Epidemiological studies indicate that diet rich in fruits and vegetables is associated with decreased cancer risk thereby indicating that dietary polyphenols can be potential chemo-preventive agents. The reversible nature of epigenetic modifications makes them a favorable target for cancer prevention. Polyphenols have been shown to reverse aberrant epigenetic patterns by targeting the regulatory enzymes, DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). In vitro and in silico studies of DNMTs and HDACs were planned to examine genistein's role as a natural epigenetic modifier in human cervical cancer cells, HeLa.

Methods: Expression of the tumour suppressor genes (TSGs) [MGMT, RARβ, p21, E-cadherin, DAPK1] as well the methylation status of their promoters were examined alongwith the activity levels of DNMT and HDAC enzymes after treatment with genistein. Expression of DNMTs and HDACs was also studied. In-silico studies were performed to determine the interaction of genistein with DNMTs and HDACs.

Results: Genistein treatment significantly reduced the expression and enzymatic activity of both DNMTs and HDACs in a time-dependent way. Molecular modeling data suggest that genistein can interact with various members of DNMT and HDAC families and support genistein mediated inhibition of their activity. Timedependent exposure of genistein reversed the promoter region methylation of the TSGs and re-established their expression.

Conclusions: In this study, we find that genistein is able to reinstate the expression of the TSGs studied by inhibiting the action of DNMTs and HDACs. This shows that genistein could be an important arsenal in the development of epigenetic based cancer therapy.

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The Emerging Roles of RASSF5 in Human Malignancy

Ras association domain family member 5 (RASSF5, also named NORE1) is an identified member of the RASSF gene family which could bind selectively to activate Ras and function as an antineoplastic effector in multiple cellular regulations. While highly expressed in majority of normal tissues, RASSF5 is epigenetically inactivated by promoter hypermethylation in numerous cancer cell lines and primary cancers, suggesting it as a potential tumor suppressor. Nevertheless, the physiologic significance of RASSF5 in tumorigenesis remains unclear. We performed a systematic literature review and assessment from PUBMED and MEDLINE databases in this article. RASSF5 is involved in a series of cellular responses including apoptosis, senescence, cell cycle regulation, differentiation and cell proliferation and the inactivation of RASSF5 has been implicated to participate in the oncogenesis, progression and poor prognosis of human cancers. In this review, we mainly elucidate the acknowledged structure, progress in the verified functions and research advances of RASSF5 and the probably relevant signaling pathways. Based on these evidences, potentiality of RASSF5 as a new therapeutic target for human cancers may play a significant role in future oncotherapy.

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A Comparison of the Toxicity of Mono, Bis, Tris and Tetrakis Phosphino Silver Complexes on SNO Esophageal Cancer Cells

Background: A broad range of metal-coordinated complexes have been studied for their anticancer activities. However, some of these complexes display high toxicity profiles to non-malignant cells, therefore limiting their use in cancer therapeutics.

Aims/Method: Several silver(I) triphenylphosphine adducts were prepared as 1:1 to 1:4 ratios of silver nitrate to triphenylphosphine. They were further used to determine their anticancer activity in a malignant SNO esophageal cell line. The silver(I) phosphine adducts include: [Ag(PPh3)]NO3 (1); [Ag(PPh3)2]NO3 (2); [Ag(PPh3)3]NO3 (3) and [Ag(PPh3)4]NO3 (4). In addition, the activity of complexes 1-4 was compared to previously reported complexes [Ag(Ph2P(CH2)2PPh2)2]NO3 (5) and [Ag(Ph2P(CH2)3PPh2)2]NO3 (6). The cytotoxicity of complexes 1-6 was also evaluated in non-malignant human dermal fibroblast cells (HDF-a).

Results: The majority of the complexes (specifically those containing PPh3) were found to be highly toxic to the SNO cells and less toxic towards HDF-a cells, as determined by the alamarBlue® assay. Morphological studies and flow cytometry confirmed that the silver(I) complexes induced apoptosis in the malignant cells.

Conclusion: These results may have an impact on research related to drug discovery and silver(I) phosphine complexes could be added to the arsenal of anticancer agents in addition to the silver-bis-diphenylphosphinoethane and silver-bis-diphenylphosphinopropane adducts.

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Antileukemic Properties of Sesquiterpene Lactones: A Systematic Review

This review summarizes the reported molecular mechanisms underlying the antileukemic property of Sesquiterpene Lactones (SLs). This systematic review was registered in the PROSPERO database and conducted following the PRISMA Statements. The MeSH terms, Sesquiterpenes, Lactones and Leukemia were used in four databases (Pubmed, Web of Science, Scopus and Bireme). There were 281 studies selected, but after exclusions, due to replication (n = 172) or not following PECOS criteria (n = 24), 148 studies remained. Of the 148 articles, only 22 were submitted to quality assessment and were scored in high level if more than two techniques, to elucidate antileukemic properties, were described, and then data were extracted. The studies mostly used human leukemia cell lines including primary and established cells, with or without chemotherapy resistance. The SLs used were obtained principally from plants. The antileukemic properties of SLs were extracted from 22 high level studies. They included cell death induction, mainly by apoptosis, as well as cell differentiation, cell cycle disruption, leukemia cancer stem cell growth inhibition and NF-κB pathway inhibition; the latter is a promising therapeutic target for lymphoid malignancies. We concluded that, in spite of the necessity of better toxicological profile characterization of SLs, the antileukemic properties of these compounds support the proposal that the SLs are promising candidates for the treatment of leukemia.

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CJK-7, a Novel Flavonoid from Paulownia tomentosa Triggers Cell Death Cascades in HCT-116 Human Colon Carcinoma Cells via Redox Signaling

Background: Colon cancer is the second most common cancer to cause death worldwide. About half of colon cancers patients require adjuvant therapy to control relapse following surgical resection. Therefore, abolition of tumor cell progression using an effective chemotherapeutic agent holds a feasible approach to treat patients suffering from colon cancer. In the present study, we evaluated the effects of geranylated flavonoid CJK-7, isolated from Paulownia tomentosa on HCT-116 human colon carcinoma cells.

Materials and Methods: The effects of CJK-7 as an active component on HCT-116 cells programmed cell death and its underlying molecular mechanism were examined by using MTT assay, morphological assessment, H2DCFDA staining, Fura-2AM staining, Hoechst-33342 staining, comet assay, Acridine orange staining, mitochondrial membrane potential (ΔΨm) assay and Western blot analyses.

Results and Conclusion: The results revealed that, CJK-7 was capable of inducing caspase-dependent cell death events in cancer cells. Moreover, it was involved in up-regulation of autophagy signaling as evidenced by enhanced expression of LC3I/II. We also noticed stimulated expression of endoplasmic reticulum stress markers and phosphorylation of c-Jun NH2-terminal kinase (JNK), which was associated with up-regulated expression of p53, PUMA, Atg5 and Beclin-1, and down-regulation of Bcl-2, stressing the interaction of ROS on the aforementioned signaling. Furthermore, exposure to ROS scavengers (N-acetyl-l-cysteine (NAC), and JNK-specific inhibitor SP600125) significantly reversed the effects of CJK-7 by down-regulating apoptosis and autophagy signatures in HCT-116 cancer cells. Collectively our findings clarify the ROS-dependent regulatory effect of CJK-7 on programmed cell death signaling events in HCT-116 cancer cells while depicting its virile pro-oxidant capacity.

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Recent Advancements in Organotin(IV) Complexes as Potential Anticancer Agents

Cancer is a multistep disease incorporating physical, chemical, environmental, metabolic and genetic factors, which play direct or indirect role in the induction and deterioration of cancer. Many of the platinum based drugs were synthesized but due to their systemic toxicity, broad spectrum of action, intrinsic and acquired drug resistivity, it has become necessary to search for the effective anticancer drugs with superior efficiency. Among non-platinum metal compounds with antitumor activity, organotin complexes have proven effective management of toxicity, specific targeted drug uptake by the cancerous cell line and significant potential in the pharmaceutical chemistry. So this article provides a critical review from 2010 onwards of the anticancer activity of the organotin complexes reported by the authors worldwide and explores the landmarks for their future projection as novel anticancer chemotypes with high therapeutic indices.

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Meet Our Associate Board Member

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A Review of the Components of Seaweeds as Potential Candidates in Cancer Therapy

The marine natural products (MNPs) isolated from seaweeds-associated microbial communities have received substantial attention owing to their exceptional nutritional and pharmacology application, such as antiviral, anticancer, antiprotozoal, antifungal, and antibacterial properties and so on. Particularly, there are several MNPs that have been displayed attractive value for the development of novel anticancer agents. This review covers the literature published in the recent 5 years on the novel anticancer MNPs discovered originating from seaweeds, and focused on the chemistry and relative anticancer activities of new MNPs which categorize their source organisms. These seaweed-derived MNPs are categorized based on their origin as brown algae, red algae, cyanobacteria, chlorophyta and others.

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ECPIRM, a Potential Therapeutic Agent for Cutaneous T-Cell Lymphoma, Inhibits Cell Proliferation and Promotes Apoptosis via a JAK/STAT Pathway

Background: Retinoids are important agents for the treatment of cutaneous T-cell lymphomas (CTCL). But side effects and drug resistance caused by activation of RAR/RXR limited their clinical application. Therefore, it is urgent to develop new agents to fight against CTCL. ECPIRM, a 13-cis retinoic acid derivative, was reported that it inhibited proliferation and induced apoptosis of SCL-1 cells.

Objective: The aim of this study was to evaluate the biological activities and mechanisms of ECPIEM.

Methods: The effect of ECPIRM on cell proliferation was determined by MTT assay and Trypan blue exclusion assay while FACS analysis was used to detect changes in cell cycle and apoptosis in HUT78 cells. The influence of ECPIRM on RAR/RXR and JAK/STAT signaling was evaluated by western blot analysis.

Results: ECPIRM, better than other agents (all-trans retinoic acid,13-cis-retinoic acid or bexarotene), inhibited proliferation and induced apoptosis significantly in HUT78 cells, but with little cytotoxicity on normal lymphocytes. Then ECPIRM induced G0/G1 phase arrest by decreasing the expression of cyclinD1, cyclinE, CDK2 and CDK4 while increasing p21. Furthermore, the unaffected expression of RAR and RXR members suggested that ECPIRM acted independently of RAR/RXR pathway in HUT78 cells. But decreased phosphorylation of JAK1, STAT3, STAT5 and downregulated Bcl-xL, Cyclin D1 and c-Myc indicated that ECPIRM inhibited the activation of JAK/STAT signaling.

Conclusion: ECPIRM inhibited proliferation, induced apoptosis and G0/G1 phase arrest in HUT78 cells through inhibiting JAK/STAT pathway but not RAR/RXR pathway, which presented ECPIRM as a promising candidate for the treatment of CTCL patients.

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The Rationale for Repurposing Sildenafil for Lung Cancer Treatment

There is now a considerable body of evidence for sildenafil possessing anticancer properties. In this article, we argue the case for testing sildenafil as a lung cancer therapy chemoadjuvant. Currently, lung cancer is a disease with insufficient treatment options, with only 20% of patients responding to systemic chemotherapy, and even incremental potential improvements should be explored. We review the literature concerning the biochemical, physiological and metabolic effects on cancer cells by sildenafil alone, and when combined with chemotherapeutic agents. Most studies have shown that sildenafil is cytotoxic to cancer cells, both as a monotherapy and as a chemoadjuvant. Sildenafil enhances cancer cell apoptosis when used as a chemoadjuvant both in vitro and in vivo. In particular, in rodent experiments sildenafil has decreased tumour size compared to chemotherapy alone. Sildenafil has also been proven as an agent to decrease drug-efflux by cancer cells and increases blood perfusion to lung tissue, which can potentially increase the dosage of chemotherapeutic agents delivered to lung cancer cells compared to healthy tissue. In addition, the proven clinical effects of sildenafil on other lung diseases suggest that it could improve other patient outcomes, such as right ventricular function and quality of life. Sildenafil may also extend the half-life of docetaxel and some small molecule inhibitors used in lung cancer treatment by acting as an inhibitor of CYP3A4. We conclude that the evidence strongly warrants clinical investigation into the use of sildenafil as an agent for the treatment of lung-cancer.

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Synthesis of Biotinylated 2-methoxystypandrone and Identification of JAK2 and IKK as its Targets

Background: 2-Methoxystypandrone (2-MS), isolated from the roots of Polygonum cuspidatum, is a potent dual inhibitor of the STAT3 and NF-κB pathways.

Objective: To investigate the molecular targets and mechanisms of 2-MS.

Method: A biotin-conjugated 2-MS analog, named 2-MS-Biotin, was designed and synthesized. The effects of 2-MS-Biotin on the STAT3 and NF-κB pathways were examined by Western blotting. The cytotoxicity of 2- MS-Biotin was evaluated using real-time cell analysis system. Proteins directly bound to 2-MS-Biotin were pulled down through streptavidin agarose beads and were detected using Western blotting.

Results: 2-MS-Biotin retained the inhibition activities of the parent compound 2-MS on the STAT3 and NF-κB pathways as well as on cancer cell growth. Also, JAK2 and IKK proteins can be effectively pulled down by 2- MS-Biotin.

Conclusion: Using 2-MS-Biotin as a tool, both JAK2 and IKK were identified as the targets of 2-MS.

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Algerian Propolis Potentiates Doxorubicin Mediated Anticancer Effect Against Human Pancreatic PANC-1 Cancer Cell Line through Cell Cycle Arrest, Apoptosis Induction and P-Glycoprotein Inhibition

Background: Pancreatic cancer is one of the most aggressive and lethal cancers, with poor prognosis and high resistance to current chemotherapeutic agents. Therefore, new therapeutic strategies and targets are underscored. Propolis has been reported to exhibit a broad spectrum of biological activities including anticancer activity.

Objective: This study was carried out to assess the possible efficacy of Algerian propolis on the antitumor effect of doxorubicin on human pancreatic cancer cell line (PANC-1).

Methods: Modifications in cell viability, apoptosis and cell cycle progression, Pgp activity and intracellular accumulation of DOX were monitored to study the synergistic effect of Algerian propolis on the antitumor effects of DOX in PANC-1 cell line.

Results: Both propolis and its combination with doxorubicin inhibited cell growth in a dose-dependent manner by inducing cell cycle arrest and apoptosis. In the presence of 100 μg/ml of propolis, the IC50 of DOX against PANC-1 cells decreased by 10.9-fold. Propolis combined with DOX increased after 48h, the number of cells in the G0G1 phase with dramatical increase in sub-G1 phase to reach 47% of total cells, corresponding to an increase of senescence or apoptotic state of the cells. Dead cell assay with annexinV/PI staining demonstrated that propolis and propolis-DOX treatment resulted in a remarkable induction of apoptosis as detected by flow cytometry. It was interesting to note that propolis at its 5IC50 was found as the most potent inducer of apoptosis. Our finding revealed that induced apoptosis in our conditions was caspase-3 and caspase-9 dependent. Flow cytometry showed that propolis increased the accumulation of doxorubicin within PANC-1 cells. Moreover, fluorescent intensity detection revealed that propolis remarkably increased the retention of rhodamine-123, 7- fold compared to 3-fold of verapamil, the most effective P-gp inhibitor.

Conclusion: In conclusion, propolis sensitize pancreatic cancer cells to DOX via enhancing the intracellular retention of DOX due to blocking the efflux activity of P-gp pump, inducing cell cycle arrest and increasing apoptosis, finding that improuve the synergism of antitumor effect of Algerian propolis and DOX in pancreatic cancer cell line. Therefore, Algerian propolis may be an effective agent in a combined treatment with doxorubicin for increased therapeutic efficacy against pancreatic cancer.

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The Measurement and Mathematical Analysis of 5-Fu Release from Magnetic Polymeric Nanocapsules, following the Application of Ultrasound

gnetic poly lactic co-glycolic acid (PLGA) nanocapsules. Also, the controlled drug-release behaviour of the nanocapsules was mathematically investigated.

Methods: The nanocapsules were synthesized, dispersed in phosphate buffered saline (PBS), transferred to a dialysis bag, and finally, irradiated by various ultrasound parameters (1 or 3MHz; 0.3-1W/cm2; 5-10 minutes). The release profile of the irradiated nanocapsules was recorded for 14 days. To find the in vitro drug release mechanism in the absence and presence of various intensities of ultrasound, the obtained data were fitted in various kinetic models for drug release.

Results: The results demonstrated that the ultrasound speeded up the rate of drug release from the nanocapsules. The mathematical analysis illustrated that when the ultrasound intensity is increased, the probability of controlled release behaviour of the nanocapsules is raised. We found that drug release from the irradiated nanocapsules follows an erosion-controlled mechanism with the decrease in the velocity of diffusion.

Conclusion: In conclusion, to attain a controlled drug-delivery strategy in the area of cancer therapy, the drug release profile of the nano-carriers may be well-controlled by ultrasound.

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Combined Evaluation of Expression of CXCR4 and Nrf2 as Prognostic Factor for Patients with Gastric Carcinoma

Background: CXC Chemokine Receptor 4 (CXCR4) and NFE–related factor 2 (Nrf2) have been observed implicated with cell malignant behavior of human cancers.

Aims: In this study, we detected their expression in gastric carcinoma (GC) tissue specimens and related the result with clinicopathological data and patient survival.

Methods: 120 GC and compared normal tissue specimens were processed to analyse the expression of CXCR4 and Nrf2. We found that the expression of CXCR4 and Nrf2 was dramatically increased in GC tissues when compared to the distant non-cancer tissues (P

Results: In the survival part, we found that GC patients with CXCR4+ and Nrf2+ had worse outcomes. The significant prognostic indicators are age, tumor size, histological grade, TNMstage, CXCR4, Nrf2, and coexpression of CXCR4 and Nrf2 in GC patients. Multivariate analysis showed that TNMstage and CXCR4+/Nrf2+ expression were risk factors. Above all we come to the conclusion that the expression of CXCR4 might partly be regulated by the level of Nrf2 and both positive expressions suggest poor prognosis of GC patients.

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CCL2 is Modulated by Cytokines and PPAR-γ in Anaplastic Thyroid Cancer

Background and Objective: Chemokine (C-C motif) ligand (CCL)2, the prototype Th2 chemokine, is secreted by tumor cells, and has growth promoting effects. Whether CCL2 protumorigenic activities will be validated, then CCL2 and its receptor CCR2 may be therapeutic targets in cancer.

Methods: We tested in "primary human anaplastic thyroid carcinoma (ATC) cells" (ANA) versus "normal thyroid follicular cells" (TFC): a) CCL2 secretion basally, after IFN-γ and/or TNF-α stimulation; b) PPARγ activation by thiazolidinediones (TZDs), rosiglitazone or pioglitazone, on CCL2 secretion, and on proliferation and apoptosis in ANA.

Results: ANA produced basally CCL2, at a higher level versus TFC. IFN-γ or TNF-α dose-dependently induced the CCL2 release in 3/6 or 5/6 ANA, respectively, but in all TFC. IFN-γ+TNF-α induced a synergistic release of CCL2 in all TFC, but only in 1/6 ATC. TZDs exerted an inhibition of CCL2 release in 3/6 ANA, while had no effect in TFC. Pioglitazone inhibition of ANA proliferation was not associated with the effect on CCL2; NF-κB and ERK1/2 were basally activated in ANA, increased by IFN-γ+TNF-α, and pioglitazone inhibited IFN- γ+TNF-α activation. CCL2 serum levels were higher in 6 ATC patients than in 5 controls (813±345 versus 345±212, pg/mL; respectively; P

Conclusion: ANA produce CCL2 basally and after cytokines stimulation, with an extremely variable pattern of modulation, suggesting different types of deregulation in the chemokine modulation. Serum CCL2 is increased in ATC patients. Further studies will be necessary to evaluate if CCL2 might be used as a marker in the followup of ATC patients.

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A Cyclin E Centered Genetic Network Contributes to Alcohol-Induced Variation in Drosophila Development

Prenatal exposure to ethanol causes a wide range of adverse physiological, behavioral and cognitive consequences. However, identifying allelic variants and genetic networks associated with variation in susceptibility to prenatal alcohol exposure is challenging in human populations, since time and frequency of exposure and effective dose cannot be determined quantitatively and phenotypic manifestations are diverse. Here, we harnessed the power of natural variation in the Drosophila melanogaster Genetic Reference Panel (DGRP) to identify genes and genetic networks associated with variation in sensitivity to developmental alcohol exposure. We measured development time from egg to adult and viability of 201 DGRP lines reared on regular or ethanol- supplemented medium and identified polymorphisms associated with variation in susceptibility to developmental ethanol exposure. We also documented genotype-dependent variation in sensorimotor behavior after developmental exposure to ethanol using the startle response assay in a subset of 39 DGRP lines. Genes associated with development, including development of the nervous system, featured prominently among genes that harbored variants associated with differential sensitivity to developmental ethanol exposure. Many of them have human orthologs and mutational analyses and RNAi targeting functionally validated a high percentage of candidate genes. Analysis of genetic interaction networks identified Cyclin E (CycE) as a central, highly interconnected hub gene. Cyclin E encodes a protein kinase associated with cell cycle regulation and is prominently expressed in ovaries. Thus, exposure to ethanol during development of Drosophila melanogaster might serve as a genetic model for translational studies on fetal alcohol spectrum disorder.

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The Canonical Wnt Pathway Drives Macropinocytosis in Cancer

Macropinocytosis has emerged as an important pathway of protein acquisition in cancer cells, particularly in tumors with activated Ras such as pancreatic and colon cancer. Macropinocytosis is also the route of entry of Bacillus Calmette-Guerin (BCG) and other microbial therapies of cancer. Despite this important role in tumor biology and therapy, the full mechanisms by which cancer cells can activate macropinocytosis remain incompletely defined. Using BCG uptake to assay macropinocytosis, we executed a genome-wide shRNA screen for macropinocytosis activators and identified Wnt pathway activation as a strong driver of macropinocytosis. Wnt-driven macropinocytosis was downstream of the beta catenin-dependent canonical Wnt pathway, was Pak1 dependent, and supported albumin-dependent growth in Ras-WT cells. In cells with activated Ras-dependent macropinocytosis, pharmacologic or genetic inhibition of Wnt signaling suppressed macropinocytosis. In a mouse model of Wnt-driven colonic hyperplasia via APC silencing, Wnt-activated macropinocytosis stimulated uptake of luminal microbiota, a process reversed by topical pharmacologic inhibition of macropinocytosis. Our findings indicate that Wnt pathway activation drives macropinocytosis in cancer, and its inhibition could provide a therapeutic vulnerability in Wnt-driven intestinal polyposis and cancers with Wnt activation.

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Kras and Tp53 mutations cause cholangiocyte- and hepatocyte-derived cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA with intermediates along this spectrum. Here we generated mouse models to examine the consequence of targeting mutant Kras and Tp53, common alterations in human iCCA, to different adult liver cell types. Selective induction of these mutations in the SOX9+ population, predominantly of mature cholangiocytes, resulted in iCCA emerging from premalignant biliary intraepithelial neoplasia (BillN). By contrast, adult hepatocytes were relatively refractory to these mutations and formed rare hepatocellular carcinomas (HCC). In this context, injury accelerated hepatocyte-derived tumorigenesis and promoted a phenotypic switch to iCCA. BilIN precursor lesions were absent in the hepatocyte-derived iCCA models, pointing towards distinct and direct emergence of a malignant cholangiocytic phenotype from injured, oncogenically primed hepatocytes. Tp53 loss enhanced reprogramming of hepatocytes to biliary cells, which may represent a mechanism facilitating formation of hepatocyte-derived iCCA. Overall, our work shows iCCA driven by Kras and Tp53 may originate from both mature cholangiocytes and hepatocytes, and factors such as chronic liver injury and underlying genetic mutations determine the path of progression and resulting cancer phenotype.

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Oncogenic properties of NEAT1 in prostate cancer cells depend on the CDC5L-AGRN transcriptional regulation circuit

The long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) has been shown to regulate multiple cancer-related cellular activities including cell proliferation, apoptosis, and migration. In this study, we confirm that repression of NEAT1 induces DNA damage, disturbs the cell cycle, and arrests the proliferation of prostate cancer cells. By taking advantage of the prostate cancer tumor transcriptome profiles from The Cancer Genome Atlas (TCGA), our data-mining pipeline identified a series of transcription factors (TF) whose regulatory activities on target genes depended on the level of NEAT1. Among them was putative TF CDC5L, which bound directly to NEAT1. Silencing NEAT1 in prostate cancer cells repressed the transcriptional activity of CDC5L, and RNA-seq and ChIP-seq analyses further revealed a handful of potential targets of CDC5L regulated by NEAT1 expression. One target of CDC5L, ARGN, mediated the strong phenotypic consequences of NEAT1 reduction, including DNA damage, cell cycle dysregulation, and proliferation arrest. In summary, we have established the requirement of the CDC5L-AGRN circuit for the essential oncogenic role of NEAT1 in prostate cancer cells.

https://ift.tt/2M3fQaq

TCIApathfinder: an R client for The Cancer Imaging Archive REST API

The Cancer Imaging Archive (TCIA) hosts publicly available de-identified medical images of cancer from over 25 body sites and over 30,000 patients. Over 400 published studies have utilized freely available TCIA images. Images and metadata are available for download through a web interface or a REST API. Here we present TCIApathfinder, an R client for the TCIA REST API. TCIApathfinder wraps API access in user-friendly R functions that can be called interactively within an R session or easily incorporated into scripts. Functions are provided to explore the contents of the large database and to download image files. TCIApathfinder provides easy access to TCIA resources in the highly popular R programming environment. TCIApathfinder is freely available under the MIT license as a package on CRAN (https://ift.tt/2Cu0Td1) and at https://ift.tt/2Cu0TK3.

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Adiposity and risks of colorectal and small intestine cancer in Chinese adults: a prospective study of 0.5 million people

Adiposity and risks of colorectal and small intestine cancer in Chinese adults: a prospective study of 0.5 million people

Adiposity and risks of colorectal and small intestine cancer in Chinese adults: a prospective study of 0.5 million people, Published online: 06 June 2018; doi:10.1038/s41416-018-0124-8

Adiposity and risks of colorectal and small intestine cancer in Chinese adults: a prospective study of 0.5 million people

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Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a BRAF-mutant subset with high CA 19-9 level and poor outcome

Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a BRAF-mutant subset with high CA 19-9 level and poor outcome

Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a <i>BRAF</i>-mutant subset with high CA 19-9 level and poor outcome, Published online: 06 June 2018; doi:10.1038/s41416-018-0115-9

Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a BRAF-mutant subset with high CA 19-9 level and poor outcome

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Efficacy of a docetaxel-5FU-oxaliplatin regimen (TEFOX) in first-line treatment of advanced gastric signet ring cell carcinoma: an AGEO multicentre study

Efficacy of a docetaxel-5FU-oxaliplatin regimen (TEFOX) in first-line treatment of advanced gastric signet ring cell carcinoma: an AGEO multicentre study

Efficacy of a docetaxel-5FU-oxaliplatin regimen (TEFOX) in first-line treatment of advanced gastric signet ring cell carcinoma: an AGEO multicentre study, Published online: 06 June 2018; doi:10.1038/s41416-018-0133-7

Efficacy of a docetaxel-5FU-oxaliplatin regimen (TEFOX) in first-line treatment of advanced gastric signet ring cell carcinoma: an AGEO multicentre study

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Body mass index (BMI) trajectories and risk of colorectal cancer in the PLCO cohort

Body mass index (BMI) trajectories and risk of colorectal cancer in the PLCO cohort

Body mass index (BMI) trajectories and risk of colorectal cancer in the PLCO cohort, Published online: 06 June 2018; doi:10.1038/s41416-018-0121-y

Body mass index (BMI) trajectories and risk of colorectal cancer in the PLCO cohort

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Agrin has a pathological role in the progression of oral cancer

Agrin has a pathological role in the progression of oral cancer

Agrin has a pathological role in the progression of oral cancer, Published online: 06 June 2018; doi:10.1038/s41416-018-0135-5

Agrin has a pathological role in the progression of oral cancer

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Somatic mutations in benign breast disease tissue and risk of subsequent invasive breast cancer

Somatic mutations in benign breast disease tissue and risk of subsequent invasive breast cancer

Somatic mutations in benign breast disease tissue and risk of subsequent invasive breast cancer, Published online: 06 June 2018; doi:10.1038/s41416-018-0089-7

Somatic mutations in benign breast disease tissue and risk of subsequent invasive breast cancer

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Exam 1: Comparative Efficacy of Colonoscope Distal Attachment Devices in Increasing Rates of Adenoma Detection: A Network Meta-analysis

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Pembrolizumab Monotherapy for NSCLC Extends Survival [News in Brief]

The PD-1 inhibitor improves OS in patients with advanced disease and PD-L1 expression of 1% or higher.

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Lynch Syndrome Linked with More Cancers [News in Brief]

Hereditary condition common among patients with MSI-high tumor types besides colorectal, endometrial cancers.

https://ift.tt/2sy80gO

Multimodality Treatment of Desmoplastic small round cell tumor: Chemotherapy and Complete Cytoreductive Surgery Improve Patient Survival

Purpose Desmoplastic small round cell tumor (DSRCT), which harbors EWSR1-WT1 t(11;22)(p13:q12) chromosomal translocation, is an aggressive malignancy that typically presents as intra-abdominal sarcomatosis in young males. Given its rarity, optimal treatment has not been defined. Experimental Design We conducted a retrospective study of 187 DSRCT patients treated at MD Anderson Cancer Center over two decades. Univariate and multivariate regression analyses were performed. We determined whether chemotherapy, complete cytoreductive surgery (CCS), hyperthermic intraperitoneal cisplatin (HIPEC), and/or whole abdominal radiation (WART) improve overall survival in DSRCT patients. Critically, since our institutional practice limits HIPEC and WART to patients with less extensive, potentially resectable disease that had benefited from neoadjuvant chemotherapy, a time-variant analysis was performed to evaluate those adjunct treatment modalities. CONCLUSIONS Improved 3- and 5-year overall survival were observed following multidisciplinary treatment that includes ES-based chemotherapy and complete tumor cytoreductive surgery, but few if any patients are cured. Prospective randomized studies will be required to prove whether HIPEC or WART are important. In the meantime, chemotherapy and CCS remain the cornerstone of treatment and provide a solid foundation to evaluate new biologically targeted therapies.

https://ift.tt/2xHUgoG

Immunotherapy of Primary Brain Tumors: Facts and Hopes

The field of cancer immunotherapy has made exciting progress for some cancer types in recent years. However, recent failures of late phase clinical trials evaluating checkpoint blockade in glioblastoma (GBM) patients represent continued challenges for brain cancer immunotherapy. This is likely due to multiple factors, including but not limited to marked genetic and antigenic heterogeneity, relatively low mutational loads and paucity of GBM-infiltrating T cells. We review recent and ongoing studies targeting the checkpoint molecules as monotherapy or in combination with other modalities, and discuss the mechanisms underlying the unresponsiveness of GBM to single modality immunotherapy approaches. We also discuss other novel immunotherapy approaches that may promote T cell responses and overcome the "cold tumor" status of GBM, including oncolytic viruses and adoptive T cell therapy.

https://ift.tt/2LZb9hM

Identification of a Genomic Region Between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance)

Purpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood. Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 bevacizumab-treated patients (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes. Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01, OR 2.4) and systolic blood pressure > 180 mmHg (P = 0.02, OR 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03, OR 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure. Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension.

https://ift.tt/2Joa3KD

PARP inhibitors in ovarian cancer: a trailblazing and transformative journey

PARP inhibitors have transformed treatment for ovarian cancer, a cancer notable for homologous recombination (HR) deficiencies and aberrant DNA repair, especially high grade serous subtype. PARP inhibitors are now approved for recurrent ovarian cancer as maintenance following response to platinum chemotherapy and BRCA mutated (BRCAm) cancer treatment.

https://ift.tt/2M1ept5

Dendritic cells in inflammatory angiogenesis and lymphangiogenesis

Daniela Bosisio | Roberto Ronca | Valentina Salvi | Marco Presta | Silvano Sozzani

https://ift.tt/2sEUqY4

FDA: Opioid Antidote Naloxone Recalled

TUESDAY, June 5, 2018 -- A recall of the opioid overdose antidote Naloxone was announced Monday. The U.S. Food and Drug Administration said the recall was triggered by the possibility of "loose particulate matter on the syringe plunger" that could...

https://ift.tt/2M3notB

USPSTF Advises PCPs to Screen Adults for Unhealthy Alcohol Use

TUESDAY, June 5, 2018 -- Screening adults, including pregnant women, and providing brief counseling in primary care settings can reduce unhealthy alcohol use, although inadequate evidence is found to weigh the balance of benefits and harms of...

https://ift.tt/2Jo50tF

FDA OKs 1st Biosimilar to Prevent Chemo-Related Infections

TUESDAY, June 5, 2018 -- The first biosimilar drug to Neulasta has been approved by the U.S. Food and Drug Administration. Fulphila (pegfilgrastim) is approved for patients with non-myeloid cancer who are receiving myelosuppressive chemotherapy and...

https://ift.tt/2M3gzIE

Similar Primary Outcome for Lower O2 Sat in Extreme Preterm

TUESDAY, June 5, 2018 -- Different target ranges for oxygen saturation as measured by pulse oximetry (SpO2) do not affect the composite primary outcome of death or major disability for extremely preterm infants, according to research published in...

https://ift.tt/2xLVejO

CDC: Office-Based Physician Visit Rates Vary by Patient Age, Sex

TUESDAY, June 5, 2018 -- There is considerable variation in office-based physician visit rates by patient age and sex, according to a June data brief published by the U.S. Centers for Disease Control and Prevention's National Center for Health...

https://ift.tt/2M4lU2u

An alkaline and surfactant-tolerant lipase from Trichoderma lentiforme ACCC30425 with high application potential in the detergent industry

Alkaline lipases with adaptability to low temperatures and strong surfactant tolerance are favorable for application in the detergent industry. In the present study, a lipase-encoding gene, TllipA, was cloned fro...

https://ift.tt/2Hm5GOH

Position estimation with a millimeter-wave massive MIMO system based on distributed steerable phased antenna arrays

In this paper, we propose a massive MIMO (multiple-input-multiple-output) architecture with distributed steerable phased antenna subarrays for position estimation in the mmWave range. We also propose localizat...

https://ift.tt/2Jy1kJl

On the effect of model mismatch for sequential Info-Greedy Sensing

We characterize the performance of sequential information-guided sensing (Info-Greedy Sensing) when the model parameters (means and covariance matrices) are estimated and inaccurate. Our theoretical results fo...

https://ift.tt/2LpleTZ

Novel Approaches to Block Complement

The complement system may contribute in many ways to transplant injury, being a promising target for specific therapeutic interventions. There is evidence that the monoclonal anti-C5 antibody eculizumab is effective in the prevention and treatment of early antibody-mediated rejection (ABMR), but terminal complement blockade might be of limited efficiency in chronic rejection. Given the diversity of immunological events triggered by activation steps upstream to C5, in particular, opsonin and anaphylatoxin formation through C3 cleavage, one may argue that, in the specific context of ABMR, inhibition of antibody-triggered classical pathway (CP) activation might be beneficial. Strategies to interfere with key CP component C1 are currently under clinical evaluation and include the therapeutic use of purified C1-inhibitor, which, besides targeting the integrity and function of the C1 complex, also affects components of the lectin pathway, the contact system, the coagulation cascade or surface molecules mediating leukocyte-endothelial interactions. In addition, a monoclonal anti-C1s antibody (BIVV009) has now entered clinical evaluation and was shown to effectively block antibody-triggered CP activation in rejecting kidney allografts. Moreover, modified apheresis techniques for preferential removal of macromolecules, including C1q, may allow for efficient complement depletion, in addition to antibody removal. The availability of effective strategies to interfere with the CP, as well as innovative approaches targeting other pathways, some of them already being tested in clinical trials, will help us figure out how complement contributes to acute and chronic graft injury, and hopefully provide us with new ways to more efficiently counteract rejection. Correspondence: Georg A. Böhmig, Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria, Phone: +43-1-40400-43630, Fax: +43-1-40400-39304, E-mail: georg.boehmig@meduniwien.ac.at Author's specific contribution G.A.B. participated in the conception, writing and revision of the paper F.E. participated in the conception, writing and revision of the paper M.W. participated in the conception, writing and revision of the paper L.R. participated in the conception, writing and revision of the paper Disclosure G.A.B. received research support (unrestricted grants) from Fresenius Medical Care, Bad Homburg, Germany, and True North Therapeutics, Inc., South San Francisco, CA, USA. F.E., M.W. and L.R. declare no conflicts of interest. Funding None Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2M109Rc

Association between non-variceal spontaneous portosystemic shunt and outcomes after TIPS in cirrhosis

Whether pre-existing nonvariceal spontaneous portosystemic shunts (SPSSs) in cirrhotic patients affect outcomes after transjugular intrahepatic portosystemic shunt (TIPS) and whether they need to be closed remains unclear.

https://ift.tt/2LqFDIe

Incidence of HCV infection amongst HIV positive men who had sex with men and prevalence data from patients followed at the Infectious Diseases Clinic of Modena, Italy

Men who had sex with men (MSM) living with HIV are at higher risk of developing sexual transmitted diseases. This study reports two years incidence rate and prevalence of HCV in a cohort of HIV positive MSM.

https://ift.tt/2JteK9j

Narrative Medicine in Amyotrophic Lateral Sclerosis and a rehabilitation project based on International Classification of Functioning, Disability and Health (ICF)

Objective To systematize the disability condition related to Amyotrophic Lateral Sclerosis (ALS) patients using the International Classification of Functioning, Disability and Health (ICF) and Narrative Medicine approach as a common tool to identify a patient's functional problems. Once identified, this can be used as the basis for an individual rehabilitation project. Design An observational study on patients residing in a central region of Italy with a diagnosis of ALS. The narrative approach involved listening to the patients' stories while guiding them with a semi-structured questionnaire of 19 ICF items taken from the WHO-DAS II. A score from 0-4 for capacity (C) and performance (P) was adopted to evaluate each patient's functioning in their daily living activities. Results The ICF questionnaire was able to discriminate among responders (p

https://ift.tt/2JyhbHN

ECT: a new look at an old friend

Purpose of review Electroconvulsive therapy (ECT) as a treatment option in psychiatry is advancing day by day. This review discusses new advancements in ECT with regards to anesthetic variables, stimulus, and response variables along with their impact on clinical outcomes. Recent findings Anesthetic variables influence clinical efficacy and patient tolerance of ECT. Although etomidate or a ketamine–propofol combination may be the first choice for many clinicians, the search for ideal induction agent continues. Dexmedetomidine, remifentanil, or ketamine may aid in augmentation of ECT; however, they are not recommended routinely. A systematic procedure for hyperventilation of the patient has been shown to have clinical repercussions. Optimizing anesthesia-ECT time interval (ASTI) has a significant impact on the success of the procedure. BIS monitoring alone cannot be relied upon for timing stimulus. High-dose brief pulse right unilateral ECT represents an acceptable first-line form of treatment, though there is currently no 'gold standard'. Other stimulus variations such as focal electrically administered seizure therapy, individualized low-amplitude seizure therapy, magnetic seizure therapy, left unilateral and left anterior right temporal electrode placements are explored to reduce memory effects. EEG ictal indices may be relied upon for seizure adequacy, and therefore may be used to both guide treatment and predict the outcome of the procedure. Summary Modern ECT is streamlined by augmentation with drugs, hyperventilation, optimizing anesthesia-ECT time interval, and various stimulus parameters guided by seizure adequacy markers. Correspondence to Pavan Kumar Kadiyala, Assistant Professor, Department of Psychiatry, ASR Academy of Medical Sciences, Eluru, AP 534005, India. Tel: +919980731234; e-mail: drkadiyala2@gmail.com Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Do we really need an anesthesiologist for routine colonoscopy in American Society of Anesthesiologist 1 and 2 patients?

Purpose of review In an era where healthcare costs are being heavily scrutinized, every expenditure is reviewed for medical necessity. Multiple national gastroenterology societies have issued statements regarding whether an anesthesiologist is necessary for routine colonoscopies in American Society of Anesthesiologist (ASA) 1 and 2 patients. Recent findings A large percentage of patients are undergoing screening colonoscopy without any sedation at all, which would not require an independent practitioner to administer medications. Advances in technique and technology are making colonoscopies less stimulating. Advantages to administering sedation, including propofol, have been seen even when not administered under the direction of an anesthesiologist and complications seem to be rare. The additional cost of having monitored anesthesia care appears to be a driving factor in whether a patient receives it or not. Summary A large multiinstitutional randomized control trial would be necessary to rule out potential confounders and to determine whether there is a safety benefit or detriment to having anesthesiologist-directed care in the setting of routine colonoscopies in ASA 1 and 2 patients. Further discussion would be necessary regarding what the monetary value of that effect is if a small difference were to be detected. Correspondence to Jeffrey D. White, MD, Department of Anesthesiology, University of Florida College of Medicine, 1600 SW Archer Road, PO Box 100254, Gainesville, FL 32610, USA. Tel: +1 352 273 6575; e-mail: jwhite@anest.ufl.edu Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Adiposity and risks of colorectal and small intestine cancer in Chinese adults: a prospective study of 0.5 million people

https://ift.tt/2HoeB1Y

Agrin has a pathological role in the progression of oral cancer

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Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a BRAF-mutant subset with high CA 19-9 level and poor outcome

https://ift.tt/2sJGa0b

Somatic mutations in benign breast disease tissue and risk of subsequent invasive breast cancer

https://ift.tt/2sA9kjd

Body mass index (BMI) trajectories and risk of colorectal cancer in the PLCO cohort

https://ift.tt/2sG9h4J

Efficacy of a docetaxel-5FU-oxaliplatin regimen (TEFOX) in first-line treatment of advanced gastric signet ring cell carcinoma: an AGEO multicentre study

https://ift.tt/2kPQmAN

Diagnosis, Treatment, and Molecular Pathology of Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome classically associated with exocrine pancreatic dysfunction and neutropenia, with a predisposition toward progressive marrow failure, risk of myelodysplastic syndrome, and leukemia. Most patients carry biallelic mutations in the Shwachman-Bodian-Diamond Syndrome gene, which is an integral component of ribosome maturation and biogenesis. This article reviews the diagnosis, clinical characteristics, and treatment modalities of SDS, and reports advances in the understanding of the molecular pathophysiology of SDS.

https://ift.tt/2LmQFi0

Critical Issues in Diamond-Blackfan Anemia and Prospects for Novel Treatment

Diamond-Blackfan anemia (DBA) is a severe congenital hypoplastic anemia caused by mutation in a ribosomal protein gene. Major clinical issues concern the optimal management of patients resistant to steroids, the first-line therapy. Hematopoietic stem cell transplantation is indicated in young patients with an HLA-matched unaffected sibling donor, and recent results with matched unrelated donor transplants indicate that these patients also do well. When neither steroids nor a transplant is possible red cell transfusions are required, and iron loading is rapid in some DBA patients, so effective chelation is vital. Also discussed are novel treatments under investigation for DBA.

https://ift.tt/2JurPPY

Somatic Mutations in Aplastic Anemia

Aplastic anemia (AA) is an immune-mediated disorder that overlaps closely with clonal disorders, such as myelodysplastic syndrome and paroxysmal nocturnal hemoglobinuria (PNH). PIGA mutations in PNH clones and functional loss of HLA, including structural HLA mutations, likely represent immune escape clones and correlate with response to immunosuppressive therapy (IST). Somatic mutations typical for myeloid malignancies and age-related clonal hematopoiesis are detected in a proportion of AA patients, but their significance is unclear and seems to depend on whether patients are tested at diagnosis or after IST, patient age and ethnicity, and the methodology of molecular testing used.

https://ift.tt/2Ls1M9t

Objective Predictors of 'Early Tolerance' to Ventral Intermediate Nucleus of Thalamus Deep Brain Stimulation in Essential Tremor Patients

Essential tremor (ET), is the most common cause of adult onset tremors. The diagnosis is made clinically on the basis of chronic, disabling action tremors. The phenotype is variable and heterogeneous; some patients experience a gradual increase in severity and disability over the years, others developed generalized tremors, including legs, head, and voice; and some individuals evolve into a pancerebellar syndrome that includes limb dysmetria and gait ataxia. In accordance with the varied clinical presentation, the tremor may be generated by different pathophysiologic mechanisms, with important therapeutic and prognostic implications(Louis et al.

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Magnetoencephalography and Ictal SPECT in Patients with Failed Epilepsy Surgery

Approximately 30% of patients with intractable focal epilepsy still have recurring seizures after the first resective surgery (Spencer and Huh, 2008). In these patients, re-evaluation for a potential reoperation can be a worthwhile attempt. Previous studies reported reoperation rates to be between 35.9% and 65.2% in patients with unfavorable outcome after initial surgery; seizure-free rate vary considerably among studies and ranged from 9.5 to 57.1%, and was estimated at 36.6% across all the studies (Surges and Elger, 2013).

https://ift.tt/2JvvKvS

Content validity of anatomic site-specific Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) item sets for assessment of acute symptomatic toxicities in radiation oncology

The Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) has not previously been validated in a site-specific manner as would be relevant to patients undergoing radiation therapy. We evaluated the content validity of PRO-CTCAE in a diverse sample of patients undergoing radiation therapy. We found strong content validity of the PRO-CTCAE, and herein we propose site-specific item sets for further validation in prospective trials.

https://ift.tt/2Jk7Ksa

Repeatability and reproducibility of radiomic features: A systematic review

We offer a qualitative synthesis of 41 studies that specifically investigated the repeatability and reproducibility of radiomic features. The repeatability and reproducibility of radiomic features are sensitive in varying degrees to image quality, and software used to extract radiomic features. Investigations of feature repeatability and reproducibility are currently limited to a small number of cancer types. No consensus was found in regards to most repeatable and reproducible features with respect to different settings.

https://ift.tt/2Ja02Vo

Findings on Surveillance Imaging after Pre-operative Partial Breast Irradiation for Early Stage Breast Cancer

This retrospective study evaluated mammographic findings after pre-operative accelerated partial breast irradiation delivered via stereotactic body radiotherapy (SBRT) or a conventionally-fractionated regimen. High-dose SBRT, in particular, increases the risk of developing a uniquely robust and well-demarcated pattern of fat necrosis on mammogram. However, a higher rate of vigorous fat necrosis was also seen in the conventionally fractionated pre-operative PBI patients. This may reflect the less extreme but still hypofractioned schedule and/or the interaction of surgical resection with an irradiated tissue bed.

https://ift.tt/2xLbgKD

Therapeutic effects of human umbilical cord–derived mesenchymal stem cells on canine radiation-induced lung injury

Radiation-induced lung injury is a common complication following radiotherapy for thoracic tumours. Our studies show that canine radiation-induced lung injury could be observed at 180 days after X-ray radiation at 15 Gy, and intratracheal mesenchymal stem cell (MSC) transplantation can reduce oxidative stress, inflammatory reactions, and TGF-β/Smad2/3 pathway activation, thereby reducing lung injury. This finding provides a basis for the application of MSCs in clinical transplantation therapies for radiation-induced lung injury.

https://ift.tt/2JdPWmC

Definitive Carbon-Ion Radiation Therapy for Locally Advanced Sinonasal Malignant Tumors: Subgroup Analysis of a Multicenter Study by the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS)

We evaluated the safety and efficacy of definitive carbon-ion radiation therapy for sinonasal malignant tumors in a retrospective multicenter study. The study included 458 patients who had locally advanced tumors that were mainly radioresistant. Carbon-ion radiation therapy resulted in good local control and overall survival with acceptable toxicities.

https://ift.tt/2Jklymy

Effect of host immune status on the efficacy of radiotherapy and recurrence-free survival among 805 Merkel cell carcinoma patients

The impact of chronic immunosuppression on RT efficacy was evaluated among non-metastatic Merkel cell carcinoma (MCC) patients treated with curative-intent. Despite higher proportions of immunosuppressed MCC patients receiving RT to the primary site compared with immune-competent MCC patients, immunosuppressed MCC patients experienced increased local failures as first relapse (25% versus 12%; p=0.0002) and lower recurrence-free survival (2-year 30% versus 57%;p<0.0001). The efficacy of conventional radiotherapy on tumor control may be impaired in an immunosuppressed host.

https://ift.tt/2Je0pOZ

Tumor infiltrating lymphocyte volume is a better predictor of neoadjuvant therapy response and overall survival in triple negative invasive breast Cancer

Triple-negative breast cancer (TNBC) has an aggressive behavior, limited therapeutic options, and high mortality rate. Neoadjuvant chemotherapy (NACT) is a standard treatment for TNBC and patients with pathological complete response (pCR) have a favorable outcome. We conducted a comprehensive evaluation of cancer clinicopathologic parameters, and correlated these parameters with the pCR rate and the overall survival. Fifty-eight patients with TNBC of no special type who underwent breast biopsy, neoadjuvant therapy, and mastectomy in our institution during 2005–2016 were included in this study.

https://ift.tt/2LmUALE

DICER1 mutation-positive Giant Botryoid Fibroepithelial polyp of the urinary bladder mimicking embryonal rhabdomyosarcoma

Fibroepithelial polyps of the urinary tract are rare lesions. They occur mainly in the upper urinary tract of children. A high disease prevalence has been reported in families with pleuropulmonary blastoma. Here we present a case of a 46-year-old woman who presented with a giant botryoid fibroepithelial polyp of the urinary bladder. Histologically, the lesion showed prominent botryoid features with an embryonal rhabdomyosarcoma-like cambium layer lacking nuclear or cellular atypia. Immunohistochemical analysis ruled out rhabdomyoblastic differentiation.

https://ift.tt/2JuSUSZ

Alanine-Glyoxylate Aminotransferase 1 (AGXT1) is a Novel Marker for Hepatocellular Carcinomas

Arginase-1 has been demonstrated as a marker for hepatocellular carcinoma with higher sensitivity and specificity than HepPar-1 and glypican-3. However, its sensitivity is diminished in moderately and poorly differentiated hepatocellular carcinomas. In current study, we evaluated the utility of AGXT1 as a diagnostic marker. Immunostains for AGXT1 and arginase-1 were performed in tissue microarrays of 139 hepatocellular carcinomas (HCCs) and 374 gastrointestinal and non-gastrointestinal carcinomas.

https://ift.tt/2Lpx4xz

Hematological abnormalities in patients with malaria and typhoid in Tamale Metropolis of Ghana

Anemia, Leukopenia, and thrombocytopenia are commonly observed hematological abnormalities in malaria and typhoid patients. In this study, we evaluated the prevalence of cytopenias in patients with mono-infect...

https://ift.tt/2Lr0aMP

Duration taken for the anal sphincter pressures to stabilize prior to anorectal manometry

Anorectal manometry (ARM) is an integral part of evaluating the anal sphincter function. The current recommendation of waiting for 5 min (lead-in-time) prior to beginning the recording has no evidence. A prolo...

https://ift.tt/2JxuMPw

Electromyographic activity of quadriceps muscle during sit-to-stand in patients with unilateral knee osteoarthritis

The sit-to-stand (STS) is a simple test to evaluate the functional performance of the quadriceps muscle in patients with knee osteoarthritis (OA). The aim was to evaluate the electromyographic (EMG) activity o...

https://ift.tt/2LoE5OZ

Sublingual nitroglycerin for early blood pressure control in hypertensive emergencies: observations from an emergency department clinical audit in Sri Lanka

Hypertensive emergencies are potentially life threatening and require prompt blood pressure control with intravenous agents. Preparation of intravenous infusions is time consuming. Usefulness of sublingual nit...

https://ift.tt/2JyeZjq

Performance evaluation of three rapid screening assays for detection of antibodies to hepatitis C virus in Cameroon

This study was aimed at evaluating the performance of three CE-marked rapid diagnostic tests (RDTs): Multisure-HCV, First Response® and Toyo®; for screening anti- HCV antibody using plasma samples.

https://ift.tt/2LrXUVZ

Greater Use of Tobacco Products Among Youth With Asthma

TUESDAY, June 5, 2018 -- Youth with asthma have considerably higher use of tobacco products than those without asthma, with electronic cigarettes (e-cigarettes) being the most commonly used tobacco product, according to research published in the...

https://ift.tt/2sK6ur6

ASCO: Ovarian Suppression + Tamoxifen Ups Breast CA Survival

TUESDAY, June 5, 2018 -- The addition of ovarian suppression to tamoxifen is associated with increased survival versus tamoxifen alone among premenopausal women with breast cancer, according to a study published online June 4 in the New England...

https://ift.tt/2kP7hUb

Increase in Requirement for Flu Vaccines at Non-VA Hospitals

TUESDAY, June 5, 2018 -- At non-Veterans Affairs (VA) hospitals, but not in VA hospitals, there was an increase in mandatory influenza vaccination requirements for health care personnel (HCP) from 2013 to 2017, according to a study published online...

https://ift.tt/2Hqjh7G

DDW: Psych Disorders Make GERD Hard to Dx by Symptoms Alone

TUESDAY, June 5, 2018 -- For patients with minor psychiatric disorders (MPD), symptoms of gastroesophageal reflux disease (GERD) are unreliable for establishing the presence of GERD, according to a study presented at the 2018 Digestive Disease Week,...

https://ift.tt/2szAneq

Mindfulness Program May Help Increase Physical Activity Levels

TUESDAY, May 5, 2018 -- A meditation and stress reduction program may be as effective as structured exercise programs for increasing physical activity, according to a study published in Medicine & Science in Sports & Exercise. Jacob D....

https://ift.tt/2sIsVx0

AHA: Limited Health Literacy Is Barrier to Cardiovascular Care

TUESDAY, June 5, 2018 -- Limited health literacy is a barrier to cardiovascular health and prevention of cardiovascular disease (CVD), according to a scientific statement from the American Heart Association published online June 4 in...

https://ift.tt/2szAk2e

Direct Supervision by Attendings Doesn't Reduce Medical Errors

TUESDAY, June 5, 2018 -- Direct supervision in which attending physicians join work rounds does not reduce the rate of medical errors, according to a study published online June 4 in JAMA Internal Medicine. Kathleen M. Finn, M.D., from Massachusetts...

https://ift.tt/2sJxqY2

DDW: Bowel Sounds May Identify Irritable Bowel Syndrome

TUESDAY, June 5, 2018 -- A noninvasive method for diagnosing irritable bowel syndrome (IBS), based on use of bowel sounds, has high sensitivity and specificity, according to a study presented at the 2018 Digestive Disease Week, held from June 2 to 5...

https://ift.tt/2szAhn4

Post-Hurricane Deaths in Puerto Rico Underestimated

TUESDAY, June 5, 2018 -- The actual number of deaths related to Hurricane Maria in Puerto Rico in 2016 is likely more than 70 times the official government estimate of 64, according to a study published online May 29 in the New England Journal of...

https://ift.tt/2HlQGQQ

DDW: Altruism, Economic Reward Motivate Fecal Donation

TUESDAY, June 5, 2018 -- In the field of fecal microbiota transplantation (FMT), altruism is the main reason people become stool donors, followed by economic compensation and positive feedback from the donation experience, according to a study...

https://ift.tt/2swZRcG

Toxin-Based Drug Moxetumomab Pasudotox May Be New Option for Rare Leukemia

People diagnosed with hairy cell leukemia (HCL) may have an effective new treatment option, a type of drug called an immunotoxin. Read more about how this treatment, moxetumomab pasudotox, faired in a phase 3 clinical trial in patients with advanced HCL.

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Evaluation of antiviral activity of Ocimum sanctum and Acacia arabica leaves extracts against H9N2 virus using embryonated chicken egg model

In the view of endemic avian influenza H9N2 infection in poultry, its zoonotic potential and emergence of antiviral resistance, two herbal plants, Ocimum sanctum and Acacia arabica, which are easily available thr...

https://ift.tt/2sycmEO

Antioxidant, anticholinesterase and antifatigue effects of Trichilia catigua (catuaba)

Trichilia catigua A. Juss. (Meliaceae) is a species known as catuaba and used in folk medicine for the treatment of fatigue, stress, impotence and memory deficit. The main phytochemical compounds identified in th...

https://ift.tt/2JhjVWz

Phenolic contents, antimicrobial and antioxidant activity of Olea ferruginea Royle (Oleaceae)

Olea ferruginea Royle (Oleaceae) has long been used as an important ethnomedicinal plant to cure fever and debility, toothache, hoarseness, throatache and skeleton disorders. In this study, phenolic contents, ant...

https://ift.tt/2syc8gW

Brucella abortus: determination of survival times and evaluation of methods for detection in several matrices

Brucella abortus is a highly pathogenic zoonotic agent, tempting for the development of a rapid diagnostic method to enable adequate treatment and prevent further spread. Enrichment of the bacteria is often used ...

https://ift.tt/2sxLYuA

Statin use and all-cause mortality in people living with HIV: a systematic review and meta-analysis

It is unknown whether statin use among people living with HIV results in a reduction in all-cause mortality. We aimed to evaluate the effect of statin use on all-cause mortality among people living with HIV.

https://ift.tt/2sE9F3u

Carbapenem non-susceptibility of Klebsiella pneumoniae isolates in hospitals from 2011 to 2016, data from the German Antimicrobial Resistance Surveillance (ARS)

Carbapenem resistance in Klebsiella pneumoniae is of significant public health concern and recently spread across several countries. We investigated the extent of carbapenem non-susceptibility in K. pneumoniae is...

https://ift.tt/2JgFFSE

Benefit of haemostatic spray in variceal bleeding: early application of spray or early application of guidelines?

We read with considerable interest the recent report by Ibrahim et al1 on the use of haemostatic powder in addition to standard of care management for oesophageal variceal bleeding. The authors have performed a randomised controlled trial of early (<2 hours) application of haemostatic powder compared with 'early' elective endoscopy (performed at 12–24 hours) and found a significant improvement in the primary outcome, which was clinical haemostasis in the first 24 hours and endoscopic haemostasis at early elective endoscopy. The authors suggest that this very early control of bleeding could translate into improved survival, which was significantly better in the powder group although the trial was not powered for this outcome. The authors highlight that despite guidelines suggesting that endoscopy should take place as soon as possible after resuscitation and always within 12–24 hours, this target is often not achieved, primarily due to the lack of availability of endoscopists experienced in the...

https://ift.tt/2sFZH1R

Effect of anticoagulants and NSAIDs on accuracy of faecal immunochemical tests (FITs) in colorectal cancer screening: a systematic review and meta-analysis

Objective

Most colorectal cancer (CRC) screening programmes are nowadays based on faecal immunochemical testing (FIT). Eligible subjects often use oral anticoagulants (OACs) or non-steroidal anti-inflammatory drugs (NSAIDs), which could possibly stimulate bleeding from both benign and premalignant lesions in the colon. The aim of this meta-analysis was to study the effect of OACs and NSAIDs use on FIT performance.

Design

A systematic search was conducted until June 2017 to retrieve studies from PubMed, Embase, MEDLINE, Web of science, Cochrane Central and Google Scholar. Studies were included when reporting on FIT results in users versus non-users of OACs and/or NSAIDs in average risk CRC screening populations. Primary outcome was positive predictive value for advanced neoplasia (PPV_AN) of FIT in relation to OACs/NSAIDs use. Values were obtained by conducting random-effect forest plots.

Results

Our literature search identified 2022 records, of which 8 studies were included. A total of 3563 participants with a positive FIT were included. Use of OACs was associated with a PPV_AN of 37.6% (95% CI 33.9 to 41.4) compared with 40.3% (95% CI 38.5 to 42.1) for non-users (p=0.75). Pooled PPV_AN in aspirin/NSAID users was 38.2% (95% CI 33.8 to 42.9) compared with 39.4% (95% CI 37.5 to 41.3) for non-users (p=0.59).

Conclusion

FIT accuracy is not affected by OACs and aspirin/NSAIDs use. Based on the current literature, withdrawal of OACs or NSAIDs before FIT screening is not recommended. Future studies should focus on duration of use, dosage and classes of drugs in association with accuracy of FIT to conduct more specific guideline recommendations.

https://ift.tt/2szsVA3

Expanded benefits of curing the extrahepatic manifestations of HCV infection

HCV infection is a major global health threat. HCV is estimated to infect ~71.1 million persons worldwide and to cause approximately 400 000 deaths annually.1 Although HCV-related mortality is reportedly due to the end-stage complications of chronic hepatitis C (decompensated cirrhosis and hepatocellular carcinoma), the above official figures do not take into consideration the mortality attributable to the multifaceted extrahepatic disorders caused by this pathogen.2 3 The list of such extrahepatic manifestations (EHM) is long and includes—but is not limited to—the cryoglobulinaemia-associated syndrome (characterised by fatigue, arthralgia, skin vasculitis, glomerulonephritis and cerebritis, among others), some subtypes of non-Hodgkin's B cell lymphoma, insulin resistance (which may progress to type 2 diabetes and its cardiovascular sequelae) and various neurological conditions, such as cognitive dysfunction. The causal link between most of these EHM and HCV infection has been established, thanks to a wealth of epidemiological and clinical data, and especially...

https://ift.tt/2Hl6HGL

Comparative effectiveness of elemental formula in the early enteral nutrition management of acute pancreatitis: a retrospective cohort study

Although enteral nutrition has become one of the standard therapies for patients with acute pancreatitis, the optimal formulae for enteral nutrition have been under debate. Elemental formula is assumed to be s...

https://ift.tt/2syKNuS

Carotid artery infusion via implantable catheters for squamous cell carcinoma of the tonsils

Abstract

Background

Chemoradiotherapy has a dominant role in therapy for head and neck cancers. However, impressive results are often disturbed by adverse events such as dysphagia, xerostomia, and functional speech and hearing loss. To avoid exceeding toxicity limits in patients with primary and recurrent cancers of the tonsils, chemotherapy was administered intra-arterially via implantable Jet-Port-Allround catheters.

Methods

We report on patients with primary and recurrent cancers of the tonsils. Eleven patients who refused chemoradiation were included in this trial. Of the seven patients without prior therapy, one was stage I, one was stage III, three were stage IVA, one was stage IVB, and one was stage IVC. The four patients who were in progression after prior chemoradiation were stage IVA. The median follow-up time was 47 months (20 to 125 months).

After the implantation of a Jet-Port-Allround catheter into the carotid artery, the patients received intra-arterial infusion chemotherapy with venous chemofiltration for systemic detoxification. The stage I patient received lower-dose chemotherapy without chemofiltration. The stage IVC patient with lung metastases and a primary tumor that extended across the midline to the contralateral tonsil received additional isolated thoracic perfusion chemotherapy.

Results

All seven chemoradiation-naïve patients exhibited clinically complete responses and are still alive after 20 to 125 months. Among the four patients who had relapsed after prior chemoradiation, the intra-arterial therapy elicited only poor responses, and the median survival time was 7.5 months. After carotid artery infusion chemotherapy, none of the patients required tube feeding. No cases of dysphagia, xerostomia, or functional speech and hearing loss have been reported among the patients without prior chemoradiotherapy.

Conclusion

Despite the administration of low total dosages, intra-arterial infusion generates high concentrations of chemotherapeutics. In combination with chemofiltration, the systemic toxicity is kept within acceptable limits. Among the non-pretreated patients, better tumor responses and long-term tumor control were noted compared with those who had prior chemoradiation. Implantable Jet-Port-Allround carotid artery catheters facilitate the application of regional chemotherapy.

https://ift.tt/2LmPHSI

Therapeutic effects of oxaliplatin-based neoadjuvant chemotherapy and chemoradiotherapy in patients with locally advanced rectal cancer: a single-center, retrospective cohort study

Abstract

Background

Neoadjuvant chemoradiotherapy (NACRT) has now become the standard treatment for locally advanced rectal cancer (LARC). NACRT has decreased local relapse (LR) rate in patients with LARC; however, distant relapse has recently attracted much attention. This study aimed to assess the feasibility and efficiency of neoadjuvant chemotherapy (NAC) for LARC.

Methods

Data on patients with cT3/4 and N+ rectal cancer who were treated in our institution from April 2010 to February 2016 were reviewed retrospectively. Twenty-seven patients who received 2–9 cycles of oxaliplatin-based NAC and 28 patients who received NACRT (45 Gy delivered in 25 fractions and 5-fluorouracil-based oral chemotherapy) were analyzed. The primary and secondary endpoints of the present study were the 3-year relapse-free survival (RFS) and the local and distant relapse rates, respectively.

Results

Regardless of the kind of neoadjuvant therapy, no patient experienced any grade 3–4 therapy-related adverse events. The frequent toxic events were grade 1 diarrhea in patients with NACRT and neutropenia in patients with NAC. A significantly higher proportion of patients with NAC underwent laparoscopic surgery and anterior resection (p = 0.037 and p = 0.003, respectively). The percentages of patients with lymph node yield less than 12 in the NAC group, and those in the NACRT group were 26 and 68%, respectively (p = 0.002). Comparing the NAC with the NACRT groups, the local relapse and distant relapse rates were 7.4 and 7.1% and 7.4 and 18%, respectively. There were no significant differences in 3-year RFS and 4-year overall survival (OS) between NAC and NACRT (3-year RFS 85.2 vs. 70.4%, p = 0.279; 4-year OS 96.3 vs. 89.1%, p = 0.145, respectively). With an analysis excluding patients who received postoperative adjuvant chemotherapy, no patients who received NAC had a distant relapse, and there was a significant difference in 3-year RFS compared with the NACRT groups (94.4 vs. 63.2%, p = 0.043).

Conclusion

These outcomes suggest that the therapeutic effect of oxaliplatin-based NAC is at least equal to that of NACRT and that NAC is a feasible and promising option for LARC.

https://ift.tt/2JzefLf

Longitudinal studies of the 18 F-FDG kinetics after ipilimumab treatment in metastatic melanoma patients based on dynamic FDG PET/CT

Abstract

Background

Immunotherapy has raised the issue of appropriate treatment response evaluation, due to the unique mechanism of action of the immunotherapeutic agents. Aim of this analysis is to evaluate the potential role of quantitative analysis of 2-deoxy-2-(¹⁸F)fluoro-d-glucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) data in monitoring of patients with metastatic melanoma undergoing ipilimumab therapy.

Methods

25 patients with unresectable metastatic melanoma underwent dynamic PET/CT (dPET/CT) of the thorax and upper abdomen as well as static, whole body PET/CT with ¹⁸F-FDG before the start of ipilimumab treatment (baseline PET/CT), after two cycles of treatment (interim PET/CT) and at the end of treatment after four cycles (late PET/CT). The evaluation of dPET/CT studies was based on semi-quantitative (standardized uptake value, SUV) calculation as well as quantitative analysis, based on two-tissue compartment modeling and a fractal approach. Patients' best clinical response, assessed at a mean of 59 weeks, was used as reference.

Results

According to their best clinical response, patients were dichotomized in those demonstrating clinical benefit (CB, n = 16 patients) and those demonstrating no clinical benefit (no-CB, n = 9 patients). No statistically significant differences were observed between CB and no-CB regarding either semi-quantitative or quantitative parameters in all scans. On contrary, the application of the recently introduced PET response evaluation criteria for immunotherapy (PERCIMT) led to a correct classification rate of 84% (21/25 patients).

Conclusion

Quantitative analysis of ¹⁸F-FDG PET data does not provide additional information in treatment response evaluation of metastatic melanoma patients receiving ipilimumab. PERCIMT criteria correlated better with clinical response.

https://ift.tt/2Lqcv4b

Validation of the Vectra XT three-dimensional imaging system for measuring breast volume and symmetry following oncological reconstruction

Abstract

Purpose

Three-dimensional surface imaging (3D-SI) of the breasts enables the measurement of breast volume and shape symmetry. If these measurements were sufficiently accurate and repeatable, they could be used in planning oncological breast surgery and as an objective measure of aesthetic outcome. The aim of this study was to validate the measurements of breast volume and symmetry provided by the Vectra XT imaging system.

Methods

To validate measurements, breast phantom models of true volume between 100 and 1000 cm³ were constructed and varying amounts removed to mimic breast tissue 'resections'. The volumes of the phantoms were measured using 3D-SI by two observers and compared to a gold standard. For intra-observer repeatability and inter-observer reproducibility in vivo, 16 patients who had undergone oncological breast surgery had breast volume and symmetry measured three times by two observers.

Results

A mean relative difference of 2.17 and 2.28% for observer 1 and 2 respectively was seen in the phantom measurements compared to the gold standard (n = 45, Bland Altman agreement). Intra-observer variation over ten repeated measurements demonstrated mean coefficients of variation (CV) of 0.58 and 0.49%, respectively. The inter-observer variation demonstrated a mean relative difference of 0.11% between the two observers. In patients, intra-observer variation over three repeated volume measurements for each observer was 3.9 and 3.8% (mean CV); the mean relative difference between observers was 5.78%. For three repeated shape symmetry measurements using RMS projection difference between the two breasts, the intra-observer variations were 8 and 14% (mean CV), the mean relative difference between observers was 0.43 mm for average symmetry values that ranged from about 3.5 to 15.5 mm.

Conclusion

This first validation of breast volume and shape symmetry measurements using the Vectra XT 3D-SI system suggests that these measurements have the potential to assist in pre-operative planning and also as a measure of aesthetic outcome.

https://ift.tt/2JaPIg1

Myeloid neoplasms with t(16;21)(q24;q22)/ RUNX1-RUNX1T3 mimics acute myeloid leukemia with RUNX1-RUNX1T1

Abstract

Chromosome translocation t(16;21)(q24;q22)/RUNX1-RUNX1T3 is an infrequent but recurrent chromosomal abnormality identified in myeloid neoplasms, with only 25 cases have been reported to date. Here, we report eight cases (six women and two men) of myeloid neoplasms associated with t(16;21)(q24;q22): five with therapy-related myeloid neoplasms, two with relapsed acute myeloid leukemia (AML), and one with blast phase of chronic myeloid leukemia. Morphologic and immunophenotypic features include granulocytic dysplasia, blasts with prominent perinuclear hof, large orange-pink granules, long and slim Auer rods, and aberrant expression of CD19. Six patients received AML-based regimens, and five achieved complete remission after initial induction therapy. Our study suggests that myeloid neoplasm with t(16;21)/RUNX1-RUNX1T1 resembles AML with t(8;21)(q22;q22)/RUNX1-RUNX1T1, in regard to morphology, immunophenotype, and response to therapy. Therefore, the clinical management of AML with t(8;21) may provide the best model for patients with myeloid neoplasms with t(16;21).

https://ift.tt/2Jci6OD

Clinical characteristics and treatment outcome of an 86-year-old patient with acute myeloid leukaemia with acute promyelocytic-like morphology and uncommon RARA fusion variant

https://ift.tt/2HmfWX9

Characterization of Staphylococcus aureus strains and evidence for the involvement of non-classical enterotoxin genes in food poisoning outbreaks

Abstract

To an increasing extent, molecular and genetic characterization is now used to investigate foodborne outbreaks. The aim of this study was to seek molecular links among coagulase-positive staphylococci (CPS) isolated from three recent food poisoning outbreaks in Romania using polymerase chain reaction and pulsed-field gel electrophoresis (PFGE) techniques. Nineteen CPS isolates were identified as Staphylococcus aureus by detection of the 23S rDNA gene. Among them, 15 carried at least one staphylococcal enterotoxin-encoding gene (se). The Calarași outbreak strains grouped in pulsotype 2 and were sed/sej/ser-positive, whereas the Arad outbreak strains clustered in pulsotype 17 and were either sed/seg/sei/sej/ser- or seg/sei-positive. The Pitești outbreak strains clustered in pulsotype 1 and, surprisingly, possessed only one enterotoxin gene, i.e. seh. Similar to other European countries, the seh gene has been identified with increasing frequency in Romanian outbreaks; this highlights the importance of considering the application of methods recommended for staphylococcal enterotoxin regulation in Europe.

https://ift.tt/2kRE8YG

Cancers, Vol. 10, Pages 185: Cutting to the Chase: How Matrix Metalloproteinase-2 Activity Controls Breast-Cancer-to-Bone Metastasis

Cancers, Vol. 10, Pages 185: Cutting to the Chase: How Matrix Metalloproteinase-2 Activity Controls Breast-Cancer-to-Bone Metastasis

Cancers doi: 10.3390/cancers10060185

Authors: Marilena Tauro Conor C. Lynch

Bone metastatic breast cancer is currently incurable and will be evident in more than 70% of patients that succumb to the disease. Understanding the factors that contribute to the progression and metastasis of breast cancer can reveal therapeutic opportunities. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes whose role in cancer has been widely documented. They are capable of contributing to every step of the metastatic cascade, but enthusiasm for the use of MMP inhibition as a therapeutic approach has been dampened by the disappointing results of clinical trials conducted more than 20 years ago. Since the trials, our knowledge of MMP biology has expanded greatly. Combined with advances in the selective targeting of individual MMPs and the specific delivery of therapeutics to the tumor microenvironment, we may be on the verge of finally realizing the promise of MMP inhibition as a treatment strategy. Here, as a case in point, we focus specifically on MMP-2 as an example to show how it can contribute to each stage of breast-cancer-to-bone metastasis and also discuss novel approaches for the selective targeting of MMP-2 in the setting of the bone-cancer microenvironment.

https://ift.tt/2JaBPy9

Naive B Cells with High-Avidity Germline-Encoded Antigen Receptors Produce Persistent IgM+ and Transient IgG+ Memory B Cells

Immunity induced by certain vaccines declines over time. By studying B cell responses to phycoerythrin, Pape et al. find that memory B cells can be short-lived when generated from precursors that experience unusually strong early signals through their un-mutated antigen receptors.

https://ift.tt/2kNwZIJ

A Single-Cell Transcriptomic Atlas of Thymus Organogenesis Resolves Cell Types and Developmental Maturation

Studies of thymus development typically lack single-cell resolution, use indirect readouts, or target narrow cell subsets. Using single-cell RNA sequencing during thymus organogenesis, Kernfeld and Genga et al. reveal cellular heterogeneity, interrogate developmental dynamics by direct observation, and pinpoint cell-specific expression patterns in stromal and blood populations.

https://ift.tt/2sCmmfk

Protein Kinase C-β Dictates B Cell Fate by Regulating Mitochondrial Remodeling, Metabolic Reprogramming, and Heme Biosynthesis

Lymphocyte activation is associated with major changes in metabolism. Tsui and colleagues demonstrate that PKCβ promotes metabolic reprogramming to drive effector fate decision in B cells.

https://ift.tt/2sCmprw

Transient negative effects of antibiotics on phages do not jeopardise the advantages of combination therapies

Abstract

Phages, the viruses of bacteria, have been proposed as antibacterial agents to complement or replace antibiotics due to the growing problem of resistance. In nature and in the clinic, antibiotics are ubiquitous and may affect phages indirectly via impacts on bacterial hosts. Even if the synergistic association of phages and antibiotics has been shown in several studies, the focus is often on bacteria with little known about the impact on phages. Evolutionary studies have demonstrated that time scale is an important factor in understanding the consequences of antimicrobial strategies, but this perspective is generally overlooked in phage-antibiotic combination studies. Here, we explore the effects of antibiotics on phages targeting the opportunistic pathogen Pseudomonas aeruginosa. We go beyond previous studies by testing the interaction between several types of antibiotics and phages, and evaluate the effects on several important phage parameters during 8 days of experimental co-evolution with bacteria. Our study reveals that antibiotics had a negative effect on phage density and efficacy early on, but not in the later stages of the experiment. The results indicate that antibiotics can affect phage adaptation, but that phages can nevertheless contribute to managing antibiotic resistance levels.

https://ift.tt/2HlluBc

Methanogens in the Antarctic Dry Valley Permafrost

Abstract

Polar permafrost is at the forefront of climate change, yet only a few studies have enriched the native methane-producing microbes that might provide positive feedbacks to climate change. Samples Ant1 and Ant2, collected in Antarctic Miers Valley from permafrost sediments, with and without biogenic methane, respectively, were evaluated for methanogenic activity and presence of methanogens. After a one-year incubation of both samples under anaerobic conditions, methane production was observed only at room temperature in microcosm Ant1 with CO₂/H₂ (20/80) as carbon and energy sources, and was monitored during the subsequent 10 years. The concentration of methane in the headspace of microcosm Ant1 changed from 0.8% to a maximum of 45%. Archaeal 16S rRNA genes from microcosm Ant1 were related to psychrotolerant Methanosarcina lacustris. Repeated efforts at achieving a pure culture of this organism were unsuccessful. Metagenomic reads obtained for the methane-producing microcosm Ant1 were assembled and resulted in a 99.84% complete genome affiliated with the genus Methanosarcina. The metagenome assembled genome contained cold-adapted enzymes and pathways suggesting that the novel uncultured Methanosarcina sp. Ant1 is adapted to sub-freezing conditions in permafrost. This is the first methanogen genome reported from the 15,000 years old permafrost of the Antarctic Dry Valleys.

https://ift.tt/2kNRjtm

Characterization of phototrophic microorganisms and description of new cyanobacteria isolated from the saline-alkaline crater-lake Dziani Dzaha (Mayotte, Indian Ocean)

Abstract

The saline-alkaline crater-lake Dziani Dzaha (Mayotte, Indian Ocean) is dominated by the bloom-forming cyanobacterium Arthrospira. However, the rest of the phototrophic community remains underexplored because of their minute dimension or lower biomass. To characterize the phototrophic microorganisms living in this ecosystem considered as a modern analog of Precambrian environments, several strains were isolated from the water column and stromatolites, and analyzed using the polyphasic approach. Based on morphological, ultrastructural and molecular (16S rRNA gene, 18S rRNA gene, 16S-23S ITS region, cpcBA-IGS locus) methods, seven filamentous cyanobacteria and the prasinophyte Picocystis salinarum were identified. Two new genera and four new cyanobacteria species belonging to the orders Oscillatoriales (Desertifilum dzianense sp. nov.) and Synechococcales (Sodalinema komarekii gen. nov., sp. nov., Sodaleptolyngbya stromatolitii gen. nov., sp. nov. and Haloleptolyngbya elongata sp. nov.) were described. This approach also allowed to identify Arthrospira fusiformis with exclusively straight trichomes instead of the spirally coiled form commonly observed in the genus. This study evidenced the importance of using the polyphasic approach to solve the complex taxonomy of cyanobacteria and to study algal assemblages from unexplored ecosystems.

https://ift.tt/2sIaEjb

Water & Sanitation: An Essential Battlefront in the War on Antimicrobial Resistance

Abstract

Water and sanitation represents a key battlefront in combating the spread of antimicrobial resistance (AMR). Basic water sanitation infrastructure is an essential first step to protecting public health, thereby limiting the spread of pathogens and the need for antibiotics. AMR presents unique human health risks, meriting new risk assessment frameworks specifically adapted to water and sanitation-borne AMR. There are numerous exposure routes to AMR originating from human waste, each of which must be quantified for its relative risk to human health. Wastewater treatment plants (WWTPs) play a vital role in centralized collection and treatment of human sewage, but there are numerous unresolved questions in terms of the microbial ecological processes occurring within and the extent to which they attenuate or amplify AMR. Research is needed to advance understanding of the fate of resistant bacteria and antibiotic resistance genes (ARGs) in various waste management systems, depending on the local constraints and intended re-use applications. WHO and national AMR action plans would benefit from a more holistic 'One Water' understanding. Here we provide a framework for research, policy, practice, and public engagement aimed at limiting the spread of AMR from water and sanitation in both low-, medium- and high-income countries, alike.

https://ift.tt/2kMokWW

The impact of chlorine and heat on the infectivity and physicochemical properties of bacteriophage MS2

Abstract

Enteric viruses and bacteriophages are exposed to various inactivating factors outside their host, and among them chlorine and heat are the most commonly used sanitizer in water industry and treatment in the food industry, respectively. Using MS2 phages as models for enteric viruses, we investigated the impact of free chlorine and heat on their physicochemical properties. Free chlorine was first evaluated alone. No increase in either capsid permeability or hydrophobicity was observed. The negative surface charge slightly increased suggesting molecular changes in the capsid. However, a weakening of the capsid by chlorine was suggested by differential scanning fluorimetry. This phenomenon was confirmed when chlorination was followed by a heat treatment. Indeed, an increase in the inactivation of MS2 phages and the permeability of their capsids to RNases was observed. More interestingly, an increase in the expression of hydrophobic domains at the phage surface was observed, but only for phages remaining infectious. The chlorine-caused weakening of the capsid suggested that, for an optimal use, the oxidant should be followed by heat. The increased permeability to RNases and the expression of hydrophobic domains may contribute to the development or improvement of molecular methods specific for infectious enteric viruses.

https://ift.tt/2HnkxrP

Methods for Field Measurement of Antibiotic Concentrations: Limitations and Outlook

Abstract

The growing prevalence of antibiotic resistance poses an increasingly serious threat to human health. Although an important driver of antibiotic resistance is the continuous exposure of bacteria to sublethal concentrations of antibiotics in natural environments, antibiotic pollutants are not currently tracked globally or systematically. This limits the international capacity to address the rise of antibiotic resistance at its source. To address this lack of data, the development of methods to measure antibiotic concentrations on-site is essential. These methods, ideally, must be sensitive to sublethal concentrations of antibiotics and require minimal technical expertise. Furthermore, factors such as cost, selectivity, biosafety, and the ability to multiplex must be evaluated in the context of field use. Based on these criteria, we provide a critical review of current methods in antibiotic detection and evaluate their adaptability for use on-site. We categorize these methods into microbiological assays, physical and chemical assays, immunoassays, aptasensors, and whole-cell biosensors. We recommend continued development of a dipstick or microfluidics approach with a bacterial promoter-based mechanism and colorimetric output. This technique would incorporate the advantageous aspects of existing methods, maximize shelf-life and ease-of-use, and require minimal resources to implement in the field.

https://ift.tt/2J8CxMq

Unusual cause of obstructive uropathy: bilateral steinstrasse

Description 

A 45-year-old man presented with decreased urinary output (<150 mL per 24 hours), anorexia, nausea and bilateral flank pain for 1 week. His serum creatinine potassium were 12.9 mg/dL and 6.0 mEq/L, respectively. He had no associated comorbidity. He had history of bilateral renal pelvic stones for which he underwent extracorporeal shock wave lithotripsy (ESWL) 2 months back, first for the right kidney (single session) then 2 weeks later for the left kidney (single session). His renal function was normal before undergoing ESWL (serum creatinine 0.9 mg/dL). No check X-ray had been done after ESWL. A plain X-ray was done that showed bilateral steinstrasse (figure 1) and on ultrasonography he had hydronephrosis in both kidneys. This caused acute renal failure due to obstructive uropathy. He was taken up for haemodialysis urgently. After two sessions of haemodialysis, he was taken up for stenting of bilateral ureters. After stenting, his renal function...

https://ift.tt/2syxH0H

Unusual case of hypocalcaemia

Description 

A 33-year-old woman presented with 1 week of dizziness and bilateral leg and hand cramps with associated numbness and tingling. She stated she was diagnosed with hypocalcaemia when she was approximately 8 years old, but could not elaborate further. She was a poor historian with learning disabilities and admittedly was non-compliant with treatment.

Physical examination revealed a round face, short stature (4'10'') and obesity (body mass index 39) with no neck scars. Her extremities were notable brachydactyly of her feet (figure 1) as well as brachydactyly of her fourth and fifth fingers (figure 2) with a positive Archibald's sign (figure 3). X-ray of her hands was significant for shortening of the fourth and fifth metacarpals (figure 4). EKG was remarkable for prolonged QT interval (figure 5). Brain CT revealed extensive calcification in the basal ganglia (figure...

https://ift.tt/2sDp83O

Severe bone marrow suppression due to methotrexate toxicity following aceclofenac-induced acute kidney injury

Methotrexate is one of the most commonly used drugs in autoimmune disorders like rheumatoid arthritis. Gastrointestinal symptoms like nausea and stomatitis, skin rashes, alopecia, central nervous system symptoms like headache and confusion, hepatotoxicity and myelosuppression are some of the adverse effects. However, low oral doses on a weekly basis seldom show any signs of toxicity. Leucovorin or folinic acid is given along with methotrexate as rescue to reduce the toxic effects like bone marrow suppression. Non-steroidal anti-inflammatory drugs, like aceclofenac, are also used in chronic inflammatory conditions like rheumatoid arthritis and osteoarthritis. Nephrotoxicity is one of the adverse effects of both methotrexate and non-steroidal anti-inflammatory drugs; and its combined administration should be done with caution. This is a case of an elderly woman, a known case of rheumatoid arthritis, who presented in severe bone marrow suppression due to methotrexate toxicity following aceclofenac-induced acute kidney injury.

https://ift.tt/2syqk9s

ALL relapse with multiple cranial nerve palsies and toxic leukoencephalopathy: treatment failure with treatment toxicity

Description 

Acute lymphoblastic leukaemia (ALL) is one of the most common malignancies of childhood. ALL is treated with high doses of methotrexate (MTX) to prevent central nervous system (CNS) and haematological relapses. MTX is administered intravenously and via intrathecal route.1 MTX can cause neurotoxicity by disrupting CNS folate homeostasis or by direct neuronal damage. MTX-induced acute toxic leukoencephalopathy can result in acute neurological deficit, seizures or encephalopathy.2 We report a 27-year-old diagnosed case of ALL who presented with neurological symptoms 2 years after she was started with intensive and maintenance phase of chemotherapy. She took multiple cycles (24) of intrathecal MTX in her intensive phase and was subsequently followed up regularly after her maintenance phase for bone marrow aspiration, which showed reduced blast cells compared with the earlier report. Few weeks after completing her chemotherapy, she complained of visual blurring in the right eye followed by...

https://ift.tt/2sHj0HR

Differential diagnosis for chronic hypokalaemia

Doctors will often see patients with chronic hypokalaemia, frequently this is secondary to gastrointestinal losses, diuretics or renal disease. However, in this case report we review a rarer cause of chronic hypokalaemia—Gitelman syndrome (GS).

GS is an uncommon genetic disorder which causes primary renal tubular hypokalaemic metabolic alkalosis with secondary hypomagnesaemia and hypocalciuria. Although rare, it is important to remember GS when considering differential diagnoses for chronic hypokalaemia. We report the case of a woman who presented to the ophthalmology department with sclerochoroidal calcification. An ophthalmologist was reviewing the medical literature, which prompted them to investigate for GS. A diagnosis was formed at that time based on the blood and urine chemistry results. However, later we were able to offer the patient genetic testing, which confirmed our provisional diagnosis.

https://ift.tt/2kOgc8n

Gitelman syndrome and primary hyperparathyroidism: a rare association

Gitelman syndrome(GS) is a rare autosomal recessive salt-losing tubulopathy of young adults, characterised by hypokalaemia, hypomagnesaemia, hypocalciuria and secondary hyperaldosteronism. Hypercalcaemia due to hypocalciuria in these patients is extremely rare.

A 25-year-old healthy woman was referred to the Endocrinology clinic for evaluation of persistent hypokalaemia. She presented with fatigue, myalgias, cramps and paraesthesia. Her physical examination was normal. Laboratory workup revealed: K⁺ 2.7 mEq/L (r.v.3.5–5.1), 24 hours urinary K⁺ 84.7 mEq/24 hours (r.v.25–125), Mg²⁺ 0.71 mg/dL (r.v.1.6–2.6), 24 hours urinary Mg²⁺ 143.1 mg/24 hours (r.v.73–122), Ca²⁺ 12 mg/dL (r.v.8.4–10.2), aldosterone 47.1 ng/mL (r.v. 4–31) and active renin 374.7 uUI/mL (r.v.4.4–46.1). She was diagnosed with GS and was treated with spironolactone, oral K⁺ and Mg²⁺ supplementation. Further investigation confirmed hypercalcaemia due to primary hyperparathyroidism owing to a single parathyroid adenoma. Following parathyroidectomy serum calcium normalised.

Current knowledge favours that hypomagnesaemia in patients with GS protects them from hypercalcaemia. In this context of multiple electrolyte imbalances, correction of hypomagnesaemia is a challenge and should be done carefully. Like in our patient, aetiology of hypercalcaemia should be promptly diagnosed and reversed.

https://ift.tt/2Hjwfny

Serious life-threatening multifocal infection in a child, caused by Panton-Valentine leucocidin-producing Staphylococcus aureus (PVL-MSSA)

Groin pain is a frequently occurring complaint in presentations to the Emergency Department. Muscular sprain is often a differential diagnosis, however serious conditions such as pyomyositis should not be ignored. This case report presents a child with atraumatic right groin pain, which was initially diagnosed as a muscular sprain. The patient later re-presented out of hours to the Emergency Department with what was found to be extensive pelvic abscesses. He was subsequently found to have bilateral pneumonia and later developed a pericardial effusion and osteomyelitis of the right iliac bone, sacroiliac joint and sacrum. With multiple surgical interventions and appropriate antibiotics, he made a full recovery and was discharged home after a total admission time of 41 days. The causative organism was found to be Panton-Valentine leucocidin-positive methicillin-susceptible Staphylococcus aureus.

https://ift.tt/2syqayS