bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of isolation and confinement on humans-implications for manned space explorations
Authors: Pagel J. I. , Choukèr A.
Published: February 2016

Human psychology and physiology are significantly altered by isolation and confinement. In light of planned exploration class interplanetary missions, the related adverse effects on the human body need to be explored and defined as they have a large impact on a mission's success. Terrestrial space analogs offer an excellent controlled environment to study some of these stressors during a space mission in isolation without the complex environment of the International Space Station. Participants subjected to these space analog conditions can encounter typical symptoms ranging from neurocognitive changes, fatigue, misaligned circadian rhythm, sleep disorders, altered stress hormone levels, and immune modulatory changes. This review focuses on both the psychological and the physiological responses observed in participants of long-duration spaceflight analog studies, such as Mars500 or Antarctic winter-over. They provide important insight into similarities and differences encountered in each simulated setting. The identification of adverse effects from confinement allows not only the crew to better prepare for but also to design feasible countermeasures that will help support space travelers during exploration class missions in the future.
Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study
Authors: Amirian E. Susan , Zhou Renke , Wrensch Margaret R. , Olson Sara H. , Scheurer Michael E. , Il'yasova Dora , Lachance Daniel , Armstrong Georgina N. , McCoy Lucie S. , Lau Ching C. , Claus Elizabeth B. , Barnholtz-Sloan Jill S. , Schildkraut Joellen , Ali-Osman Francis , Sadetzki Siegal , Johansen Christoffer , Houlston Richard S. , Jenkins Robert B. , Bernstein Jonine L. , Merrell Ryan T. , Davis Faith G. , Lai Rose , Shete Sanjay , Amos Christopher I. , Melin Beatrice S. , Bondy Melissa L.
Published: February 2016

Background: Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk.

Methods: The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema.

Results: Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58–0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma.

Conclusion: A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental.

Impact: As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. Cancer Epidemiol Biomarkers Prev; 25(2); 282–90. ©2016 AACR.
Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care
Authors: El Messaoudi Safia , Mouliere Florent , Du Manoir Stanislas , Bascoul-Mollevi Caroline , Gillet Brigitte , Nouaille Michelle , Fiess Catherine , Crapez Evelyne , Bibeau Frederic , Theillet Charles , Mazard Thibault , Pezet Denis , Mathonnet Muriel , Ychou Marc , Thierry Alain R.
Published: February 2016

Purpose: Circulating cell-free DNA (ccfDNA) is a valuable source of tumor material obtained from a simple blood sampling that enables noninvasive analysis of the tumor genome. Our goal was to carry out a multiparametric analysis of ccfDNA and evaluate its prognostic value by investigating the overall survival (OS) of 97 metastatic colorectal cancer patients (mCRC).

Experimental Design: Qualitative parameters (determination of the main KRAS exon2 and BRAF V600E mutations) and quantitative parameters (total ccfDNA concentration, mutant ccfDNA concentration, the proportion of mutant ccfDNA, and ccfDNA integrity index) were determined simultaneously in a single run using a unique Q-PCR multimarker approach (100% success rate).

Results: The median follow-up time was 36 months and median OS was 22 months. Patients showing high ccfDNA levels had significantly shorter OS (18.07 months vs. 28.5 months, P = 0.0087). Moreover, multivariate analysis revealed that a high ccfDNA level is an independent prognostic factor (P = 0.034). All ccfDNA parameters were of prognostic interest: patients with higher levels of mutant ccfDNA and higher mutation loads for the detected mutations had shorter OS (P = 0.0089 and P = 0.05, respectively). In addition, the level of ccfDNA fragmentation correlated positively with decreased OS in the exclusive KRAS/BRAF-mutant cohort of patients (P = 0.0052) and appeared as a strong independent prognostic factor (P = 0.0072), whereas it was not significant in the exclusive KRAS/BRAF WT cohort of patients (P = 0.67).

Conclusions: Our data provide for the first time qualitative and quantitative evidence in favor of multiparametric ccfDNA analysis in mCRC patients for prognostic assessment. Clin Cancer Res; 22(12); 3067–77. ©2016 AACR.
Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring—The TADE Study
Authors: Fox Peter , Balleine Rosemary L. , Lee Clara , Gao Bo , Balakrishnar Bavanthi , Menzies Alexander M. , Yeap Shang Heng , Ali Sayed Sahanawaz , Gebski Val , Provan Pamela , Coulter Sally , Liddle Christopher , Hui Rina , Kefford Richard , Lynch Jodi , Wong Mark , Wilcken Nicholas , Gurney Howard
Published: February 2016

Purpose: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels.

Experimental Design: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA.

Results: Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07).

Conclusions: Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes. Clin Cancer Res; 22(13); 3164–71. ©2016 AACR.

See related commentary by Hertz and Rae, p. 3121
Salivary Biomarkers for Detection of Oral Squamous Cell Carcinoma in a Taiwanese Population
Authors: Gleber-Netto Frederico Omar , Yakob Maha , Li Feng , Feng Ziding , Dai Jianliang , Kao Huang-Kai , Chang Yu-Liang , Chang Kai-Ping , Wong David T.W.
Published: February 2016

Purpose: This study evaluated the discriminatory power of salivary transcriptomic and proteomic biomarkers in distinguishing oral squamous cell carcinoma cases from controls and potentially malignant oral disorders (PMOD).

Experimental Design: A total of 180 samples (60 OSCC patients, 60 controls, and 60 PMOD patients) were used in the study. Seven transcriptomic markers (IL8, IL1β, SAT1, OAZ1, DUSP1, S100P, and H3F3A) were measured using qPCR, and two proteomic markers (IL8 and IL1β) were evaluated by ELISA.

Results: Among 7 transcriptomic markers, transcript level of DUSP1 was significantly lower in OSCC patients than in controls and PMOD patients. Between the proteomic markers, the protein concentration of IL8 and IL1β was significantly higher in OSCC patients than controls and dysplasia patients. Univariate fractional polynomial (FP) models revealed that salivary IL8 protein (IL8p) has the highest AUC value between OSCC patients and controls (0.74) and between OSCC and PMOD patients (0.72). Applying a 2-marker FP model, salivary IL8p combined with IL1β gave the best AUC value for discrimination between OSCC patients and controls, as well as the IL8p combined with H3F3A mRNA, which gave the best AUC value for discrimination between OSCC and PMOD patients. Multivariate models analysis combining salivary analytes and risk factor exposure related to oral carcinogenesis formed the best combinatory variables for differentiation between OSCC versus PMOL (AUC = 0.80), OSCC versus controls (AUC = 0.87), and PMOD versus controls (AUC = 0.78).

Conclusions: The combination of transcriptomic and proteomic salivary markers is of great value for oral cancer detection and differentiation from PMOD patients and controls. Clin Cancer Res; 22(13); 3340–7. ©2016 AACR.
MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non–Small Cell Lung Carcinoma with Poor Prognosis
Authors: Tong Joanna H. , Yeung Sai F. , Chan Anthony W.H. , Chung Lau Y. , Chau Shuk L. , Lung Raymond Wai Ming , Tong Carol Y. , Chow Chit , Tin Edith K.Y. , Yu Yau H. , Li Hui , Pan Yi , Chak Wing P. , Ng Calvin S.H. , Mok Tony S.K. , To Ka F.
Published: February 2016

Purpose: Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the clinicopathologic correlations in a large cohort of treatment-naïve non–small cell lung carcinoma (NSCLC).

Experimental Design: Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (METΔ14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively.

Results: METΔ14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. METΔ14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). METΔ14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P < 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio ≥5) was mutually exclusive to the major driver genes except METΔ14. Oncogenic METΔ14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. METΔ14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both METΔ14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis.

Conclusions: The high incidence of METΔ14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. Clin Cancer Res; 22(12); 3048–56. ©2016 AACR.

See related commentary by Drilon, p. 2832
Phase I Study of PSMA-Targeted Docetaxel-Containing Nanoparticle BIND-014 in Patients with Advanced Solid Tumors
Authors: Von Hoff Daniel D. , Mita Monica M. , Ramanathan Ramesh K. , Weiss Glen J. , Mita Alain C. , LoRusso Patricia M. , Burris Howard A. , Hart Lowell L. , Low Susan C. , Parsons Donald M. , Zale Stephen E. , Summa Jason M. , Youssoufian Hagop , Sachdev Jasgit C.
Published: February 2016

Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)–targeted nanoparticle, containing docetaxel.

Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m2 and 15 to 45 mg/m2, respectively.

Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non–small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors.

Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m2 every three weeks or 40 mg/m2 weekly. Clin Cancer Res; 22(13); 3157–63. ©2016 AACR.
IL15 Trispecific Killer Engagers (TriKE) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence,In VivoExpansion, and Enhanced Function
Authors: Vallera Daniel A. , Felices Martin , McElmurry Ron , McCullar Valarie , Zhou Xianzheng , Schmohl Joerg Uwe , Zhang Bin , Lenvik Alexander J. , Panoskaltsis-Mortari Angela , Verneris Michael R. , Tolar Jakub , Cooley Sarah , Weisdorf Daniel J. , Blazar Bruce R. , Miller Jeffrey S.
Published: February 2016

Purpose: The effectiveness of NK cell infusions to induce leukemic remission is limited by lack of both antigen specificity and in vivo expansion. To address the first issue, we previously generated a bispecific killer engager (BiKE) containing single-chain scFv against CD16 and CD33 to create an immunologic synapse between NK cells and CD33+ myeloid targets. We have now incorporated a novel modified human IL15 crosslinker, producing a 161533 trispecific killer engager (TriKE) to induce expansion, priming, and survival, which we hypothesize will enhance clinical efficacy.

Experimental Design: Reagents were tested in proliferation and functional assays and in an in vivo xenograft model of AML.

Results: When compared with the 1633 BiKE, the 161533 TriKE induced superior NK cell cytotoxicity, degranulation, and cytokine production against CD33+ HL-60 targets and increased NK survival and proliferation. Specificity was shown by the ability of a 1615EpCAM TriKE to kill CD33-EpCAM+ targets. Using NK cells from patients after allogeneic stem cell transplantation when NK cell function is defective, the 161533 TriKE restored potent NK function against primary AML targets and induced specific NK cell proliferation. These results were confirmed in an immunodeficient mouse HL-60-Luc tumor model where the 161533 TriKE exhibited superior antitumor activity and induced in vivo persistence and survival of human NK cells for at least 3 weeks.

Conclusions: Off-the-shelf 161533 TriKE imparts antigen specificity and promotes in vivo persistence, activation, and survival of NK cells. These qualities are ideal for NK cell therapy of myeloid malignancies or targeting antigens of solid tumors. Clin Cancer Res; 22(14); 3440–50. ©2016 AACR.

See related commentary by Talmadge, p. 3419
Arresting the Inflammatory Drive of Chronic Lymphocytic Leukemia with Ibrutinib
Authors: Bachireddy Pavan , Wu Catherine J.
Published: February 2016

The clinical success of agents targeting the B-cell receptor signaling pathway in chronic lymphocytic leukemia (CLL) may also derive from disrupting the CLL microenvironment. Investigation of the immunomodulatory effects of these agents illuminates the unique immunobiology of CLL and highlights potential targets for dismantling the chronic inflammatory drive. Clin Cancer Res; 22(7); 1547–9. ©2016 AACR.

See related article by Niemann et al., p. 1572
ABT-414, an Antibody–Drug Conjugate Targeting a Tumor-Selective EGFR Epitope
Authors: Phillips Andrew C. , Boghaert Erwin R. , Vaidya Kedar S. , Mitten Michael J. , Norvell Suzanne , Falls Hugh D. , DeVries Peter J. , Cheng Dong , Meulbroek Jonathan A. , Buchanan Fritz G. , McKay Laura M. , Goodwin Neal C. , Reilly Edward B.
Published: February 2016

Targeting tumor-overexpressed EGFR with an antibody–drug conjugate (ADC) is an attractive therapeutic strategy; however, normal tissue expression represents a significant toxicity risk. The anti-EGFR antibody ABT-806 targets a unique tumor-specific epitope and exhibits minimal reactivity to EGFR in normal tissue, suggesting its suitability for the development of an ADC. We describe the binding properties and preclinical activity of ABT-414, an ABT-806 monomethyl auristatin F conjugate. In vitro, ABT-414 selectively kills tumor cells overexpressing wild-type or mutant forms of EGFR. ABT-414 inhibits the growth of xenograft tumors with high EGFR expression and causes complete regressions and cures in the most sensitive models. Tumor growth inhibition is also observed in tumor models with EGFR mutations, including activating mutations and those with the exon 2–7 deletion [EGFR variant III (EGFRvIII)], commonly found in glioblastoma multiforme. ABT-414 exhibits potent cytotoxicity against glioblastoma multiforme patient-derived xenograft models expressing either wild-type EGFR or EGFRvIII, with sustained regressions and cures observed at clinically relevant doses. ABT-414 also combines with standard-of-care treatment of radiation and temozolomide, providing significant therapeutic benefit in a glioblastoma multiforme xenograft model. On the basis of these results, ABT-414 has advanced to phase I/II clinical trials, and objective responses have been observed in patients with both amplified wild-type and EGFRvIII-expressing tumors. Mol Cancer Ther; 15(4); 661–9. ©2016 AACR.
Immunotherapy and Oncogenic Pathways: The PTEN Connection
Authors: Rizvi Naiyer A. , Chan Timothy A.
Published: February 2016

Summary: Peng and colleagues describe the effects of PTEN inactivation on antitumor immunity and response to immune checkpoint blockade in melanoma. These results shed light on the intricate interplay between oncogenic pathways and antitumor immune response. Cancer Discov; 6(2); 128–9. ©2016 AACR.

See related article by Peng et al., p. 202.
Whole Transcriptome Analysis of Hypertension Induced Cardiac Injury Using Deep Sequencing
Authors: Li Tao-Tao , Li Xiao-Yan , Jia Li-Xin , Zhang Jing , Zhang Wen-Mei , Li Yu-Lin , Qi Yong-Fen , Du Jie
Published: February 2016

Background/Aims: Hypertension plays a critical role in the cardiac inflammation and injury. However, the mechanism of how hypertension causes the cardiac injury at a molecular level remains to be elucidated. Methods: RNA-Seq has been demonstrated to be an effective approach for transcriptome analysis, which is essential to reveal the molecular constituents of cells and tissues. In this study, we investigated the global molecular events associated with the mechanism of hypertension induced cardiac injury using RNA-Seq analysis. Results: Our results showed that totally 1,801 genes with different expression variations were identified after Ang II infusion at 1, 3 and 7 days. Go analysis showed that the top 5 high enrichment Go terms were response to stress, response to wounding, cellular component organization, cell activation and defense response. KEGG pathway analysis revealed the top 5 significantly overrepresented pathways were associated with ECM-receptor interaction, focal adhesion, protein digestion and absorption, phagosome and asthma. Moreover, protein-protein interaction network analysis indicated that ubiquitin C may play a key role in the processes of hypertension-induced cardiac injury. Conclusion: Our study provides a comprehensive understanding of the transcriptome events in hypertension-induced cardiac pathology.
Doxycycline in Eradication Therapy of Helicobacter pylori - A Systematic Review and Meta-Analysis
Authors: Niv Yaron
Published: February 2016

Background: Since resistance of Helicobacter pylori is developing very fast all over the world, new treatment regimens for eradication are urgently needed. Aim: To compare eradication success rate of H. pylori treatment regimens with and without doxycycline. Methods: English medical literature searches were conducted for regimens including doxycycline for eradication of H. pylori. Searches were performed up to August 31, 2015, using MEDLINE, PubMed, EMBASE, Scopus and CENTRAL. Meta-analysis was performed by using comprehensive meta-analysis software. Pooled ORs and 95% CIs were calculated comparing treatment regimens for eradication of H. pylori infection with and without doxycycline. Results: The OR for eradication success rate in a fixed model was in favor for treatment regimens with doxycycline: 1.292, 95% CI 1.048-1.594, p = 0.016. There was no significant heterogeneity in the included studies: Q = 15.130, d.f. (Q) = 8, I2 = 47.126, p > 0.10. When treatment regimens with doxycycline were compared only with treatment regimens with tetracycline, no significant difference was found in eradication success rate: OR 0.95, 95% CI 0.68-1.32, p = 0.77. But when treatment regimens with doxycycline were compared with treatment regimens without tetracycline, the OR in favor of doxycycline was even higher: OR 1.59, 95% CI 1.21-2.09, p < 0.001. Conclusion: In this meta-analysis, we confirmed doxycycline efficiency in the eradication of H. pylori. Thus, triple, quadruple or even high dose dual therapy with regimens containing doxycycline should be considered.
Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review
Authors: Barreto Lidiane Carine Lima Santos , Oliveira Fernanda Santos , Nunes Paula Santos , de França Costa Iandra Maria Pinheiro , Garcez Catarina Andrade , Goes Gabriel Mattos , Neves Eduardo Luis Aquino , de Souza Siqueira Quintans Jullyana , de Souza Araújo Adriano Antunes
Published: February 2016

Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. CMT is classified into 2 main subgroups: CMT type 1 (CMT1; demyelinating form) and CMT type 2 (CMT2; axonal form). The objectives of this study were to systematically review and assess the quality of studies reporting the incidence and/or prevalence of CMT worldwide. Summary: A total of 802 studies were initially identified, with only 12 meeting the inclusion criteria. CMT prevalence was reported in 10 studies and ranged from 9.7/100,000 in Serbia to 82.3/100,000 in Norway. The frequency of the main subtypes varied from 37.6 to 84% for CMT1 and from 12 to 35.9% for CMT2; the country with the lowest prevalence of CMT1 was Norway, and the country with the highest prevalence of CMT1 was Iceland; on the other hand, CMT2 was least prevalent in the United Kingdom and most prevalent in Norway. Key Messages: This review reveals the gaps that still exist in the epidemiological knowledge of CMT around the world. Published studies are of varying quality and utilise different methodologies, thus precluding a robust conclusion. Additional research focusing on epidemiological features of CMT in different nations and different ethnic groups is needed.
Uremic Toxicity-Induced Eryptosis and Monocyte Modulation: The Erythrophagocytosis as a Novel Pathway to Renal Anemia
Authors: Bonan Natalia Borges , Steiner Thiago M. , Kuntsevich Viktoriya , Virzì Grazia Maria , Azevedo Marina , Nakao Lia Sumie , Barreto Fellype Carvalho , Ronco Claudio , Thijssen Stephan , Kotanko Peter , Pecoits-Filho Roberto , Moreno-Amaral Andréa N.
Published: February 2016

Background: We tested the effect of uremia on red blood cell (RBC) eryptosis, CD14++/CD16+ monocytes and erythrophagocytosis. Design: RBC and monocytes from chronic kidney disease (CKD) stages 3/4 (P-CKD3/4) or hemodialysis (HD) patients and healthy controls (HCs) cells incubated with sera pools from patients with CKD stages 2/3 (S-CKD2/3) or 4/5 (S-CKD4/5) were evaluated to assess eryptosis, monocyte phenotypes and reactive oxygen species (ROS) by cytometer. Erythrophagocytosis was evaluated by subsequent co-incubation of preincubated HC-monocytes and autologous-RBC. Results: HC-eryptosis (1.3 ± 0.9%) was lower than in HD (4.3 ± 0.5%) and HC-RBC incubated with S-CKD4/5 (5.6 ± 1%). CD14++/CD16+ were augmented in P-CKD3/4 (34.6 ± 8%) and HC-monocytes incubated with S-CKD4/5 (26.4 ± 7%) than in HC (5.4 ± 1%). In these cells, ROS was increased (44.5 ± 9%; control 9.6 ± 2%) and inhibited by N-acetylcysteine (25 ± 13%). Erythrophagocytosis was increased in CD14++/CD16+ (60.8 ± 10%) than in CD14++/CD16- (15.5 ± 2%). Conclusions: Sera pools from CKD patients increase eryptosis and promote a proinflammatory monocyte phenotype. Both processes increased erythrophagocytosis, thereby suggesting a novel pathway for renal anemia.
Prevalence of Multiple Sclerosis in the Republic of Moldova
Authors: Marcoci Cristina , Lisnic Vitalie , Gavriliuc Mihail , Odainic Olesea , Sangheli Marina , Belenciuc Anna , Leone Maurizio Angelo , Casetta Ilaria , Pugliatti Maura
Published: February 2016

Background: The occurrence of multiple sclerosis (MS) increases in populations featuring both high and low disease burden, and variations across regions at the same latitude are reported. MS epidemiological data in Eastern Europe are scarce and out of date. We report on sex- and age-specific prevalence of MS in the Republic of Moldova. Methods: Benefitting from a nationwide survey aimed to quantify the MS burden in Moldovans (3,559,541 population in 2012), multiple epidemiological sources were scrutinized. Results: On prevalence day, December 31, 2012, 747 MS patients (McDonald criteria) resided in the study area, yielding a crude prevalence of 20.9 per 100,000 (95% CI 14.7-27.1), 25.7 (95% CI 20.5-30.5) in women and 15.8 (95% CI 12.2-19.3) in men (F:M ratio of 1.63), and standardized estimates of 20.2, 24.3 and 15.5 per 100,000, respectively. Prevalence was highest in the age group 40-49 years (43.9 per 100,000) and higher in rural (72.6%) than in urban (27.4%) areas. Conclusions: This is the first report on sex- and age-specific prevalence of MS in the Republic of Moldova, which was lower than in Europe on average, but consistent with that of neighboring countries, Romania and Ukraine. Moldovans represent a population wherein MS natural history is not yet influenced by use of disease-modifying drugs.
Effect of -55CT Polymorphism of UCP3 on Insulin Resistance and Cardiovascular Risk Factors after a High Protein/Low Carbohydrate versus a Standard Hypocaloric Diet
Authors: de Luis Daniel Antonio , Aller Rocío , Izaola Olatz , Romero Enrique
Published: February 2016

Background: The C/C genotype of a polymorphism in the uncoupling protein3 (UCP3) promoter (-55C->T) (rs1800849) is associated with an increased body mass index. Objective: The aim of our study was to investigate the effect of polymorphism on the UCP3 promoter (-55C->T) on insulin resistance and cardiovascular risk factors secondary to a high protein/low carbohydrate vs. a standard hypocaloric diets (1,000 kcal/day). Design: A population of 283 obese subjects was analyzed in a randomized trial. A nutritional evaluation was performed at the beginning and at the end of a 9-month period in which subjects received 1 of 2 diets (diet HP: high protein/low carbohydrate vs. diet S: standard diet). Results: Weight improvement was higher in non-T carriers. With both diets and only in wild genotype (diet HP vs. diet S), total cholesterol (-9.7 ± 4.0 vs. -11.1 ± 2.0 mg/dl; p > 0.05) and low density lipoprotein (LDL) cholesterol (-8.3 ± 3.0 vs. -5.5 ± 2.7 mg/dl; p > 0.05) decreased. The improvement in these parameters was similar in subjects with diet HP than HS. With diet HP and only in wild genotype, glucose (-5.2 ± 2.2 mg/dl; p < 0.05), triglycerides (-15.5 ± 3.9 mg/dl; p < 0.05), insulin levels (-3.9 ± 3.1 UI/l; p < 0.05) and homeostasis model assessment (HOMA-R; -0.6 ± 0.1 units; p < 0.05) decreased. Conclusion: Carriers of T allele have a different response than non-carrier subjects, with a lack of decrease of LDL cholesterol, glucose, insulin levels and HOMA-R. The weight loss was lower in T carriers. HP diet showed a better metabolic response than S diet in 55CC homozygous.
Is Tickling Torture? Assessing Welfare towards Slow Lorises (Nycticebus spp.) within Web 2.0 Videos
Authors: Nekaris I. , Anne K. , Musing Louisa , Vazquez Asier Gil , Donati Giuseppe
Published: February 2016

Videos, memes and images of pet slow lorises have become increasingly popular on the Internet. Although some video sites allow viewers to tag material as ‘animal cruelty', no site has yet acknowledged the presence of cruelty in slow loris videos. We examined 100 online videos to assess whether they violated the ‘five freedoms' of animal welfare and whether presence or absence of these conditions contributed to the number of thumbs up and views received by the videos. We found that all 100 videos showed at least 1 condition known as negative for lorises, indicating absence of the necessary freedom; 4% showed only 1 condition, but in nearly one third (31.3%) all 5 chosen criteria were present, including human contact (57%), daylight (87%), signs of stress/ill health (53%), unnatural environment (91%) and isolation from conspecifics (77%). The public were more likely to like videos where a slow loris was kept in the light or displayed signs of stress. Recent work on primates has shown that imagery of primates in a human context can cause viewers to perceive them as less threatened. Prevalence of a positive public opinion of such videos is a real threat towards awareness of the conservation crisis faced by slow lorises.
Overcoming Resistance to Endocrine Therapy in Breast Cancer: New Approaches to a Nagging Problem
Authors: Luqmani Yunus A. , Alam-Eldin Nada
Published: February 2016

In the majority of women, breast cancer progresses through increased transcriptional activity due to over-expressed oestrogen receptors (ER). Therapeutic strategies include: (i) reduction of circulating ovarian oestrogens or of peripherally produced oestrogen (in postmenopausal women) with aromatase inhibitors and (ii) application of selective ER modulators for receptor blockade. The success of these interventions is limited by the variable but persistent onset of acquired resistance and by an intrinsic refractiveness which manifests despite adequate levels of ER in about 50% of patients with advanced metastatic disease. Loss of functional ER leads to endocrine insensitivity, loss of cellular adhesion and polarity, and increased migratory potential due to trans-differentiation of the epithelial cancer cells into a mesenchymal-like phenotype (epithelial-mesenchymal transition; EMT). Multiple mechanisms contributing to therapeutic failure have been proposed: (i) loss or modification of ER expression including epigenetic mechanisms, (ii) agonistic actions of selective ER modulators that may be enhanced through an increased expression of co-activators, (iii) attenuation of the tamoxifen metabolism through expression of genetic variants of P450 cytochromes which leads to more or less active metabolites and (iv) increased growth factor signalling particularly through epidermal growth factor receptor activation of pathways involving keratinocyte growth factor, platelet-derived growth factor, and nuclear factor κB. In addition, the small non-coding microRNAs, recently recognized as critical gene regulators, exhibit differential expression in tamoxifen-sensitive versus resistant cell lines. Several studies suggest the potential of using these either as targets or as therapeutic agents to modulate EMT regulators as a means of reversing the aggressive metastatic phenotype by reversal of the EMT, with the added benefit of re-sensitization to anti-oestrogens.
Descriptions of four new species of Dicopomorpha Ogloblin (Hymenoptera: Chalcidoidea: Mymaridae) from India with a key to Indian species
Authors: Rameshkumar A. , Manickavasagam S.
Published: February 2016

Four new species of Dicopomorpha Ogloblin (Hymenoptera: Chalcidoidea: Mymaridae), D. albithorax, D. funiculata, D. longiscapa  and D. minuta are described and illustrated.  A key to the Indian species of Dicopomorpha is provided.

 
Platelet Control of Fibrin Distribution and Microelasticity in Thrombus Formation Under Flow
Authors: Swieringa Frauke , Baaten Constance C.F.M.J. , Verdoold Remco , Mastenbroek Tom G. , Rijnveld Niek , van der Laan Koen O. , Breel Ernst J. , Collins Peter W. , Lancé Marcus D. , Henskens Yvonne M.C. , Cosemans Judith M.E.M. , Heemskerk Johan W.M. , van der Meijden Paola E.J.
Published: February 2016

Objective—

Platelet- and fibrin-dependent thrombus formation is regulated by blood flow and exposure of collagen and tissue factor. However, interactions between these blood-borne and vascular components are not well understood.

Approach and Results—

Here, we developed a method to assess whole-blood thrombus formation on microspots with defined amounts of collagen and tissue factor, allowing determination of the mechanical properties and intrathrombus composition. Confining the collagen content resulted in diminished platelet deposition and fibrin formation at high shear flow conditions, but this effect was compensated by a larger thrombus size and increased accumulation of fibrin in the luminal regions of the thrombi at the expense of the base regions. These thrombi were more dependent on tissue factor–triggered thrombin generation. Microforce nanoindentation analysis revealed a significantly increased microelasticity of thrombi with luminal-oriented fibrin. At a low shear rate, fibrin fibers tended to luminally cover the thrombi, again resulting in a higher microelasticity. Studies with blood from patients with distinct hemostatic insufficiencies indicated an impairment in the formation of a platelet–fibrin thrombus in the cases of dilutional coagulopathy, thrombocytopenia, Scott syndrome, and hemophilia B.

Conclusions—

Taken together, our data indicate that (1) thrombin increases the platelet thrombus volume; (2) tissue factor drives the formation of fibrin outside of the platelet thrombus; (3) limitation of platelet adhesion redirects fibrin from bottom to top of the thrombus; (4) a lower shear rate promotes thrombus coverage with fibrin; (5) the fibrin distribution pattern determines thrombus microelasticity; and (6) the thrombus-forming process is reduced in patients with diverse hemostatic defects.
Cholesteryl Ester Transfer Protein Inhibition Is Not Yet Dead—Pro
Authors: Barter Philip J. , Rye Kerry-Anne
Published: February 2016

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from nonatherogenic high-density lipoproteins to potentially proatherogenic non–high-density lipoprotein fractions. Human genetic studies and human cohort studies have concluded that
CETP
gene polymorphisms associated with decreased CETP activity are accompanied by a significantly lower risk of atherosclerotic cardiovascular disease. Inhibition of CETP in rabbits reduces development of diet-induced atherosclerosis. Inhibition of CETP in humans reduces non–high-density lipoprotein cholesterol while increasing high-density lipoproteins cholesterol, consistent with a reduced risk of having an atherosclerotic cardiovascular disease event. The failure of randomized human clinical outcome trials with 3 different CETP inhibitors may have been the consequence of either off-target adverse effects of the drug used or problems with the design of the trials. The hypothesis that CETP inhibition reduces atherosclerotic cardiovascular disease risk is still untested. The future of CETP inhibition as a cardio-protective strategy will depend on the outcome of the ongoing Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial with the CETP inhibitor, anacetrapib.
Macrophage IKKα Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis
Authors: Babaev Vladimir R. , Ding Lei , Zhang Youmin , May James M. , Lin P. Charles , Fazio Sergio , Linton MacRae F.
Published: February 2016

Objective—

The IκB kinase (IKK) is an enzyme complex that initiates the nuclear factor κB transcription factor cascade, which is important in regulating multiple cellular responses. IKKα is directly associated with 2 major prosurvival pathways, PI3K/Akt and nuclear factor κB, but its role in cell survival is not clear. Macrophages play critical roles in the pathogenesis of atherosclerosis, yet the impact of IKKα signaling on macrophage survival and atherogenesis remains unclear.

Approach and Results—

Here, we demonstrate that genetic IKKα deficiency, as well as pharmacological inhibition of IKK, in mouse macrophages significantly reduces Akt S
473
phosphorylation, which is accompanied by suppression of mTOR complex 2 signaling. Moreover, IKKα null macrophages treated with lipotoxic palmitic acid exhibited early exhaustion of Akt signaling compared with wild-type cells. This was accompanied by a dramatic decrease in the resistance of IKKα
−/−
monocytes and macrophages to different proapoptotic stimuli compared with wild-type cells. In vivo, IKKα deficiency increased macrophage apoptosis in atherosclerotic lesions and decreased early atherosclerosis in both female and male low-density lipoprotein receptor (LDLR)
−/−
mice reconstituted with IKKα
−/−
hematopoietic cells and fed with the Western diet for 8 weeks compared with control LDLR
−/−
mice transplanted with wild-type cells.

Conclusions—

Hematopoietic IKKα deficiency in mouse suppresses Akt signaling, compromising monocyte/macrophage survival and this decreases early atherosclerosis.
Absence of Coronary Artery Calcium Identifies Asymptomatic Diabetic Individuals at Low Near-Term But Not Long-Term Risk of Mortality
Authors: Valenti Valentina , Hartaigh Bríain ó , Cho Iksung , Schulman-Marcus Joshua , Gransar Heidi , Heo Ran , Truong Quynh A. , Shaw Leslee J. , Knapper Joseph , Kelkar Anita A. , Sciarretta Sebastiano , Chang Hyuk-Jae , Callister Tracy Q. , Min James K.
Published: February 2016

Background—

Data regarding coronary artery calcification (CAC) prognosis in diabetic individuals are limited to 5-years follow-up. We investigated the long-term risk stratification of CAC among diabetic compared with nondiabetic individuals.

Methods and Results—

Nine thousand seven hundred and fifteen asymptomatic individuals undergoing CAC scoring were followed for a median (interquartile range) of 14.7 (13.9–15.6) years. The incidence density rate and hazard ratios with 95% confidence intervals were used to calculate all-cause mortality. Incremental prognostic utility of CAC was evaluated using the area under the receiver operator characteristic curve and net reclassification improvement. Diabetics (54.7±10.8 years; 59.4% male) comprised 8.3% of the cohort (n=810), of which 188 (23.2%) died. For CAC=0, the rate of mortality was similar between diabetic and nondiabetic individuals for the first 5 years (
P
>0.05), with a nonlinear increased risk of mortality for diabetics after 5 years (
P
<0.05). The adjusted risk of death for those in the highest (CAC>400) versus the lowest (CAC=0) category of CAC increased by a hazards of 4.64 (95% confidence interval =3.74–5.76) and 3.41 (95% confidence interval =2.22–5.22) for nondiabetic and diabetic individuals, respectively. The presence of CAC improved discrimination (area under the receiver operator characteristic curve range: 0.73–0.74;
P
<0.01) and reclassification (category-free net reclassification improvement range: 0.53–0.50;
P
<0.001) beyond conventional risk factors in nondiabetic and diabetic individuals, respectively.

Conclusions—

CAC=0 is associated with a favorable 5-year prognosis for asymptomatic diabetic and nondiabetic individuals. After 5 years, the risk of mortality increases significantly for diabetic individuals even in the presence of a baseline CAC=0.
Temporal Course of Dynamic Cerebral Autoregulation in Patients With Intracerebral Hemorrhage
Authors: Ma Hongyin , Guo Zhen-Ni , Liu Jia , Xing Yingqi , Zhao Ren , Yang Yi
Published: February 2016

Background and Purpose—

Cerebral autoregulation is crucial in patients with intracerebral hemorrhage. Dynamic cerebral autoregulation is probably altered in acute intracerebral hemorrhage; however, the temporal course of dynamic cerebral autoregulation and its correlation with clinical factors and outcomes are poorly understood.

Methods—

Forty-three acute supratentorial intracerebral hemorrhage patients (53.7±10.0 years old, 30 men) were enrolled for serial measurements performed on days 1 to 2, 4 to 6, 10 to 12, and 30 days after ictus. Noninvasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously using transcranial Doppler and a servo-controlled plethysmograph, respectively. Transfer function analysis was used to derive the autoregulatory parameters, including phase difference (PD), gain, and the rate of recovery of cerebral blood flow velocity. Results were compared with healthy controls and correlated with clinical factors and the 90-day outcome.

Results—

PD did not differ between affected and unaffected hemispheres over time. A significant lower PD (indicating dynamic cerebral autoregulation impaired) was found in bilateral hemispheres on days 1 to 2, 4 to 6, and 10 to 12, followed by later recovery on day 30. Lower bilateral PD on days 1 to 2 was associated with poorer Glasgow Coma Scale score at that time. Lower affected-side PD on days 4 to 6 was an independent predictive value for a poorer modified Rankin Scale at 90 days.

Conclusions—

In patients with supratentorial intracerebral hemorrhage, dynamic cerebral autoregulation is bilaterally impaired lasting at least 10 to 12 days and recovers within a month. Individual PD value is associated with clinical status at acute stage and affected-side PD on days 4 to 6 can be an independent predictor for clinical outcome.
Peripheral Blood
MCEMP1
Gene Expression as a Biomarker for Stroke Prognosis
Authors: Raman Kripa , O’Donnell Martin J. , Czlonkowska Anna , Duarte Yan Carlos , Lopez-Jaramillo Patricio , Peñaherrera Ernesto , Sharma Mike , Shoamanesh Ashkan , Skowronska Marta , Yusuf Salim , Paré Guillaume
Published: February 2016

Background and Purpose—

A limitation when making early decisions on stroke management is the lack of rapid diagnostic and prognostic testing. Our study sought to identify peripheral blood RNA biomarkers associated with stroke. The secondary aims were to assess the discriminative capacity of RNA biomarkers for primary stroke type and stroke prognosis at 1-month.

Methods—

Whole-blood gene expression profiling was conducted on the discovery cohort: 129 first-time stroke cases that had blood sampling within 5 days of symptom onset and 170 control participants with no history of stroke.

Results—

Through multiple regression analysis, we determined that expression of the gene
MCEMP1
had the strongest association with stroke of 11 181 genes tested.
MCEMP1
increased by 2.4-fold in stroke when compared with controls (95% confidence interval, 2.0–2.8;
P
=8.2×10
−22
). In addition, expression was elevated in intracerebral hemorrhage when compared with ischemic stroke cases (
P
=3.9×10
−4
).
MCEMP1
was also highest soon after symptom onset and had no association with stroke risk factors. Furthermore,
MCEMP1
expression independently improved discrimination of 1-month outcome. Indeed, discrimination models for disability and mortality that included
MCEMP1
expression, baseline modified Rankin Scale score, and primary stroke type improved discrimination when compared with a model without
MCEMP1
(disability Net Reclassification Index, 0.76;
P
=3.0×10
−6
and mortality Net Reclassification Index, 1.3;
P
=1.1×10
−9
). Significant associations with
MCEMP1
were confirmed in an independent validation cohort of 28 stroke cases and 34 controls.

Conclusions—

This study demonstrates that peripheral blood expression of
MCEMP1
may have utility for stroke diagnosis and as a prognostic biomarker of stroke outcome at 1-month.
The Morality of Livestock Farming
Authors: Fukuda Kaoru
Published: February 2016

This article describes how livestock farmers respond to moral enquiries about their means of livelihood, by referring to ethnographic data collected in the Scottish Borders. The focus is on three controversial aspects of livestock farming: welfare issues of intensive farming methods, guilt about depriving nonhuman animals of their lives for food, and the moral dilemma of breeding and rearing animals merely to be killed. There was a feeling of uneasiness among farmers about sending the animals they looked after to the slaughterhouse. This, however, was rationalized with the recognition that livestock were bred and reared to be eaten in the first place. By examining farmers’ utterances, it is suggested that livestock farmers are conditioned to consider their vocation as a part of the social system, over which they have little control.
Quasi-Vertical Profiles—A New Way to Look at Polarimetric Radar Data
Authors: Ryzhkov Alexander , Zhang Pengfei , Reeves Heather , Kumjian Matthew , Tschallener Timo , Trömel Silke , Simmer Clemens
Published: February 2016

A novel methodology is introduced for processing and presenting polarimetric data collected by weather surveillance radars. It involves azimuthal averaging of radar reflectivity Z, differential reflectivity ZDR, cross-correlation coefficient ρhv, and differential phase ΦDP at high antenna elevation, and presenting resulting quasi-vertical profiles (QVPs) in a height-versus-time format. Multiple examples of QVPs retrieved from the data collected by S-, C-, and X-band dual-polarization radars at elevations ranging from 6.4° to 28° illustrate advantages of the QVP technique. The benefits include an ability to examine the temporal evolution of microphysical processes governing precipitation production and to compare polarimetric data obtained from the scanning surveillance weather radars with observations made by vertically looking remote sensors, such as wind profilers, lidars, radiometers, cloud radars, and radars operating on spaceborne and airborne platforms. Continuous monitoring of the melting layer and the layer of dendritic growth with high vertical resolution, and the possible opportunity to discriminate between the processes of snow aggregation and riming, constitute other potential benefits of the suggested methodology.