TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes

BACKGROUND

Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML).

METHODS

Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis.

RESULTS

TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53–mutated (n = 53) versus wild-type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs ≥60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P = .04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P = .001), and overall survival (at 2 years: 9% vs 24%; P ≤ .0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy).

CONCLUSIONS

The type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016. © 2016 American Cancer Society.

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The Promise of Molecularly Targeted and Immunotherapy for Advanced Melanoma

Opinion Statement

Advanced melanoma, rarely diagnosed at the time of primary melanoma excision but most often occurring later via lymphatic or hematogenous dissemination, is the cause of death for approximately 10,000 people in the USA each year, with the rate of incidence and death increasing yearly. Its causes are multifactorial and depend in large part on solar ultraviolet damage to DNA as well as underlying genetic predisposition. Cutaneous melanoma is the most common, but other subsets of importance are mucosal and uveal primaries, with different biology and treatment considerations. Mutational oncogenic "drivers" may be targeted with chronically administered, oral kinase inhibitors, currently consisting of the mitogen-activated protein kinase (MAPK) inhibitor combinations of BRAF plus MEK-targeted drugs. These agents work quickly to relieve symptoms and induce remissions but generally have limited durations of disease control. Immunotherapies include the immune checkpoint inhibitors that block CTLA4 or PD-1-negative immune signaling as well as interleukin-2, a cytokine that stimulates T lymphocytes and natural killer cells. A combination of CTLA4 plus PD-1 blockade has the highest activity ever reported for metastatic melanoma, at the cost of high autoimmune-like toxicities. However, immunotherapies of this type may provide durable responses and even cure a subset of patients. Thus, these immunotherapeutic agents are recommended as first-line therapy for most patients with advanced melanoma. Patients with rapidly progressive, symptomatic melanoma whose tumor carries a BRAF mutation may benefit more from initial therapy with combined MAPK inhibitors.

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Filaggrin gene mutations and new SNPs in asthmatic patients: a cross-sectional study in a Spanish population

Several null-mutations in the FLG gene that produce a decrease or absence of filaggrin in the skin and predispose to atopic dermatitis and ichthyosis vulgaris have been described. The relationship with asthma is ...

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Speech Audiometry Findings from HIV+ and HIV- Adults in the MACS and WIHS Longitudinal Cohort Studies

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Torre Peter, Howard J. Hoffman, Gayle Springer, Christopher Cox, Mary A. Young, Joseph B. Margolick, Michael Plankey
The purpose of this study was to compare various speech audiometry measures between HIV+ and HIV- adults and to further evaluate the association between speech audiometry and HIV disease variables in HIV+ adults only. Three hundred ninety-six adults from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) completed speech audiometry testing. There were 262 men, of whom 117 (44.7%) were HIV+, and 134 women, of whom 105 (78.4%) were HIV+. Speech audiometry was conducted as part of the standard clinical audiological evaluation that included otoscopy, tympanometry, and pure-tone air- and bone-conduction thresholds. Specific speech audiometry measures included speech recognition thresholds (SRT) and word recognition scores in quiet presented at 40dB sensation level (SL) in reference to the SRT. SRT data were categorized in 5-dB steps from 0–25dB hearing level (HL) with one category as ≥30dB HL while word recognition scores were categorized as <90%, 90-99%, and 100%. A generalized estimating equations model was used to evaluate the association between HIV status and both ordinal outcomes. The SRT distributions across HIV+ and HIV- adults were similar. HIV+ and HIV- adults had a similar percentages of word recognition scores<90%, a lower percentage of HIV- adults had 90-99%, but HIV- adults had a higher percentage of 100%. After adjusting for covariables, HIV+ adults were borderline significantly more likely to have a higher SRT than HIV- adults (odds ratio [OR]=1.45, p=0.06). Among HIV+ adults, HIV-related variables (i.e., CD4+ T-cell counts, HIV viral load, and ever history of clinical AIDS) were not significantly associated with either SRT or word recognition score data. There was, however, a ceiling effect for word recognition scores, probably the result of obtaining this measure in quiet with a relatively high presentation level. A more complex listening task, such as speech-in-noise testing, may be a more clinically informative test to evaluate the effects of HIV on speech communication.



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Tailoring the Electronic and Catalytic Properties of Au25 Nanoclusters via Ligand Engineering

ACS Nano

DOI: 10.1021/acsnano.6b03964

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FeedaMail: Microbiology via ola Kala on Inoreader

	Microbiology via ola Kala on Inoreader
	(Sponsor this newsletter) Bacterial community composition in relation to bedrock type and macrobiota in soils from the Sor Rondane Mountains, East Antarctica Antarctic soils are known to be oligotrophic and of having low buffering capacities. It is expected that this is particularly the case for inland high-altitude regions. We hypothesized that the bedrock type and the presence of macrobiota in these soils enforce a high selective pressure on their bacterial communities. To test this, we analyzed the bacterial community structure in 52 soil samples from the western Sør Rondane Mountains (Dronning Maud Land, East Antarctica), using the Illumina MiSeq platform in combination with ARISA fingerprinting. The samples were taken along broad environmental gradients in an area covering nearly 1000 km2. Ordination and variation partitioning analyses revealed that the total organic carbon content was the most significant variable in structuring the bacterial communities, followed by pH, electric conductivity, bedrock type and the moisture content, while spatial distance was of relatively minor importance. Acidobacteria (Chloracidobacteria) and Actinobacteria (Actinomycetales) dominated gneiss derived mineral soil samples, while Proteobacteria (Sphingomonadaceae), Cyanobacteria, Armatimonadetes and candidate division FBP-dominated soil samples with a high total organic carbon content that were mainly situated on granite derived bedrock. Read More » Bacterial and fungal symbionts of parasitic Dendroctonus bark beetles Bark beetles (Curculionidae: Scolytinae) are one of the most species-rich herbivorous insect groups with many shifts in ecology and host-plant use, which may be mediated by their bacterial and fungal symbionts. While symbionts are well studied in economically important, tree-killing species, little is known about parasitic species whose broods develop in living trees. Here, using culture-dependent and independent methods, we provide a comprehensive overview of the associated bacteria, yeasts and filamentous fungi of the parasitic Dendroctonus micans, D. punctatus and D. valens, and compare them to those of other tree-inhabiting insects. Despite inhabiting different geographical regions and/or host trees, the three species showed similar microbial communities. Enterobacteria were the most prevalent bacteria, in particular Rahnella, Pantoea and Ewingella, in addition to Streptomyces. Likewise, the yeasts Candida/Cyberlindnera were the most prominent fungi. All these microorganisms are widespread among tree-inhabiting insects with various ecologies, but their high prevalence overall might indicate a beneficial role such as detoxification of tree defenses, diet supplementation or protection against pathogens. As such, our results enable comparisons of symbiont communities of parasitic bark beetles with those of other beetles, and will contribute to our understanding of how microbial symbioses facilitate dietary shifts in insects. Read More » Prodigiosin inhibits motility and activates bacterial cell death revealing molecular biomarkers of programmed cell death The antimicrobial activity of prodigiosin from Serratia nematodiphila darsh1, a bacterial pigment was tested against few food borne bacterial pathogens Bacillus cereus, Staphylococcus aureus, Pseudomonas aerugino... Read More » Dispersal of human and plant pathogens biofilms via nitric oxide donors at 4 °C Recent studies suggest that nitric oxide donors capable of manipulating nitric oxide-mediated signaling in bacteria could induce dispersal of biofilms. Encased in extracellular polymeric substances, human and ... Read More »
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Identification of a five-lncRNA signature for the diagnosis and prognosis of gastric cancer

Abstract

Gastric cancer (GC) is one of the most aggressive malignancies and has a poor prognosis. Identifying novel diagnostic and prognostic markers is of great importance for the management and treatment of GC. Long non-coding RNAs (lncRNAs), which are involved in multiple processes during the development and progression of cancer, may act as potential biomarkers of GC. Here, by performing data mining using four microarray data sets of GC downloaded from the Gene Expression Omnibus (GEO) database with different classifiers and risk score analyses, we identified a five-lncRNA signature (AK001094, AK024171, AK093735, BC003519 and NR_003573) displaying both diagnostic and prognostic values for GC. The results of the Kaplan-Meier survival analysis and log-rank test showed that the risk score based on this five-lncRNA signature was closely associated with overall survival time (p = 0.0001). Further analysis revealed that the risk score is an independent predictor of prognosis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of 30 pairs of GC tissue samples confirmed that the five lncRNAs were dysregulated in GC, and receiver operating characteristic (ROC) curves showed the high diagnostic ability of combining the five lncRNAs, with an area under the curve (AUC) of 0.95 ± 0.025. The five lncRNAs involved in several cancer-related pathways were identified using gene set enrichment analysis (GSEA). These findings indicate that the five-lncRNA signature may have a good clinical applicability for determining the diagnosis and predicting the prognosis of GC.

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VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway

Abstract

We previously developed (2-deoxyglucose)-(ABT-263) combination therapy (2DG-ABT), which induces apoptosis by activating Bak in the mitochondria of highly glycolytic cells with varied genetic backgrounds. However, the rates of apoptosis induced by 2DG-ABT were lower in von Hippel-Lindau (VHL)-deficient cancer cells. The re-expression of VHL protein in these cells lowered IGF1R expression in a manner independent of oxygen concentration. Lowering IGF1R expression via small interfering RNA (siRNA) sensitized the cells to 2DG-ABT, suggesting that IGF1R interfered with the activation of apoptosis by the mitochondria. To determine which of the two pathways activated by IGF1R, the Ras-ERK pathway or the PI3K-AKT pathway, was involved in the impairment of mitochondria activation, the cells were treated with a specific inhibitor of either PI3K or ERK, and 2DG-ABT was added to activate the mitochondria. The apoptotic rates resulting from 2DG-ABT treatment were higher in the cells treated with the PI3K inhibitor, while the rates remained approximately the same in the cells treated with the ERK inhibitor. In 2DG-ABT-sensitive cells, a 4-h 2DG treatment caused the dissociation of Mcl-1 from Bak, while ABT treatment alone caused the dissociation of Bcl-xL from Bak without substantially reducing Mcl-1 levels. In 2DG-ABT-resistant cells, Mcl-1 dissociated from Bak only when AKT activity was inhibited during the 4-h 2DG treatment. Thus, in VHL-deficient cells, IGF1R activated AKT and stabilized the Bak-Mcl-1 complex, thereby conferring cell resistance to apoptosis.

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miR-326 reverses chemoresistance in human lung adenocarcinoma cells by targeting specificity protein 1

Abstract

Cisplatin resistance is a major obstacle in the treatment of lung adenocarcinoma (LAD), and its mechanism has not been fully elucidated. Here, we report that miR-326 is downregulated in cisplatin-resistant A549/CDDP cells compared with parental A549 cells. Overexpression of miR-326 reversed cisplatin chemoresistance of LAD cells in vitro and in vivo. Moreover, we identified the specificity protein 1 (SP1) gene as a novel direct target of miR-326. Knockdown of SP1 revealed similar effects as that of ectopic miR-326 expression. Decreased miR-326 expression was also detected in tumor tissues sampled from LAD patients treated with cisplatin-based chemotherapy and was proved to be correlated with high expression of SP1 and decreased sensitivity to cisplatin. Furthermore, we show that the long noncoding RNA HOTAIR repression reverses chemoresistance of LAD cells partially through modulation of miR-326/SP1 pathway. In summary, we unveil a branch of the HOTAIR/miR-326/SP1 pathway that regulates chemoresistance of LAD cells.

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Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression

Abstract

During tumorigenesis, cancer cells generate complex, unresolved interactions with the surrounding oxystressed cellular milieu called tumor microenvironment ™ that favors spread of cancer to other body parts. This dissemination of cancer cells from the primary tumor site is the main clinical challenge in cancer treatment. In addition, the significance of enhanced oxidative stress in TM during cancer progression still remains elusive. Thus, the present study was performed to investigate the molecular and cytoskeletal alterations in breast cancer cells associated with oxystressed TM that potentiates metastasis. Our results showed that depending on the extent of oxidative stress in TM, cancer cells exhibited enhanced migration and survival with reduction of chemosensitivity. Corresponding ultrastructural analysis showed radical cytoskeletal modifications that reorganize cell-cell interactions fostering transition of epithelial cells to mesenchymal morphology (EMT) marking metastasis, which was reversed upon antioxidant treatment. Decreased E-cadherin and increased vimentin, Twist1/2 expression corroborated the initiation of EMT in oxystressed TM-influenced cells. Further evaluation of cellular energetics demonstrated significant metabolic reprogramming with inclination towards glucose or external glutamine from TM as energy source depending on the breast cancer cell type. These observations prove the elemental role of oxystressed TM in cancer progression, initiating EMT and metabolic reprogramming. Further cell-type specific metabolomic analysis would unravel the alternate mechanisms in cancer progression for effective therapeutic intervention.

Graphical abstract

Schematic representation of the study and proposed mechanism of oxystressed TM influenced cancer progression. Cancer cells exhibit a close association with tumor microenvironment ™, and oxystressed TM enhances cancer cell migration and survival and reduces chemosensitivity. Oxystressed TM induces dynamic cytomorphological variations, alterations in expression patterns of adhesion markers, redox homeostasis, and metabolic reprogramming that supports epithelial to mesenchymal transition and cancer progression.

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IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells

Abstract

Internal ribosome entry site (IRES)-mediated translation is a specialized mode of protein synthesis which malignant cells depend on to survive adverse microenvironmental conditions. Our lab recently reported the identification of a group of compounds which selectively interfere with IRES-mediated translation, completely blocking de novo IGF1R synthesis, and differentially modulating synthesis of the two c-Myc isoforms. Here, we examine the phenotypic consequences of sustained IRES inhibition in human triple-negative breast carcinoma and glioblastoma cells. A sudden loss of viability affects the entire tumor cell population after ∼72-h continuous exposure to the lead compound. The extraordinarily steep dose-response relationship (Hill-Slope coefficients −15 to −35) and extensive physical connections established between the cells indicate that the cells respond to IRES inhibition collectively as a population rather than as individual cells. Prior to death, the treated cells exhibit prominent features of terminal differentiation, with marked gains in cytoskeletal organization, planar polarity, and formation of tight junctions or neuronal processes. In addition to IGF1R and Myc, specific changes in connexin 43, BiP, CHOP, p21, and p27 also correlate with phenotypic outcome. This unusual mode of tumor cell death is absolutely dependent on exceeding a critical threshold in cell density, suggesting that a quorum-sensing mechanism may be operative. Death of putative tumor stem cells visualized in situ helps to explain the inability of tumor cells to recover and repopulate once the compound is removed. Together, these findings support the concept that IRES-mediated translation is of fundamental importance to maintenance of the undifferentiated phenotype and survival of undifferentiated malignant cells.

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ClearFlow launches PleuraFlow pediatric cardiothoracic surgery device

ClearFlow said today it launched its PleuraFlow device designed for removing clots from chest tubes used to evacuate shed blood during pediatric cardiothoracic surgeries.

The Anaheim, Calif.-based company said it won FDA 510(k) clearance earlier this year expanding the indications of use for a PleuraFlow system for pediatric patients.

"We commonly hear from pediatric heart surgeons, pediatric intensive care specialists and ICU nurses that they encounter problems with chest tube clogging after heart surgery in children, and sometimes this results in preventable major complications or even fatal consequences. The older makeshift bedside techniques of stripping or milking conventional chest tubes has been shown ineffective to prevent these problems, and can even be harmful, and thus are banned in many hospitals. We are pleased to announce that children's hospitals can now adopt preventative protocols to routinely clear chest tubes of clogging with a proven, FDA cleared medical device solution," CEO Paul Molloy said in a press release.

ClearFlow said the device is designed to work with the smaller diameter tubes required for pediatric heart surgery and to avoid techniques for avoiding fclots that can break the sterile field and be potentially harmful.

"There has long been a need to facilitate patency of chest tubes in the smallest diameters used for pediatric heart surgery since the smaller the tube, the more prone it is to occlude. Expanding the product offerings to facilitate prevention of chest tube clogging in children requiring complex heart operations is an important step to meet this critical unmet need," co-founder Dr. Ed Boyle said in a prepared statement.

The post ClearFlow launches PleuraFlow pediatric cardiothoracic surgery device appeared first on MassDevice.

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Sight Sciences wins IDE for Visco 360

Venture-backed ophthalmic medical device company Sight Sciences said today it won FDA investigational device exemption approval to initiate a clinical trial of its Visco 360 Viscosurgical System for treating patients with glaucoma.

The multi-center, randomized trial will compare ab interno canaloplasty with the Visco 360 system against selective laster trabeculoplasty. The study will investigate the safety and effectiveness of the Visco 360 system in canaloplasty versus SLT for reducing intraocular pressure in primary open angle glaucoma patients, the company said.

"I have performed hundreds of ab externo canaloplasties over the years with excellent results. I am excited to participate in the Visco 360 study to characterize the safety and effectiveness of ab interno canaloplasty for patients with primary open angle glaucoma who do not need a combined procedure with cataract surgery. I believe that glaucoma specialists, comprehensive ophthalmologists, and any anterior segment surgeons will find this familiar ab interno approach to canaloplasty extremely useful for the care of their mild to moderate glaucoma patients and I look forward to participating in this important pivotal study," principal investigator Dr. Steven Sarkisian of the University of Oklahoma said in a press release.

The company's Visco 360 Viscosurgical System is a single-handed, single-use device combining a custom access cannula, flexible microcatheter with an atraumatic tip, internal infusion pump and viscoelsastic reservoir. The system fetures a control wheel designed to retract the microcatheter.

"We are extremely excited to begin this pivotal clinical trial investigating the use of our Visco 360 device for this specific indication. We believe there is a huge unmet need for an effective ab interno glaucoma procedure that is not performed in conjunction with cataract removal and we look forward to working with all of our clinical partners in the execution of this large, robust FDA clinical study," CEO Paul Badawi said in prepared remarks.

In March, Sight Sciences said it closed an oversubscribed $7 million Series B round of financing.

Sight Sciences produces the Trab 360 and Visco 360 surgical devices as well as a portfolio of technologies in the advanced stages of development for treating evaporative dry eye.

The round was led by Dallas-based private equity firm Hicks Equity Partners, and Sight Sciences said that all Series A investors participated in the B round, including Series A co-lead Scientific Health Development, Allegro Investment Funds and other institutional and angel investors.

The post Sight Sciences wins IDE for Visco 360 appeared first on MassDevice.

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Predicting turbulent flow friction coefficient using ANFIS technique

Abstract

The friction coefficient is widely used for technical and economical design of pipes in irrigation, land drainage, urban sewage systems and intake structures. In the present study, the friction factor in pipes is estimated by using adaptive neuro-fuzzy inference system (ANFIS) and grid partition method. The data derived from the Colebrook's equation were considered for ascertaining the neuro-fuzzy model. Present approach developed an ANFIS technique to predict the friction coefficient as output variable based on pipe relative roughness and Reynold's number as input variables. The performance of the ANFIS model was evaluated against conventional procedures. Correlation coefficient (R2), root mean squared error and mean absolute error were used as comparing statistical indicators for the assessment of the proposed approach's performance. It was found that the adaptive neuro-fuzzy inference system model is more accurate than other empirical equations in modeling friction factor.

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Relapsed Glioblastoma: Treatment Strategies for Initial and Subsequent Recurrences

Opinion Statement

At the time of glioblastoma (GBM) recurrence, a sharp analysis of prognostic factors, disease characteristics, response to adjuvant treatment, and clinical conditions should be performed. A prognostic assessment could allow a careful selection between patients that could be proposed to intensified approaches or palliative setting. Participation in clinical trials aims to improve outcome, and should be encouraged due to dismal prognosis of GBM patients after recurrence. Reoperation should be proposed if the tumor is amenable to a complete resection and if prognostic factors suggest that patient could benefit from a second surgery. Second-line chemotherapy should be chosen based on MGMT status, time to disease recurrence, and toxicity profile. If enrollment into a clinical trial is not possible, a nitrosourea-based regimen is the preferred choice, carefully evaluating any previous temozolomide (TMZ)-related toxicity. In MGMT-methylated patients relapsing after TMZ completion, a rechallenge could be proposed. After second progression, the clinical advantage of subsequent lines of chemotherapy still needs to be clarified. However, based on performance status, patients' preference, and disease behavior, a third-line treatment could be considered. Available treatments include nitrosoureas, bevacizumab, or carboplatin plus etoposide. However, more effective therapeutic options are needed.

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Circulating Tumor DNA to Monitor Therapy for Aggressive B-Cell Lymphomas

Opinion statement

The goal of therapy for aggressive B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) is to achieve cure. Combination chemotherapy with rituximab cures most patients, but those with recurrent disease have a poor prognosis. Medical imaging scans such as computed tomography (CT) and positron emission tomography (PET) are the principal methods to assess response and monitor for disease relapse after therapy but are fundamentally limited by risks of radiation, cost, and a lack of tumor specificity. Novel sequencing-based DNA monitoring methods are capable of quantifying small amounts of circulating tumor DNA (ctDNA) before, during, and after therapy for mature B-cell lymphomas. Detection of ctDNA encoding clonal rearranged variable-diversity-joining (VDJ) receptor gene sequences has demonstrated improved analytical sensitivity and enhanced tumor specificity compared to imaging scans in DLBCL, offering broad clinical applicability across a range of aggressive B-cell lymphomas. Molecular monitoring of ctDNA has vaulted into the spotlight as a promising non-invasive tool with immediate clinical impact on monitoring for recurrence after therapy prior to clinical symptoms. As these clinical observations are validated, ctDNA monitoring needs to be investigated as a tool for response-adapted therapy and as a marker of minimal residual disease upon completion of therapy in aggressive B-cell lymphomas. Molecular monitoring of ctDNA holds tremendous promise that may ultimately transform our ability to monitor disease in aggressive B-cell lymphomas.

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Quality of treatment plans and accuracy of in vivo portal dosimetry in hybrid intensity-modulated radiation therapy and volumetric modulated arc therapy for prostate cancer

Publication date: Available online 25 July 2016
Source:Radiotherapy and Oncology
Author(s): James L. Bedford, Gregory Smyth, Ian M. Hanson, Alison C. Tree, David P. Dearnaley, Vibeke N. Hansen
Background and purposeDelivering selected parts of volumetric modulated arc therapy (VMAT) plans using step-and-shoot intensity modulated radiotherapy (IMRT) beams has the potential to increase plan quality by allowing specific aperture positioning. This study investigates the quality of treatment plans and the accuracy of in vivo portal dosimetry in such a hybrid approach for the case of prostate radiotherapy.Material and methodsConformal and limited-modulation VMAT plans were produced, together with five hybrid IMRT/VMAT plans, in which 0%, 25%, 50%, 75% or 100% of the segments were sequenced for IMRT, while the remainder were sequenced for VMAT. Integrated portal images were predicted for the plans. The plans were then delivered as a single hybrid beam using an Elekta Synergy accelerator with Agility head to a water-equivalent phantom and treatment time, isocentric dose and portal images were measured.ResultsIncreasing the IMRT percentage improves dose uniformity to the planning target volume (p<0.01 for 50% IMRT or more), substantially reduces the volume of rectum irradiated to 65Gy (p=0.02 for 25% IMRT) and increases the monitor units (p<0.001). Delivery time also increases substantially. All plans show accurate delivery of dose and reliable prediction of portal images.ConclusionsHybrid IMRT/VMAT can be efficiently planned and delivered as a single beam sequence. Beyond 25% IMRT, the delivery time becomes unacceptably long, with increased risk of intrafraction motion, but 25% IMRT is an attractive compromise. Integrated portal images can be used to perform in vivo dosimetry for this technique.



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Thymoquinone: An edible redox-active quinone for the pharmacotherapy of neurodegenerative conditions and glial brain tumors. A short review

Publication date: October 2016
Source:Biomedicine & Pharmacotherapy, Volume 83
Author(s): Ilhan Elmaci, Meric A. Altinoz
There exist few efficient agents in the neurological and neurosurgical armamentarium for treatment of neurotrauma, refractory seizures and high grade glial tumors. Pathophysiological conditions of diverse neural injuries have converging common pathways including oxidative stress and apoptosis. Targeted therapies have been throughly investigated, but limited success has been achieved until now. Phytochemical drugs may provide easily achievable and cheap adjunctive sources. Thymoquinone is an edible quinone obtained from Nigella sativa seed oil and exerts powerful antiinflammatory, antioxidant and antitumor activities in experimental models. Recently emerging studies conducted with animal models suggest that thymoquinone – bearing a very simple molecular structure – significantly crosses the blood brain barrier and exerts neuromodulatory activities. Indeed, in animal studies, the following actions of thymoquinone were demonstrated: 1—Protection against ischemic brain damage. 2—Reduction of epileptic seizures and associated cerebral oxidative injury. 3—Reduction of morphine tolerance and associated oxidative brain damage. 4—Anxiolytic effects and reduction of immobility stress-associated cerebral oxidative injury. 5—Reduction of diabetes-induced cerebral oxidative stress, 6—Reduction of cerebral oxidative injuries induced by noxious exposures including toluene, lead and ionizing radiation. Substantial in vitro data suggest that thymoquinone may be beneficial in treatment of glial tumors. However, there is no clinical study investigating its antitumor effects. In fact, thymoquinone suppresses growth and invasion, and induces apoptosis of glial tumor cells via degrading tubulins and inhibiting 20S proteasome, telomerase, autophagy, FAK and metalloproteinases. A simple and easily available agent may be a promising adjunctive treatment option in neurological and neurosurgical practice.



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Speech Audiometry Findings from HIV+ and HIV- Adults in the MACS and WIHS Longitudinal Cohort Studies

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Torre Peter, Howard J. Hoffman, Gayle Springer, Christopher Cox, Mary A. Young, Joseph B. Margolick, Michael Plankey
The purpose of this study was to compare various speech audiometry measures between HIV+ and HIV- adults and to further evaluate the association between speech audiometry and HIV disease variables in HIV+ adults only. Three hundred ninety-six adults from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) completed speech audiometry testing. There were 262 men, of whom 117 (44.7%) were HIV+, and 134 women, of whom 105 (78.4%) were HIV+. Speech audiometry was conducted as part of the standard clinical audiological evaluation that included otoscopy, tympanometry, and pure-tone air- and bone-conduction thresholds. Specific speech audiometry measures included speech recognition thresholds (SRT) and word recognition scores in quiet presented at 40dB sensation level (SL) in reference to the SRT. SRT data were categorized in 5-dB steps from 0–25dB hearing level (HL) with one category as ≥30dB HL while word recognition scores were categorized as <90%, 90-99%, and 100%. A generalized estimating equations model was used to evaluate the association between HIV status and both ordinal outcomes. The SRT distributions across HIV+ and HIV- adults were similar. HIV+ and HIV- adults had a similar percentages of word recognition scores<90%, a lower percentage of HIV- adults had 90-99%, but HIV- adults had a higher percentage of 100%. After adjusting for covariables, HIV+ adults were borderline significantly more likely to have a higher SRT than HIV- adults (odds ratio [OR]=1.45, p=0.06). Among HIV+ adults, HIV-related variables (i.e., CD4+ T-cell counts, HIV viral load, and ever history of clinical AIDS) were not significantly associated with either SRT or word recognition score data. There was, however, a ceiling effect for word recognition scores, probably the result of obtaining this measure in quiet with a relatively high presentation level. A more complex listening task, such as speech-in-noise testing, may be a more clinically informative test to evaluate the effects of HIV on speech communication.



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Tailoring the Electronic and Catalytic Properties of Au25 Nanoclusters via Ligand Engineering

ACS Nano

DOI: 10.1021/acsnano.6b03964

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FeedaMail: Microbiology via ola Kala on Inoreader

	Microbiology via ola Kala on Inoreader
	(Sponsor this newsletter) Bacterial community composition in relation to bedrock type and macrobiota in soils from the Sor Rondane Mountains, East Antarctica Antarctic soils are known to be oligotrophic and of having low buffering capacities. It is expected that this is particularly the case for inland high-altitude regions. We hypothesized that the bedrock type and the presence of macrobiota in these soils enforce a high selective pressure on their bacterial communities. To test this, we analyzed the bacterial community structure in 52 soil samples from the western Sør Rondane Mountains (Dronning Maud Land, East Antarctica), using the Illumina MiSeq platform in combination with ARISA fingerprinting. The samples were taken along broad environmental gradients in an area covering nearly 1000 km2. Ordination and variation partitioning analyses revealed that the total organic carbon content was the most significant variable in structuring the bacterial communities, followed by pH, electric conductivity, bedrock type and the moisture content, while spatial distance was of relatively minor importance. Acidobacteria (Chloracidobacteria) and Actinobacteria (Actinomycetales) dominated gneiss derived mineral soil samples, while Proteobacteria (Sphingomonadaceae), Cyanobacteria, Armatimonadetes and candidate division FBP-dominated soil samples with a high total organic carbon content that were mainly situated on granite derived bedrock. Read More » Bacterial and fungal symbionts of parasitic Dendroctonus bark beetles Bark beetles (Curculionidae: Scolytinae) are one of the most species-rich herbivorous insect groups with many shifts in ecology and host-plant use, which may be mediated by their bacterial and fungal symbionts. While symbionts are well studied in economically important, tree-killing species, little is known about parasitic species whose broods develop in living trees. Here, using culture-dependent and independent methods, we provide a comprehensive overview of the associated bacteria, yeasts and filamentous fungi of the parasitic Dendroctonus micans, D. punctatus and D. valens, and compare them to those of other tree-inhabiting insects. Despite inhabiting different geographical regions and/or host trees, the three species showed similar microbial communities. Enterobacteria were the most prevalent bacteria, in particular Rahnella, Pantoea and Ewingella, in addition to Streptomyces. Likewise, the yeasts Candida/Cyberlindnera were the most prominent fungi. All these microorganisms are widespread among tree-inhabiting insects with various ecologies, but their high prevalence overall might indicate a beneficial role such as detoxification of tree defenses, diet supplementation or protection against pathogens. As such, our results enable comparisons of symbiont communities of parasitic bark beetles with those of other beetles, and will contribute to our understanding of how microbial symbioses facilitate dietary shifts in insects. Read More » Prodigiosin inhibits motility and activates bacterial cell death revealing molecular biomarkers of programmed cell death The antimicrobial activity of prodigiosin from Serratia nematodiphila darsh1, a bacterial pigment was tested against few food borne bacterial pathogens Bacillus cereus, Staphylococcus aureus, Pseudomonas aerugino... Read More » Dispersal of human and plant pathogens biofilms via nitric oxide donors at 4 °C Recent studies suggest that nitric oxide donors capable of manipulating nitric oxide-mediated signaling in bacteria could induce dispersal of biofilms. Encased in extracellular polymeric substances, human and ... Read More »
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Identification of a five-lncRNA signature for the diagnosis and prognosis of gastric cancer

Abstract

Gastric cancer (GC) is one of the most aggressive malignancies and has a poor prognosis. Identifying novel diagnostic and prognostic markers is of great importance for the management and treatment of GC. Long non-coding RNAs (lncRNAs), which are involved in multiple processes during the development and progression of cancer, may act as potential biomarkers of GC. Here, by performing data mining using four microarray data sets of GC downloaded from the Gene Expression Omnibus (GEO) database with different classifiers and risk score analyses, we identified a five-lncRNA signature (AK001094, AK024171, AK093735, BC003519 and NR_003573) displaying both diagnostic and prognostic values for GC. The results of the Kaplan-Meier survival analysis and log-rank test showed that the risk score based on this five-lncRNA signature was closely associated with overall survival time (p = 0.0001). Further analysis revealed that the risk score is an independent predictor of prognosis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of 30 pairs of GC tissue samples confirmed that the five lncRNAs were dysregulated in GC, and receiver operating characteristic (ROC) curves showed the high diagnostic ability of combining the five lncRNAs, with an area under the curve (AUC) of 0.95 ± 0.025. The five lncRNAs involved in several cancer-related pathways were identified using gene set enrichment analysis (GSEA). These findings indicate that the five-lncRNA signature may have a good clinical applicability for determining the diagnosis and predicting the prognosis of GC.

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VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway

Abstract

We previously developed (2-deoxyglucose)-(ABT-263) combination therapy (2DG-ABT), which induces apoptosis by activating Bak in the mitochondria of highly glycolytic cells with varied genetic backgrounds. However, the rates of apoptosis induced by 2DG-ABT were lower in von Hippel-Lindau (VHL)-deficient cancer cells. The re-expression of VHL protein in these cells lowered IGF1R expression in a manner independent of oxygen concentration. Lowering IGF1R expression via small interfering RNA (siRNA) sensitized the cells to 2DG-ABT, suggesting that IGF1R interfered with the activation of apoptosis by the mitochondria. To determine which of the two pathways activated by IGF1R, the Ras-ERK pathway or the PI3K-AKT pathway, was involved in the impairment of mitochondria activation, the cells were treated with a specific inhibitor of either PI3K or ERK, and 2DG-ABT was added to activate the mitochondria. The apoptotic rates resulting from 2DG-ABT treatment were higher in the cells treated with the PI3K inhibitor, while the rates remained approximately the same in the cells treated with the ERK inhibitor. In 2DG-ABT-sensitive cells, a 4-h 2DG treatment caused the dissociation of Mcl-1 from Bak, while ABT treatment alone caused the dissociation of Bcl-xL from Bak without substantially reducing Mcl-1 levels. In 2DG-ABT-resistant cells, Mcl-1 dissociated from Bak only when AKT activity was inhibited during the 4-h 2DG treatment. Thus, in VHL-deficient cells, IGF1R activated AKT and stabilized the Bak-Mcl-1 complex, thereby conferring cell resistance to apoptosis.

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miR-326 reverses chemoresistance in human lung adenocarcinoma cells by targeting specificity protein 1

Abstract

Cisplatin resistance is a major obstacle in the treatment of lung adenocarcinoma (LAD), and its mechanism has not been fully elucidated. Here, we report that miR-326 is downregulated in cisplatin-resistant A549/CDDP cells compared with parental A549 cells. Overexpression of miR-326 reversed cisplatin chemoresistance of LAD cells in vitro and in vivo. Moreover, we identified the specificity protein 1 (SP1) gene as a novel direct target of miR-326. Knockdown of SP1 revealed similar effects as that of ectopic miR-326 expression. Decreased miR-326 expression was also detected in tumor tissues sampled from LAD patients treated with cisplatin-based chemotherapy and was proved to be correlated with high expression of SP1 and decreased sensitivity to cisplatin. Furthermore, we show that the long noncoding RNA HOTAIR repression reverses chemoresistance of LAD cells partially through modulation of miR-326/SP1 pathway. In summary, we unveil a branch of the HOTAIR/miR-326/SP1 pathway that regulates chemoresistance of LAD cells.

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Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression

Abstract

During tumorigenesis, cancer cells generate complex, unresolved interactions with the surrounding oxystressed cellular milieu called tumor microenvironment ™ that favors spread of cancer to other body parts. This dissemination of cancer cells from the primary tumor site is the main clinical challenge in cancer treatment. In addition, the significance of enhanced oxidative stress in TM during cancer progression still remains elusive. Thus, the present study was performed to investigate the molecular and cytoskeletal alterations in breast cancer cells associated with oxystressed TM that potentiates metastasis. Our results showed that depending on the extent of oxidative stress in TM, cancer cells exhibited enhanced migration and survival with reduction of chemosensitivity. Corresponding ultrastructural analysis showed radical cytoskeletal modifications that reorganize cell-cell interactions fostering transition of epithelial cells to mesenchymal morphology (EMT) marking metastasis, which was reversed upon antioxidant treatment. Decreased E-cadherin and increased vimentin, Twist1/2 expression corroborated the initiation of EMT in oxystressed TM-influenced cells. Further evaluation of cellular energetics demonstrated significant metabolic reprogramming with inclination towards glucose or external glutamine from TM as energy source depending on the breast cancer cell type. These observations prove the elemental role of oxystressed TM in cancer progression, initiating EMT and metabolic reprogramming. Further cell-type specific metabolomic analysis would unravel the alternate mechanisms in cancer progression for effective therapeutic intervention.

Graphical abstract

Schematic representation of the study and proposed mechanism of oxystressed TM influenced cancer progression. Cancer cells exhibit a close association with tumor microenvironment ™, and oxystressed TM enhances cancer cell migration and survival and reduces chemosensitivity. Oxystressed TM induces dynamic cytomorphological variations, alterations in expression patterns of adhesion markers, redox homeostasis, and metabolic reprogramming that supports epithelial to mesenchymal transition and cancer progression.

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IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells

Abstract

Internal ribosome entry site (IRES)-mediated translation is a specialized mode of protein synthesis which malignant cells depend on to survive adverse microenvironmental conditions. Our lab recently reported the identification of a group of compounds which selectively interfere with IRES-mediated translation, completely blocking de novo IGF1R synthesis, and differentially modulating synthesis of the two c-Myc isoforms. Here, we examine the phenotypic consequences of sustained IRES inhibition in human triple-negative breast carcinoma and glioblastoma cells. A sudden loss of viability affects the entire tumor cell population after ∼72-h continuous exposure to the lead compound. The extraordinarily steep dose-response relationship (Hill-Slope coefficients −15 to −35) and extensive physical connections established between the cells indicate that the cells respond to IRES inhibition collectively as a population rather than as individual cells. Prior to death, the treated cells exhibit prominent features of terminal differentiation, with marked gains in cytoskeletal organization, planar polarity, and formation of tight junctions or neuronal processes. In addition to IGF1R and Myc, specific changes in connexin 43, BiP, CHOP, p21, and p27 also correlate with phenotypic outcome. This unusual mode of tumor cell death is absolutely dependent on exceeding a critical threshold in cell density, suggesting that a quorum-sensing mechanism may be operative. Death of putative tumor stem cells visualized in situ helps to explain the inability of tumor cells to recover and repopulate once the compound is removed. Together, these findings support the concept that IRES-mediated translation is of fundamental importance to maintenance of the undifferentiated phenotype and survival of undifferentiated malignant cells.

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Echocardiography and Alternative Cardiac Imaging Strategies for Long-Term Cardiotoxicity Surveillance of Cancer Survivors Treated with Chemotherapy and/or Radiation Exposure

Abstract

Cardiotoxicity from chemotherapy is a leading cause of morbidity and mortality in cancer survivors. Cardiotoxic effects include left ventricular systolic dysfunction, coronary artery disease, hypertension, bradycardia, arrhythmias, pericardial disease, valvular disease, and radiation-induced restrictive cardiomyopathy. Noninvasive cardiac imaging has been at the forefront of detecting cardiotoxicity in patients receiving chemotherapeutic agents known to adversely affect cardiac structure and function. Regimens for cardiotoxicity surveillance prior to and during chemotherapy administration have been proposed; however, optimal screening for and treatment of long-term cancer survivors have yet to be clarified. This review focuses on the most common imaging modalities for assessing cardiac dysfunction along with newer imaging technologies, and reviews suggested long-term surveillance strategies in cancer survivors following chemotherapy and radiation therapy.

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Pulling it all together: The road to lasting bilingualism for children with developmental disabilities

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Elizabeth Kay-Raining Bird, Natacha Trudeau, Ann Sutton
Children with DD must and do become bilingual, but the research reported in this special issue raises questions about equitable access to bilingual opportunities and provision of appropriate supports to ensure their optimal bilingual growth in these children. The purpose of the present article was to apply the findings from our international collaboration to inform policy and practice on bilingualism in children with developmental disabilities (DD). To do this, we first overview the research presented in detail in other articles of this special issue: a narrative literature review, a review of site policies and practices related to special education and language education, a qualitative analysis of key informant interviews, and a quantitative analysis of surveys of practitioners. From these overviews emerge a complex set of contextual factors that impact bilingual development in children with DD. We then use the Bioecological model of Bronfenbrenner and Morris (2007) and conceptual maps (C-maps) to examine the particular circumstances of three hypothetical children with DD who are in very different bilingual contexts. In so doing, areas of both positive and negative influence on lasting bilingualism are identified for each child. We end with recommendations for increasing access to and support for bilingualism in children with DD.



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Speech Audiometry Findings from HIV+ and HIV- Adults in the MACS and WIHS Longitudinal Cohort Studies

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Torre Peter, Howard J. Hoffman, Gayle Springer, Christopher Cox, Mary A. Young, Joseph B. Margolick, Michael Plankey
The purpose of this study was to compare various speech audiometry measures between HIV+ and HIV- adults and to further evaluate the association between speech audiometry and HIV disease variables in HIV+ adults only. Three hundred ninety-six adults from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) completed speech audiometry testing. There were 262 men, of whom 117 (44.7%) were HIV+, and 134 women, of whom 105 (78.4%) were HIV+. Speech audiometry was conducted as part of the standard clinical audiological evaluation that included otoscopy, tympanometry, and pure-tone air- and bone-conduction thresholds. Specific speech audiometry measures included speech recognition thresholds (SRT) and word recognition scores in quiet presented at 40dB sensation level (SL) in reference to the SRT. SRT data were categorized in 5-dB steps from 0–25dB hearing level (HL) with one category as ≥30dB HL while word recognition scores were categorized as <90%, 90-99%, and 100%. A generalized estimating equations model was used to evaluate the association between HIV status and both ordinal outcomes. The SRT distributions across HIV+ and HIV- adults were similar. HIV+ and HIV- adults had a similar percentages of word recognition scores<90%, a lower percentage of HIV- adults had 90-99%, but HIV- adults had a higher percentage of 100%. After adjusting for covariables, HIV+ adults were borderline significantly more likely to have a higher SRT than HIV- adults (odds ratio [OR]=1.45, p=0.06). Among HIV+ adults, HIV-related variables (i.e., CD4+ T-cell counts, HIV viral load, and ever history of clinical AIDS) were not significantly associated with either SRT or word recognition score data. There was, however, a ceiling effect for word recognition scores, probably the result of obtaining this measure in quiet with a relatively high presentation level. A more complex listening task, such as speech-in-noise testing, may be a more clinically informative test to evaluate the effects of HIV on speech communication.



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Pulling it all together: The road to lasting bilingualism for children with developmental disabilities

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Elizabeth Kay-Raining Bird, Natacha Trudeau, Ann Sutton
Children with DD must and do become bilingual, but the research reported in this special issue raises questions about equitable access to bilingual opportunities and provision of appropriate supports to ensure their optimal bilingual growth in these children. The purpose of the present article was to apply the findings from our international collaboration to inform policy and practice on bilingualism in children with developmental disabilities (DD). To do this, we first overview the research presented in detail in other articles of this special issue: a narrative literature review, a review of site policies and practices related to special education and language education, a qualitative analysis of key informant interviews, and a quantitative analysis of surveys of practitioners. From these overviews emerge a complex set of contextual factors that impact bilingual development in children with DD. We then use the Bioecological model of Bronfenbrenner and Morris (2007) and conceptual maps (C-maps) to examine the particular circumstances of three hypothetical children with DD who are in very different bilingual contexts. In so doing, areas of both positive and negative influence on lasting bilingualism are identified for each child. We end with recommendations for increasing access to and support for bilingualism in children with DD.



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Speech Audiometry Findings from HIV+ and HIV- Adults in the MACS and WIHS Longitudinal Cohort Studies

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Torre Peter, Howard J. Hoffman, Gayle Springer, Christopher Cox, Mary A. Young, Joseph B. Margolick, Michael Plankey
The purpose of this study was to compare various speech audiometry measures between HIV+ and HIV- adults and to further evaluate the association between speech audiometry and HIV disease variables in HIV+ adults only. Three hundred ninety-six adults from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) completed speech audiometry testing. There were 262 men, of whom 117 (44.7%) were HIV+, and 134 women, of whom 105 (78.4%) were HIV+. Speech audiometry was conducted as part of the standard clinical audiological evaluation that included otoscopy, tympanometry, and pure-tone air- and bone-conduction thresholds. Specific speech audiometry measures included speech recognition thresholds (SRT) and word recognition scores in quiet presented at 40dB sensation level (SL) in reference to the SRT. SRT data were categorized in 5-dB steps from 0–25dB hearing level (HL) with one category as ≥30dB HL while word recognition scores were categorized as <90%, 90-99%, and 100%. A generalized estimating equations model was used to evaluate the association between HIV status and both ordinal outcomes. The SRT distributions across HIV+ and HIV- adults were similar. HIV+ and HIV- adults had a similar percentages of word recognition scores<90%, a lower percentage of HIV- adults had 90-99%, but HIV- adults had a higher percentage of 100%. After adjusting for covariables, HIV+ adults were borderline significantly more likely to have a higher SRT than HIV- adults (odds ratio [OR]=1.45, p=0.06). Among HIV+ adults, HIV-related variables (i.e., CD4+ T-cell counts, HIV viral load, and ever history of clinical AIDS) were not significantly associated with either SRT or word recognition score data. There was, however, a ceiling effect for word recognition scores, probably the result of obtaining this measure in quiet with a relatively high presentation level. A more complex listening task, such as speech-in-noise testing, may be a more clinically informative test to evaluate the effects of HIV on speech communication.



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Pulling it all together: The road to lasting bilingualism for children with developmental disabilities

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Elizabeth Kay-Raining Bird, Natacha Trudeau, Ann Sutton
Children with DD must and do become bilingual, but the research reported in this special issue raises questions about equitable access to bilingual opportunities and provision of appropriate supports to ensure their optimal bilingual growth in these children. The purpose of the present article was to apply the findings from our international collaboration to inform policy and practice on bilingualism in children with developmental disabilities (DD). To do this, we first overview the research presented in detail in other articles of this special issue: a narrative literature review, a review of site policies and practices related to special education and language education, a qualitative analysis of key informant interviews, and a quantitative analysis of surveys of practitioners. From these overviews emerge a complex set of contextual factors that impact bilingual development in children with DD. We then use the Bioecological model of Bronfenbrenner and Morris (2007) and conceptual maps (C-maps) to examine the particular circumstances of three hypothetical children with DD who are in very different bilingual contexts. In so doing, areas of both positive and negative influence on lasting bilingualism are identified for each child. We end with recommendations for increasing access to and support for bilingualism in children with DD.



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Speech Audiometry Findings from HIV+ and HIV- Adults in the MACS and WIHS Longitudinal Cohort Studies

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Torre Peter, Howard J. Hoffman, Gayle Springer, Christopher Cox, Mary A. Young, Joseph B. Margolick, Michael Plankey
The purpose of this study was to compare various speech audiometry measures between HIV+ and HIV- adults and to further evaluate the association between speech audiometry and HIV disease variables in HIV+ adults only. Three hundred ninety-six adults from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) completed speech audiometry testing. There were 262 men, of whom 117 (44.7%) were HIV+, and 134 women, of whom 105 (78.4%) were HIV+. Speech audiometry was conducted as part of the standard clinical audiological evaluation that included otoscopy, tympanometry, and pure-tone air- and bone-conduction thresholds. Specific speech audiometry measures included speech recognition thresholds (SRT) and word recognition scores in quiet presented at 40dB sensation level (SL) in reference to the SRT. SRT data were categorized in 5-dB steps from 0–25dB hearing level (HL) with one category as ≥30dB HL while word recognition scores were categorized as <90%, 90-99%, and 100%. A generalized estimating equations model was used to evaluate the association between HIV status and both ordinal outcomes. The SRT distributions across HIV+ and HIV- adults were similar. HIV+ and HIV- adults had a similar percentages of word recognition scores<90%, a lower percentage of HIV- adults had 90-99%, but HIV- adults had a higher percentage of 100%. After adjusting for covariables, HIV+ adults were borderline significantly more likely to have a higher SRT than HIV- adults (odds ratio [OR]=1.45, p=0.06). Among HIV+ adults, HIV-related variables (i.e., CD4+ T-cell counts, HIV viral load, and ever history of clinical AIDS) were not significantly associated with either SRT or word recognition score data. There was, however, a ceiling effect for word recognition scores, probably the result of obtaining this measure in quiet with a relatively high presentation level. A more complex listening task, such as speech-in-noise testing, may be a more clinically informative test to evaluate the effects of HIV on speech communication.



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Pulling it all together: The road to lasting bilingualism for children with developmental disabilities

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Elizabeth Kay-Raining Bird, Natacha Trudeau, Ann Sutton
Children with DD must and do become bilingual, but the research reported in this special issue raises questions about equitable access to bilingual opportunities and provision of appropriate supports to ensure their optimal bilingual growth in these children. The purpose of the present article was to apply the findings from our international collaboration to inform policy and practice on bilingualism in children with developmental disabilities (DD). To do this, we first overview the research presented in detail in other articles of this special issue: a narrative literature review, a review of site policies and practices related to special education and language education, a qualitative analysis of key informant interviews, and a quantitative analysis of surveys of practitioners. From these overviews emerge a complex set of contextual factors that impact bilingual development in children with DD. We then use the Bioecological model of Bronfenbrenner and Morris (2007) and conceptual maps (C-maps) to examine the particular circumstances of three hypothetical children with DD who are in very different bilingual contexts. In so doing, areas of both positive and negative influence on lasting bilingualism are identified for each child. We end with recommendations for increasing access to and support for bilingualism in children with DD.



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Speech Audiometry Findings from HIV+ and HIV- Adults in the MACS and WIHS Longitudinal Cohort Studies

Publication date: Available online 25 July 2016
Source:Journal of Communication Disorders
Author(s): Torre Peter, Howard J. Hoffman, Gayle Springer, Christopher Cox, Mary A. Young, Joseph B. Margolick, Michael Plankey
The purpose of this study was to compare various speech audiometry measures between HIV+ and HIV- adults and to further evaluate the association between speech audiometry and HIV disease variables in HIV+ adults only. Three hundred ninety-six adults from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) completed speech audiometry testing. There were 262 men, of whom 117 (44.7%) were HIV+, and 134 women, of whom 105 (78.4%) were HIV+. Speech audiometry was conducted as part of the standard clinical audiological evaluation that included otoscopy, tympanometry, and pure-tone air- and bone-conduction thresholds. Specific speech audiometry measures included speech recognition thresholds (SRT) and word recognition scores in quiet presented at 40dB sensation level (SL) in reference to the SRT. SRT data were categorized in 5-dB steps from 0–25dB hearing level (HL) with one category as ≥30dB HL while word recognition scores were categorized as <90%, 90-99%, and 100%. A generalized estimating equations model was used to evaluate the association between HIV status and both ordinal outcomes. The SRT distributions across HIV+ and HIV- adults were similar. HIV+ and HIV- adults had a similar percentages of word recognition scores<90%, a lower percentage of HIV- adults had 90-99%, but HIV- adults had a higher percentage of 100%. After adjusting for covariables, HIV+ adults were borderline significantly more likely to have a higher SRT than HIV- adults (odds ratio [OR]=1.45, p=0.06). Among HIV+ adults, HIV-related variables (i.e., CD4+ T-cell counts, HIV viral load, and ever history of clinical AIDS) were not significantly associated with either SRT or word recognition score data. There was, however, a ceiling effect for word recognition scores, probably the result of obtaining this measure in quiet with a relatively high presentation level. A more complex listening task, such as speech-in-noise testing, may be a more clinically informative test to evaluate the effects of HIV on speech communication.



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Tailoring the Electronic and Catalytic Properties of Au25 Nanoclusters via Ligand Engineering

ACS Nano

DOI: 10.1021/acsnano.6b03964

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Transcriptomic analyses of the radiation response in head and neck squamous cell carcinoma subclones with different radiation sensitivity: time-course gene expression profiles and gene association networks

Abstract

Background

Acquired and inherent radioresistance of tumor cells is related to tumor relapse and poor prognosis – not only in head and neck squamous cell carcinoma (HNSCC). The underlying molecular mechanisms are largely unknown. Therefore, systemic in-depth analyses are needed to identify key regulators of radioresistance. In the present study, subclones of the CAL-33 HNSCC cell line with different radiosensitivity were analyzed to identify signaling pathways related to the different phenotypes.

Methods

Subclones with altered radiosensitivity were generated by fractionated irradiation of the parental CAL-33 cells. Differences in radiosensitivity were confirmed in colony formation assays. Selected subclones were characterized at the genomic and transcriptomic level by SKY, array CGH, and mRNA-microarray analyses. Time-course gene expression analyses upon irradiation using a natural cubic spline regression model identified temporally differentially expressed genes. Moreover, early and late responding genes were identified. Gene association networks were reconstructed using partial correlation. The Reactome pathway database was employed to conduct pathway enrichment analyses.

Results

The characterization of two subclones with enhanced radiation resistance (RP) and enhanced radiosensitivity (SP) revealed distinct genomic and transcriptomic changes compared to the parental cells. Differentially expressed genes after irradiation shared by both subclones pointed to important pathways of the early and late radiation response, including senescence, apoptosis, DNA repair, Wnt, PI3K/AKT, and Rho GTPase signaling. The analysis of the most important nodes of the gene association networks revealed pathways specific to the radiation response in different phenotypes of radiosensitivity. Exemplarily, for the RP subclone the senescence-associated secretory phenotype (SASP) together with GPCR ligand binding were considered as crucial. Also, the expression of endogenous retrovirus ERV3-1in response to irradiation has been observed, and the related gene association networks have been identified.

Conclusions

Our study presents comprehensive gene expression data of CAL-33 subclones with different radiation sensitivity. The resulting networks and pathways associated with the resistant phenotype are of special interest and include the SASP. The radiation-associated expression of ERV3-1 also appears highly attractive for further studies of the molecular mechanisms underlying acquired radioresistance. The identified pathways may represent key players of radioresistance, which could serve as potential targets for molecularly designed, therapeutical intervention.

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Differences in mortality by immigrant status in Italy. Results of the Italian Network of Longitudinal Metropolitan Studies

Abstract

Despite a rapid increase in immigration from low-income countries, studies on immigrants' mortality in Italy are scarce. We aimed to describe differences in all and cause-specific mortality among immigrants and Italians residing in Turin and Reggio Emilia (Northern Italy), two cities participating in the Italian Network of Longitudinal Metropolitan Studies (IN-LiMeS). We used individual data from the municipal population registers linked to the cause of death registers. All people aged 1–64 years residing between 2001 and 2010 were enrolled (open cohort) and followed up until 2013. The mortality of citizens from high migratory pressure countries (as a whole, and for each macro-area group) was compared with that of Italians; differences were estimated by Poisson regression adjusted by age and calendar year mortality rate ratios (MRRs), and by age-standardized mortality ratios for the analysis of cause-specific mortality. Compared with Italians, immigrants had lower overall mortality (MRR for men: 0.82, 95 % CI: 0.75–0.90; for women: 0.71, 95 % CI: 0.63–0.81). Sub-Saharan Africans experienced a significant higher mortality than Italians (MRR for men 1.29, 95 % CI: 1.03–1.61; for women: 1.70, 95 % CI: 1.22–2.36). Higher mortality for immigrants compared to Italians was observed for infectious diseases, congenital anomalies, some site-specific tumours and homicide mortality. Our study showed heterogeneity in mortality across the macro-areas of origin, and in particular Sub-Saharan Africans seemed to be a vulnerable population. The extension to other cohorts of IN-LiMeS will allow the health status of immigrants and vulnerable groups to be studied and monitored in more depth.

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Improving early diagnosis of symptomatic cancer

Nature Reviews Clinical Oncology. doi:10.1038/nrclinonc.2016.109

Authors: Willie Hamilton, Fiona M. Walter, Greg Rubin & Richard D. Neal

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Haematological cancer: High-risk SMM — early action required

Nature Reviews Clinical Oncology. doi:10.1038/nrclinonc.2016.121

Author: Diana Romero

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Genetics: Are circRNAs involved in cancer pathogenesis?

Nature Reviews Clinical Oncology. doi:10.1038/nrclinonc.2016.113

Author: Carlo M. Croce

In a paper published recently in Cell, Guarnerio et al. suggest that circular RNAs derived from cancer-associated chromosomal translocations have an oncogenic role; however, the experimental approach that the authors used was inadequate to generate sufficient evidence to prove this role, calling their study into question.

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The U.S. Blew $1.4 Billion on Abstinence Education in Africa

That is the amount of money the U.S. spent over a 10-year period from 2004 through 2013 promoting abstinence before marriage as a way of preventing HIV in 14 countries in sub-Saharan Africa. Unfortunately, according to the most comprehensive independent study conducted to date of the effort, the...

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Meet Luca, the Ancestor of All Living Things

A surprisingly specific genetic portrait of the ancestor of all living things has been generated by scientists who say that the likeness sheds considerable light on the mystery of how life first emerged on Earth. This venerable ancestor was a single-cell, bacterium-like organism. But it has a...

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Summer Travel and the Zika Virus #rio2016

Health officials have warned pregnant women to avoid travel to the more than 45 countries and territories in which the Zika virus is circulating. Infection during pregnancy can lead to birth defects in infants, particularly brain damage and abnormally small heads, called microcephaly. But wit...

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Zika epidemic could burn out in 3 years but return in a decade

The Zika epidemic could be over in three years – but by then up to 93.4 million people may have been infected, including 1.65 million women of childbearing age, and tens of thousands of babies could be affected. But even if the epidemic fizzles out, this could be a temporary relief: a decade lat...

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Large Protein Nanocages Could Improve Drug Design and Delivery

Using novel computational and biochemical approaches, scientists have accurately designed and built from scratch 10 large protein icosahedra -- polyhedra with 20 faces -- similar to viral capsids that carry viral DNA. The designed structures are made of two different engineered proteins, present...

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The Epidemiology and Transmissibility of Zika Virus in Giradot and San Andres Island, Colombia, Sept. 2015 to Jan. 2016

Transmission of Zika virus (ZIKV) was first detected in Colombia in September 2015. As of April 2016, Colombia had reported over 65,000 cases of Zika virus disease (ZVD). We analysed daily surveillance data of ZVD cases reported to the health authorities of San Andres and Girardot, Colombia, bet...

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Black Death for Corals: The Polymicrobial Pathogenesis of Black Band Disease

This June Disney released the anticipated Pixar Animation Studios sequel Finding Dory to earn the largest animated film opening receipts in North America ever. The popularity of the original Finding Nemo in 2003 led to reportedly increased demand for clownfish like Nemo for pets; some conce...

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Local radiotherapy alone following neoadjuvant chemotherapy and surgery in combined clinical stage II and III breast cancer

Abstract

Purpose

The outcomes and recurrence patterns for patients with combined clinical stage II and III breast cancer treated with local but not regional radiotherapy after neoadjuvant chemotherapy (NAC) and surgery are poorly documented.

Methods

We performed a retrospective review of a prospectively collected database comprised of breast cancer patients who received NAC at our institution. 172 patients met the specified criteria of receiving NAC, surgery inclusive of axillary nodal dissection and post-operative local (but not regional) radiotherapy.

Results

One hundred eleven patients (64.5 %) were of combined clinical stage II and 61 (35.5 %) stage III at diagnosis. 103 patients (59.9 %) were clinically node positive with 101 cN1. On post-NAC pathology 29 (16.9 %) patients had a complete response, 30 (17.6 %) were combined yp stage I, 104 (60.5 %) yp stage II and 9 (5.2 %) yp stage III. 77 (44.8 %) were node positive on post-NAC pathology, all ypN1. 52.3 % were treated with breast conservation. At a median follow up of 67 months, 56 patients experienced breast cancer recurrence and 47 had died with breast cancer the dominant cause. Actuarial 5 and 10 year estimated freedom from locoregional recurrence (FFLRR), freedom from distant metastases (FFDM), disease free (DFS) and overall survival (OS) were 90 and 83.5, 74.5 and 64, 69.5 and 56, 79.5 and 65 % respectively. The most common pattern of failure was distant alone (without local or regional failure). Regional failure as the only site of first failure occurred in just three patients but was a component of first failure in a further twelve. Predictive factors on multivariate analysis for FFLRR were clinical stage II and estrogen receptor positivity. Prognostic factors were ypN0 stage and estrogen receptor positive status.

Conclusions

Local radiotherapy alone may be reasonable for selected patients. Isolated distant recurrence is the dominant mode of failure for breast cancer patients who have received local radiotherapy without regional coverage following NAC.

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Transcriptomic analyses of the radiation response in head and neck squamous cell carcinoma subclones with different radiation sensitivity: time-course gene expression profiles and gene association networks

Abstract

Background

Acquired and inherent radioresistance of tumor cells is related to tumor relapse and poor prognosis – not only in head and neck squamous cell carcinoma (HNSCC). The underlying molecular mechanisms are largely unknown. Therefore, systemic in-depth analyses are needed to identify key regulators of radioresistance. In the present study, subclones of the CAL-33 HNSCC cell line with different radiosensitivity were analyzed to identify signaling pathways related to the different phenotypes.

Methods

Subclones with altered radiosensitivity were generated by fractionated irradiation of the parental CAL-33 cells. Differences in radiosensitivity were confirmed in colony formation assays. Selected subclones were characterized at the genomic and transcriptomic level by SKY, array CGH, and mRNA-microarray analyses. Time-course gene expression analyses upon irradiation using a natural cubic spline regression model identified temporally differentially expressed genes. Moreover, early and late responding genes were identified. Gene association networks were reconstructed using partial correlation. The Reactome pathway database was employed to conduct pathway enrichment analyses.

Results

The characterization of two subclones with enhanced radiation resistance (RP) and enhanced radiosensitivity (SP) revealed distinct genomic and transcriptomic changes compared to the parental cells. Differentially expressed genes after irradiation shared by both subclones pointed to important pathways of the early and late radiation response, including senescence, apoptosis, DNA repair, Wnt, PI3K/AKT, and Rho GTPase signaling. The analysis of the most important nodes of the gene association networks revealed pathways specific to the radiation response in different phenotypes of radiosensitivity. Exemplarily, for the RP subclone the senescence-associated secretory phenotype (SASP) together with GPCR ligand binding were considered as crucial. Also, the expression of endogenous retrovirus ERV3-1in response to irradiation has been observed, and the related gene association networks have been identified.

Conclusions

Our study presents comprehensive gene expression data of CAL-33 subclones with different radiation sensitivity. The resulting networks and pathways associated with the resistant phenotype are of special interest and include the SASP. The radiation-associated expression of ERV3-1 also appears highly attractive for further studies of the molecular mechanisms underlying acquired radioresistance. The identified pathways may represent key players of radioresistance, which could serve as potential targets for molecularly designed, therapeutical intervention.

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