bluuebunny/crossref_metadata_2025 huggingface dataset:
From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations
Authors: Green Charlotte J. , Pramfalk Camilla , Morten Karl J. , Hodson Leanne
Published: October 2014

The liver is a main metabolic organ in the human body and carries out a vital role in lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, encompassing a spectrum of conditions from simple fatty liver (hepatic steatosis) through to cirrhosis. Although obesity is a known risk factor for hepatic steatosis, it remains unclear what factor(s) is/are responsible for the primary event leading to retention of intrahepatocellular fat. Studying hepatic processes and the etiology and progression of disease in vivo in humans is challenging, not least as NAFLD may take years to develop. We present here a review of experimental models and approaches that have been used to assess liver triglyceride metabolism and discuss their usefulness in helping to understand the aetiology and development of NAFLD.
In vivo analysis of Purkinje cell firing properties during postnatal mouse development
Authors: Arancillo Marife , White Joshua J. , Lin Tao , Stay Trace L. , Sillitoe Roy V.
Published: October 2014

Purkinje cell activity is essential for controlling motor behavior. During motor behavior Purkinje cells fire two types of action potentials: simple spikes that are generated intrinsically and complex spikes that are induced by climbing fiber inputs. Although the functions of these spikes are becoming clear, how they are established is still poorly understood. Here, we used in vivo electrophysiology approaches conducted in anesthetized and awake mice to record Purkinje cell activity starting from the second postnatal week of development through to adulthood. We found that the rate of complex spike firing increases sharply at 3 wk of age whereas the rate of simple spike firing gradually increases until 4 wk of age. We also found that compared with adult, the pattern of simple spike firing during development is more irregular as the cells tend to fire in bursts that are interrupted by long pauses. The regularity in simple spike firing only reached maturity at 4 wk of age. In contrast, the adult complex spike pattern was already evident by the second week of life, remaining consistent across all ages. Analyses of Purkinje cells in alert behaving mice suggested that the adult patterns are attained more than a week after the completion of key morphogenetic processes such as migration, lamination, and foliation. Purkinje cell activity is therefore dynamically sculpted throughout postnatal development, traversing several critical events that are required for circuit formation. Overall, we show that simple spike and complex spike firing develop with unique developmental trajectories.
Optimizing effort: increased efficiency of motor memory with time away from practice
Authors: Pekny Sarah E. , Shadmehr Reza
Published: October 2014

In motor tasks, efficiency can be measured via the commands that are produced to accomplish a goal. To maximize efficiency, the nervous system should produce task-relevant motor commands while avoiding behaviors that are task-irrelevant. The current view is that this is achieved through training, i.e., the optimum motor commands are learned by trial and error. However, in contrast to this view, there are numerous examples in which during an experiment, task-irrelevant commands are continuously produced. To address this, we trained human volunteers to reach in a force field. With practice, they learned to produce forces that compensated for the field, generating task-relevant commands that were necessary to achieve success. As expected, training also resulted in generalization, the transfer of learning to other movements. We designed the task so that any forces produced as a result of generalization were unnecessary and therefore task-irrelevant. Importantly, there were no explicit cues to indicate that production of these forces was task-irrelevant. Rather, the only indicator was effort itself. Could this inefficiency of the motor commands be reduced? We found that even with extensive practice, the production of task-irrelevant forces persisted. However, if subjects were given sufficient time away from practice (6 or 24 h but not 3 or 30 min), they spontaneously reduced production of the task-irrelevant forces. Therefore, practice alone was insufficient to allow for increased efficiency of motor output. Time away from practice was a required element for optimization of effort.
Human aldosterone synthase gene polymorphism promotes miRNA binding and regulates gene expression
Authors: Maharjan Shreekrishna , Mopidevi Brahmaraju , Kaw Meenakshi Kaul , Puri Nitin , Kumar Ashok
Published: October 2014

Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. Like other complex diseases, hypertension is caused by a combination of genetic and environmental factors. The renin-angiotensin-aldosterone system plays an important role in the regulation of blood pressure. The octapeptide angiotensin II (ANG II) is one of the most active vasopressor agents and is obtained from the precursor molecule, angiotensinogen, by the combined proteolytic action of renin and angiotensin-converting enzyme. ANG II increases the expression of aldosterone synthase (coded by Cyp11B2 gene), which is the rate-limiting enzyme in the biosynthesis of aldosterone. Previous studies have shown that increased expression of aldosterone synthase increases blood pressure and cardiac hypertrophy in transgenic mice. Human Cyp11B2 gene has a T/C polymorphism at −344 positions in its 5′-untranslated region (UTR), and the −344T allele is associated with hypertension. Human Cyp11B2 gene also has an A/G polymorphism at 735 position in its 3′-UTR (rs28491316) that is in linkage disequilibrium with single nucleotide polymorphism at −344. We show here that 1) microRNA (miR)-766 binds to the 735G-allele and not the 735A-allele of the hCyp11B2 gene and 2) transfection of miR-766 reduces the human aldosterone synthase mRNA and protein level in human adrenocortical cells H295R. These studies suggest that miR-766 may downregulate the expression of human aldosterone synthase gene and reduce blood pressure in human subjects containing −344T allele.
Immobilization ofAspergillus oryzae  β-Galactosidase on Cellulose Acetate-Polymethylmethacrylate Membrane and Its Application in Hydrolysis of Lactose from Milk and Whey
Authors: Ansari Shakeel Ahmed , Satar Rukhsana , Kashif Zaidi Syed , Ahmad Abrar
Published: October 2014

The present study demonstrates the immobilization ofAspergillus oryzaeβ-galactosidase on cellulose acetate-polymethylmethacrylate (CA-PMMA) membrane and its application in hydrolyzing lactose in dairy industries. The effect of physical and chemical denaturants like pH, temperature, product inhibition by galactose, storage stability, and reuse number of the enzyme immobilized on CA-PMMA membrane has been investigated. Lactose was hydrolyzed from milk and whey in batch reactors at 50°C by free and immobilizedβ-galactosidase (IβG). Optimum pH for the free and immobilized enzyme was found to be the same, that is, 4.5. However, IβG retained greater fractions of catalytic activity at lower and higher pH ranges. The temperature optimum for the immobilized enzyme was increased by 10°C. Moreover, Michaelis-Menten constant was increased for IβG as compared to the native one while maximum reaction rate was reduced for the immobilized enzyme. The preserved activity of free and immobilized enzyme was found to be 45% and 83%, respectively, after five weeks of storage at 4°C. Reusability of IβG was observed to be 86% even after fifth repeated use, thereby signifying its application in lactose hydrolysis (as shown in lab-scale batch reactors) in various dairy products including milk and whey.
Study on the Therapeutic Benefit on Lactoferrin in Patients with Colorectal Cancer Receiving Chemotherapy
Authors: Moastafa Tarek M. , El-Sissy Alaa El-Din Elsayed , El-Saeed Gehan K. , Koura Mai Salah El-Din
Published: October 2014

A double-blinded parallel randomized controlled clinical trial was conducted on two groups of colorectal cancer patients to study the therapeutic benefit of orally administered bovine lactoferrin (bLF) on colorectal cancer patients having age ranges from 20 to 71 years and who received 5-fluorouracil and leucovorin calcium. Test group (15 patients) received oral bLF 250 mg/day beside chemotherapy for three months. Control group (15 patients) received chemotherapy only. Serum lactoferrin (LF), serum glutathione-s-transferase enzyme (GST), interferon gamma (INF-γ), tumor marker carcinoembryonic antigen (CEA), renal function tests, hepatic function tests, and complete blood count were measured for both groups before and at the end of the trial. Although, there was a significant effect of oral bLF (250 mg/day) that indicated a significant improvement in mean percent of change of all parameters 3 months after treatment, there was no significant difference between results of patients in the test group and patients in the control group after treatment. This result suggests that oral bLF has significant therapeutic effect on colorectal cancer patients. Our study suggests that daily administration of bLF showed a clinically beneficial effect to colorectal cancer patients with better disease prognosis but that needs further looking into.
Adsorption of Phenol from Aqueous Solution UsingLantana camara, Forest Waste: Kinetics, Isotherm, and Thermodynamic Studies
Authors: Girish C. R. , Ramachandra Murty V.
Published: October 2014

The present work investigates the potential ofLantana camara, a forest waste, as an adsorbent for the phenol reduction in wastewater. Batch studies were conducted with adsorbent treated with HCl and KOH to determine the influence of various experimental parameters such as pH, contact time, adsorbent dosage, and phenol concentration. The experimental conditions were optimized for the removal of phenol from wastewater. Equilibrium isotherms for the adsorption of phenol were analyzed by Freundlich, Langmuir, Temkin, and Dubinin-Radushkevich isotherm models. Thermodynamic parameters like the Gibbs free energy (ΔG°), enthalpy (ΔH°), and entropy (ΔS°) were also determined and they showed that the adsorption process was feasible, spontaneous, and exothermic in the temperature range of 298–328 K. The kinetic data were fitted with pseudo-second-order model. The equilibrium data that followed Langmuir model with the monolayer adsorption capacity was found to be 112.5 mg/g and 91.07 mg/g for adsorbent treated with HCl and KOH, respectively, for the concentration of phenol ranging from 25 to 250 mg/L. This indicates that theLantana camarawas a promising adsorbent for the removal of phenol from aqueous solutions.
Nontraumatic Lesions of the Clavicle in a Paediatric Population: Incidence and Management
Authors: Clement N. D. , Nicol G. , Porter D. E.
Published: October 2014

Background. The incidence of paediatric nontraumatic clavicle lesions is unknown and there is limited literature regarding the management of such patients.Methods. A review of a prospectively complied radiological database held at the study was conducted for a defined 10-year period. The study centre is the only paediatric service available for a defined catchment population. The case notes of all patients with nontraumatic lesions were reviewed, and the mode of presentation, the diagnostic dilemmas, and the management were recorded.Results. A total of 2133 clavicle radiographs were performed during the study period, with only five having a nontraumatic history. The overall incidence of paediatric nontraumatic clavicle lesions was 0.38 per 100,000 per year. Three patients were diagnosed with chronic recurrent osteomyelitis, one with chronic bifocal osteomyelitis, and one with Langerhans cell histiocytosis. All patients with osteomyelitis demonstrated a typical natural history of a chronic relapsing remitting infection. Three underwent bone biopsy; however, no organism was identified.Conclusion. This study demonstrated that the incidence of nontraumatic clavicle lesions is small, and those patients presenting with osteomyelitis should not routinely undergo a bone biopsy and close observation with the appropriate antibiotic therapy is advised.
Novel Organically Modified Core-Shell Clay for Epoxy Composites—“SOBM Filler 1”
Authors: Iheaturu Nnamdi Chibuike , Madufor Innocent Chimezie
Published: October 2014

Preparation of a novel organically modified clay from spent oil base drilling mud (SOBM) that could serve as core-shell clay filler for polymers is herein reported. Due to the hydrophilic nature of clay, its compatibility with polymer matrix was made possible through modification of the surface of the core clay sample with 3-aminopropyltriethoxysilane (3-APTES) compound prior to its use. Fourier transform infrared (FT-IR) spectroscopy was used to characterize clay surface modification. Electron dispersive X-ray diffraction (EDX) and scanning electron microscopy (SEM) were used to expose filler chemical composition and morphology, while electrophoresis measurement was used to examine level of filler dispersion. Results show an agglomerated core clay powder after high temperature treatment, while EDX analysis shows that the organically modified clay is composed of chemical inhomogeneities, wherein elemental compositions in weight percent vary from one point to the other in a probe of two points. Micrographs of the 3-APTES coupled SOBM core-shell clay filler clearly show cloudy appearance, while FT-IR indicates 25% and 5% increases in fundamental vibrations band at 1014 cm−1 and 1435 cm−1, respectively. Furthermore, 3-APTES coupled core-shell clay was used to prepare epoxy composites and tested for mechanical properties.
Finite Buffer GI/M(n)/1 Queue with Bernoulli-Schedule Vacation Interruption under N-Policy
Authors: Vijaya Laxmi P. , Suchitra V.
Published: October 2014

We study a finite buffer N-policy GI/M(n)/1 queue with Bernoulli-schedule vacation interruption. The server works with a slower rate during vacation period. At a service completion epoch during working vacation, if there are at least N customers present in the queue, the server interrupts vacation and otherwise continues the vacation. Using the supplementary variable technique and recursive method, we obtain the steady state system length distributions at prearrival and arbitrary epochs. Some special cases of the model, various performance measures, and cost analysis are discussed. Finally, parameter effect on the performance measures of the model is presented through numerical computations.
Pharmacokinetic Alteration of Baclofen by Multiple Oral Administration of Herbal Medicines in Rats
Authors: Kim Tae Hwan , Park Gi-Young , Shin Soyoung , Kwon Dong Rak , Seo Won Sik , Shin Jeong Cheol , Choi Jin Ho , Joo Sang Hoon , Weon Kwon-Yeon , Min Byung Sun , Baek Kyung Min , Upadhyay Mahesh , Zhao Bing Tian , Woo Mi Hee , Kwon So Hee , Shin Beom Soo
Published: October 2014

The potential pharmacokinetic (PK) interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY) and Achyranthes bidentata radix (AB) extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW), OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg) was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration‐time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half‐life of 3.42–4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (Cmax) and longer time to reach Cmax (Tmax) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (Furine). The absorption rate (Ka) of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance.
Knowledge and Attitude of Faculty Members Working in Dental Institutions towards the Dental Treatment of Patients with HIV/AIDS
Authors: Oberoi Sukhvinder Singh , Sharma Nilima , Mohanty Vikrant , Marya Charumohan , Rekhi Amit , Oberoi Avneet
Published: October 2014

Background. Dentists have an ethical responsibility to provide treatment to HIV-infected patients, particularly because oral lesions are common among these patients. However, there are no official guidelines as to how to treat people living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (PLWHA) or how to screen for potentially infectious people.Materials and Method. A descriptive cross-sectional questionnaire based study which assessed the knowledge and attitude of the faculty members towards the treatment of patients with HIV/AIDS was carried out in the Sudha Rustagi College of Dental Sciences, Faridabad, and Maulana Azad Institute of Dental Sciences, New Delhi.Results. The willingness to treat patients with HIV was found to be 86.0% among the faculty members in the present study. The majority (79%) of the faculty members thought that treating an HIV-positive patient is ethical responsibility of the dentist. There was a positive attitude (88.0%) among faculty members that routine dental care should be a part of the treatment of patients with HIV/AIDS.Conclusion. The level of knowledge regarding HIV and AIDS was acceptable in the present study. However, continuing dental education (CDE) programmes should be conducted on a regular basis for updating the knowledge level of the faculty members towards the dental treatment of patients with HIV/AIDS patients.
Material Properties of the Mandibular Trabecular Bone
Authors: Lakatos Éva , Magyar Lóránt , Bojtár Imre
Published: October 2014

The present paper introduces a numerical simulation aided, experimental method for the measurement of Young’s modulus of the trabecular substance in the human mandible. Compression tests were performed on fresh cadaveric samples containing trabecular bone covered with cortical layer, thus avoiding the destruction caused by the sterilization, preservation, and storage and the underestimation of the stiffness resulting from the individual failure of the trabeculae cut on the surfaces. The elastic modulus of the spongiosa was determined by the numerical simulation of each compression test using a specimen specific finite element model of each sample. The received mandibular trabecular bone Young’s modulus values ranged from 6.9 to 199.5 MPa.
Effect of Hygrothermal Aging on the Mechanical Properties of Fluorinated and Nonfluorinated Clay-Epoxy Nanocomposites
Authors: Hamim Salah U. , Singh Raman P.
Published: October 2014

Hydrophilic nature of epoxy polymers can lead to both reversible and irreversible/permanent changes in epoxy upon moisture absorption. The permanent changes leading to the degradation of mechanical properties due to combined effect of moisture and elevated temperature on EPON 862, Nanomer I.28E, and Somasif MAE clay-epoxy nanocomposites are investigated in this study. The extent of permanent degradation on fracture and flexural properties due to the hygrothermal aging is determined by drying the epoxy and their clay-epoxy nanocomposites after moisture absorption. Significant permanent damage is observed for fracture toughness and flexural modulus, while the extent of permanent damage is less significant for flexural strength. It is also observed that permanent degradation in Somasif MAE clay-epoxy nanocomposites is higher compared to Nanomer I.28E clay-epoxy nanocomposites. Fourier transform infrared (FTIR) spectroscopy revealed that both clays retained their original chemical structure after the absorption-desorption cycle without undergoing significant changes. Scanning electron microscopy (SEM) images of the fracture surfaces provide evidence that Somasif MAE clay particles offered very little resistance to crack propagation in case of redried specimens when compared to Nanomer I.28E counterpart. The reason for the observed higher extent of permanent degradation in Somasif MAE clay-epoxy system has been attributed to the weakening of the filler-matrix interface.
Comparing in Cylinder Pressure Modelling of a DI Diesel Engine Fuelled on Alternative Fuel Using Two Tabulated Chemistry Approaches
Authors: Ngayihi Abbe Claude Valery , Nzengwa Robert , Danwe Raidandi
Published: October 2014

The present work presents the comparative simulation of a diesel engine fuelled on diesel fuel and biodiesel fuel. Two models, based on tabulated chemistry, were implemented for the simulation purpose and results were compared with experimental data obtained from a single cylinder diesel engine. The first model is a single zone model based on the Krieger and Bormann combustion model while the second model is a two-zone model based on Olikara and Bormann combustion model. It was shown that both models can predict well the engine’s in-cylinder pressure as well as its overall performances. The second model showed a better accuracy than the first, while the first model was easier to implement and faster to compute. It was found that the first method was better suited for real time engine control and monitoring while the second one was better suited for engine design and emission prediction.
The Long Term Effect of Elective Colpoperineoplasty on Sexual Function in the Reproductive Aged Women in Iran
Authors: Jamali Safieh , Abedi Parvin , Rasekh Athar , Mohammadjafari Razieh
Published: October 2014

Objective. Many women are suffering from sexual dysfunction followed by vaginal laxity in their reproductive age. The aim of this study was to evaluate the long term effect of colpoperineoplasty on sexual function in Iranian reproductive aged women. Methods. This was a prospective observational study in which 79 women with vaginal laxity who were candidate for selective colpoperineoplasty in Jahrom, Iran, were recruited. Data on sexual function was collected via the Female Sexual Function (FSFI) questionnaire preoperatively, six months and 18 months after colpoperineoplasty. The paired t-test, Wilcoxon, Mann-Whitney, and Repeated Measure test were utilized for statistical purposes. Results. Seventy-six women completed the study by 18 months. The mean FSFI score changed from 24.19 ± 3.09 in baseline to 26.92 ± 3.41 after six months (P < 0.001); however dyspareunia and vaginal dryness were increased significantly. After 18 months all areas of sexual function including pain and lubrication improved significantly compared to the 6th month (P < 0.001). Sexual satisfaction was increased significantly six and 18 months after surgery (P < 0.001), and the total score of sexual function increased to 32.61 ± 1.32 after 18 months (P < 0.001). Conclusion. The long term effect of colpoperineoplasty in women who suffer from vaginal laxity is promising. It seems that patient’s dissatisfaction of sexual function can be a basis for colpoperineoplasty.
Recent Advancements in Prognostic Factors of Epithelial Ovarian Carcinoma
Authors: Ezzati Mohammad , Abdullah Amer , Shariftabrizi Ahmad , Hou June , Kopf Michael , Stedman Jennifer K. , Samuelson Robert , Shahabi Shohreh
Published: October 2014

Ovarian cancer remains the most common cause of gynecologic cancer-related death among women in developed countries. Nevertheless, subgroups of ovarian cancer patients experience relatively longer survival. Efforts to identify prognostic factors that characterize such patients are ongoing, with investigational areas including tumor characteristics, surgical management, inheritance patterns, immunologic factors, and genomic patterns. This review discusses various demographic, clinical, and molecular factors implicating longevity and ovarian cancer survival. Continued efforts at identifying these prognosticators may result in invaluable adjuncts to the treatment of ovarian cancer, with the ultimate goal of advancing patient care.
Prevalence of Trichomoniasis, Vaginal Candidiasis, Genital Herpes, Chlamydiasis, and Actinomycosis among Urban and Rural Women of Haryana, India
Authors: Arora Brij Bala , Maheshwari Megha , Devgan Naiya , Arora D. R.
Published: October 2014

Despite being curable reproductive tract infections (RTIs) including sexually transmitted infections continue to be a major health problem in developing countries. The present study was undertaken to know the prevalence of trichomoniasis, vaginal candidiasis, genital herpes, chlamydiasis, and actinomycosis in rural and urban women of Haryana by using wet mount, PAP smear, and fluorescent microscopic examination. Patients suspected of suffering from bacterial vaginosis were given treatment and were not included in the study. RTIs were seen in 16.6% of urban and 28.7% of rural women. The highest prevalence seen was that of trichomoniasis in both rural (24.2%) and urban (15.7%) women, followed by candidiasis (4.2% in rural and 0.6% in urban women), genital herpes (0.3% in rural and 0.2% in urban women), and chlamydiasis (0.02% in rural and 0.05% in urban women). Pelvic actinomycosis was seen in 1.4% of rural and 0.06% of urban women using intrauterine contraceptive devices. Mixed infection of Trichomonas vaginalis with Candida spp. was seen in 6.3% of rural women only. It is desirable to have a baseline profile of the prevalence of various agents causing RTIs in a particular geographic area and population which will help in better syndromic management of the patients.
Polymorphisms Influencing Prostate-Specific Antigen Concentration May Bias Genome-Wide Association Studies on Prostate Cancer
Authors: Dluzniewski Paul J. , Xu Jianfeng , Ruczinski Ingo , Isaacs William B. , Platz Elizabeth A.
Published: October 2014

Background: Genome-wide association studies (GWAS) have produced weak (OR = 1.1–1.5) but significant associations between single nucleotide polymorphisms (SNPs) and prostate cancer. However, these associations may be explained by detection bias caused by SNPs influencing PSA concentration. Thus, in a simulation study, we quantified the extent of bias in the association between a SNP and prostate cancer when the SNP influences PSA concentration.

Methods: We generated 2,000 replicate cohorts of 20,000 men using real-world estimates of prostate cancer risk, prevalence of carrying ≥1 minor allele, PSA concentration, and the influence of a SNP on PSA concentration. We modeled risk ratios (RR) of 1.00, 1.25, and 1.50 for the association between carrying ≥1 minor allele and prostate cancer. We calculated mean betas from the replicate cohorts and quantified bias under each scenario.

Results: Assuming no association between a SNP and prostate cancer, the estimated mean bias in betas ranged from 0.02 to 0.10 for ln PSA being 0.05 to 0.20 ng/mL higher in minor allele carriers; the mean biased RRs ranged from 1.03 to 1.11. Assuming true RRs = 1.25 and 1.50, the biased RRs were as large as 1.39 and 1.67, respectively.

Conclusion: Estimates of the association between SNPs and prostate cancer can be biased to the magnitude observed in published GWAS, possibly resulting in type I error. However, large associations (RR > 1.10) may not fully be explained by this bias.

Impact: The influence of SNPs on PSA concentration should be considered when interpreting results from GWAS on prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 88–93. ©2014 AACR.
Cabozantinib Overcomes Crizotinib Resistance in ROS1 Fusion–Positive Cancer
Authors: Katayama Ryohei , Kobayashi Yuka , Friboulet Luc , Lockerman Elizabeth L. , Koike Sumie , Shaw Alice T. , Engelman Jeffrey A. , Fujita Naoya
Published: October 2014

Purpose: ROS1 rearrangement leads to constitutive ROS1 activation with potent transforming activity. In an ongoing phase I trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib shows remarkable initial responses in patients with non–small cell lung cancer (NSCLC) harboring ROS1 fusions; however, cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in ROS1. Thus, understanding the crizotinib-resistance mechanisms in ROS1-rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required.

Experimental Design: The sensitivity of CD74–ROS1–transformed Ba/F3 cells to multiple ALK inhibitors was examined. Acquired ROS1 inhibitor–resistant mutations in CD74–ROS1 fusion were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3 cells. To overcome the resistance mutation, we performed high-throughput drug screening with small-molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials. The effect of the identified drug was assessed in the CD74–ROS1–mutant Ba/F3 cells and crizotinib-resistant patient-derived cancer cells (MGH047) harboring G2032R-mutated CD74–ROS1.

Results: We identified multiple novel crizotinib-resistance mutations in the ROS1 kinase domain, including the G2032R mutation. As the result of high-throughput drug screening, we found that the cMET/RET/VEGFR inhibitor cabozantinib (XL184) effectively inhibited the survival of CD74–ROS1 wild-type (WT) and resistant mutants harboring Ba/F3 and MGH047 cells. Furthermore, cabozantinib could overcome all the resistance by all newly identified secondary mutations.

Conclusions: We developed a comprehensive model of acquired resistance to ROS1 inhibitors in NSCLC with ROS1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. Clin Cancer Res; 21(1); 166–74. ©2014 AACR.
Immunomodulatory Antibody Therapy of Cancer: The Closer, the Better
Authors: Dronca Roxana S. , Dong Haidong
Published: October 2014

Immune checkpoint blockade therapies have demonstrated promising therapeutic effects; however, clinical outcomes are variable, with only a subgroup of cancer patients achieving durable complete responses. New therapeutic strategies, including local administration of immunomodulatory antibodies, have been considered as better routes for improving the overall efficacy of antibody-based therapy. Clin Cancer Res; 21(5); 944–6. ©2014 AACR.

See related articles by Mangsbo et al., p. 1115, and Dai et al., p. 1127
Phase II Study of Personalized Peptide Vaccination for Previously Treated Advanced Colorectal Cancer
Authors: Kibe Shiro , Yutani Shigeru , Motoyama Satoru , Nomura Takanobu , Tanaka Natsuki , Kawahara Akihiko , Yamaguchi Tomohiko , Matsueda Satoko , Komatsu Nobukazu , Miura Masatomo , Hinai Yudai , Hattori Satoshi , Yamada Akira , Kage Masayoshi , Itoh Kyogo , Akagi Yoshito , Sasada Tetsuro
Published: October 2014

The prognosis of advanced colorectal cancer (aCRC) remains poor, and development of new therapeutic approaches, including immunotherapy, is needed urgently. Herein we report on our phase II study of personalized peptide vaccination (PPV) in 60 previously treated patients with aCRC, who had failed at least one regimen of standard chemotherapy and/or targeted therapy. For PPV, a maximum of four HLA-matched peptides were individually selected from a pool of 31 different peptide candidates based on preexisting host immunity, and administered subcutaneously without severe adverse events. Boosting of IgG and cytotoxic T lymphocyte (CTL) responses specific to the administered peptides was observed in 49% and 63%, respectively, of the patients, who completed the first cycles of six vaccinations. Median overall survival (OS) time was 498 days, with 1- and 2-year survival rates of 53% and 22%, respectively. Multivariate Cox regression analysis of prevaccination factors showed that plasma IL6, IP-10, and BAFF levels were significantly prognostic for OS [hazard ratio (HR), 1.508, P = 0.043; HR, 1.579, P = 0.024; HR, 0.509, P = 0.002, respectively]. In addition, increased peptide-specific CTL responses after vaccination were significantly predictive of favorable OS (HR, 0.231; P = 0.021), suggesting a causal relationship between biologic and clinical efficacy of PPV. On the basis of the safety profile and potential clinical efficacy, we believe that clinical trials of PPV would be warranted for previously treated patients with aCRC. Cancer Immunol Res; 2(12); 1154–62. ©2014 AACR.
From Symptoms to Neurobiology: Pathological Gambling in the Light of the New Classification in DSM-5
Authors: Romanczuk-Seiferth Nina , van den Brink Wim , Goudriaan Anna E.
Published: October 2014

Pathological gambling (PG), as defined until recently in the DSM-IV, shares many clinical characteristics with substance use disorders (SUDs), such as craving and loss of control. Moreover, an increasing body of literature also revealed neurobiological similarities between PG and substance-related addictions. Further, specific treatments for SUD are also effective in pathological gamblers. These observations resulted in a recent change in the diagnostic classification of PG in DSM-5: maladaptive gambling behavior is now subsumed as ‘gambling disorder' (GD) under the category ‘substance-related and addictive disorders'. On the basis of similarities in clinical characteristics between GD and SUDs, this article proposes 3 main clusters of diagnostic criteria: ‘loss of control', ‘craving/withdrawal' and ‘neglect of other areas in life'. These symptom clusters can then be related to the experimental paradigms commonly used in the neuroscience of addiction, including neuropsychological, neurophysiological and neuroimaging studies. In this paper, we present the neurobiological evidence for PG by focusing on key functional magnetic resonance imaging studies related to these 3 symptom clusters. It is concluded that these symptom clusters provide a useful framework for systematic comparisons of new evidence in GD and SUDs in the future.
Do Immunocompromised Children Benefit from Having Surgical Lung Biopsy Performed?
Authors: Goldstein Gal , Keller Nathan , Bilik Ron , Bielorai Bella , Toren Amos
Published: October 2014

Background: Surgical lung biopsy is considered a gold standard for the evaluation of pulmonary disease in immunocompromised children. However, in the literature, its accuracy and the rate of complications vary. Objective: We aimed to evaluate the yield of surgical lung biopsies in the management of persistent pulmonary findings in immunocompromised children. Methods: We performed a retrospective review of clinical records of immunocompromised children who underwent surgical lung biopsies, and evaluated the impact that preoperative factors had on outcomes. Results: Twenty-five patients underwent 27 surgical lung biopsies. The underlying immunodeficiency included allogeneic stem cell transplantation (n = 12), chemotherapy for solid tumors (n = 6), hematologic malignancy (n = 4), primary immunodeficiency (n = 4) and chronic steroid use (n = 1). Biopsies provided a specific histopathologic or microbiologic diagnosis in 10 cases (37%). No preoperative factor predicted a diagnostic biopsy. Five of the 27 biopsies were beneficial for the patients (18%). A major complication related to the procedure was reported for 1 biopsy (4%). Conclusions: We conclude that surgical lung biopsy in pediatric immunocompromised patients appears to be safe, but has a relatively low diagnostic yield and an even lower yield with regards to the benefit it provides. © 2014 S. Karger AG, Basel
Intracoronary Delivery of Injectable Bioabsorbable Scaffold (IK-5001) to Treat Left Ventricular Remodeling After ST-Elevation Myocardial Infarction
Authors: Frey Norbert , Linke Axel , Süselbeck Tim , Müller-Ehmsen Jochen , Vermeersch Paul , Schoors Danny , Rosenberg Mark , Bea Florian , Tuvia Shmuel , Leor Jonathan
Published: October 2014

Background—

We aimed to test, for the first time, the feasibility of intracoronary delivery of an innovative, injectable bioabsorbable scaffold (IK-5001), to prevent or reverse adverse left ventricular remodeling and dysfunction in patients after ST-segment–elevation myocardial infarction.

Methods and Results—

Patients (n=27) with moderate-to-large ST-segment–elevation myocardial infarctions, after successful revascularization, were enrolled. Two milliliters of IK-5001, a solution of 1% sodium alginate plus 0.3% calcium gluconate, was administered by selective injection through the infarct-related coronary artery within 7 days after myocardial infarction. IK-5001 is assumed to permeate the infarcted tissue, cross-linking into a hydrogel and forming a bioabsorbable cardiac scaffold. Coronary angiography, 3 minutes after injection, confirmed that the injection did not impair coronary flow and myocardial perfusion. Furthermore, IK-5001 deployment was not associated with additional myocardial injury or re-elevation of cardiac biomarkers. Clinical assessments, echocardiographic studies, 12-lead electrocardiograms, 24-hour Holter monitoring, blood tests, and completion of Minnesota Living with Heart Failure Questionnaires were repeated during follow-up visits at 30, 90, and 180 days after treatment. During a 6-month follow-up, these tests confirmed favorable tolerability of the procedure, without device-related adverse events, serious arrhythmias, blood test abnormalities, or death. Serial echocardiographic studies showed preservation of left ventricular indices and left ventricular ejection fraction.

Conclusions—

This first-in-man pilot study shows that intracoronary deployment of an IK-5001 scaffold is feasible and well tolerated. Our results have promoted the initiation of a multicenter, randomized controlled trial to confirm the safety and efficacy of this new approach in high-risk patients after ST-segment–elevation myocardial infarction.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01226563.
Two new species of Martintella Artigas, 1996 (Diptera, Asilidae, Asilinae)
from Costa Rica
Authors: VIEIRA RODRIGO , RAFAEL JOSÉ ALBERTINO , FISHER ERIC M.
Published: October 2014

Two new species of Martintella Artigas, 1996, Martintella aurata sp. nov. and Martintella fernandoi sp. nov., from Costa Rica are described and illustrations of species of the genus are provided.
Somatochlora shennong sp. nov. from Hubei, China (Odonata: Corduliidae)
Authors: ZHANG HAO-MIAO , VOGT TIMOTHY E. , CAI QING-HUA
Published: October 2014

A new species, Somatochlora shennong sp. nov. (holotype ♂, Dajiuhu National Wetland Park in Shennongjia National Nature Reserve, Hubei Province, China, 9 August 2012) is described, illustrated, and compared with the related species S. dido Needham and S. taiwana Inoue & Yokota.
A new species of freshwater crab of the genus Sodhiana Yeo & Ng, 2012
(Decapoda: Brachyura: Gecarcinucidae) from southern Iran
Authors: SHARIFIAN SANA , KAMRANI EHSAN , SHARIFIAN SALIM
Published: October 2014

A new species of freshwater crab, Sodhiana iranica n. sp. (Decapoda: Brachyura: Gecarcinucidae), is described from Bastak, Iran. This is fourth species of Sodhiana Yeo & Ng, 2012, described, and is the second one known from Iran. It can be distinguished from congeners by the form of its carapace and the structure of the male first gonopod.
Narracje litotyczne w wielkiej narracji teatru antropologicznego na przykładzie pracy Teatru Węgajty/Projektu Terenowego w Domu Pomocy Społecznej w Jonkowie
Authors: Paprocka Kamila
Published: October 2014

Litotes situated in the grand narration of the anthropological theatre: a case study of Teatr Węgajty/Projekt Terenowy

This article is an excerpt of the author's MA thesis: Litotes in the anthropological theatre’s grand narrative. The case of Teatr Węgajty/ Projekt Terenowy. It analyses the attitude of the anthropological theatre towards principles that constituted its foundation, such as the fascination with the traditional culture and work in the local community. The anthropological theatre’s grand narrative is replaced by the small narrative of teatr potrzebny (‘theatre of necessity’), which originates from the excluded, forgotten litotes. The paper provides documentation and an analysis of teatr potrzebny, taking the example of the work of Teatr Węgajty/Projekt Terenowy in a Social Welfare Home in Jonkowo.

 

Narracje litotyczne w wielkiej narracji teatru antropologicznego na przykładzie pracy Teatru Węgajty/Projektu Terenowego w Domu Pomocy Społecznej w Jonkowie

Artykuł stanowi fragment mojej pracy magisterskiej Narracje litotyczne w wielkiej narracji teatru antropologicznego na przykładzie pracy Teatru Węgajty/Projektu Terenowego. Analizuję w nim możliwości teatru antropologicznego poprzez pokazanie elementów, które legły u jego podstaw: fascynacji kulturą tradycyjną oraz pracy w lokalnej wspólnocie. „Wielka narracja” teatru antropologicznego zastąpiona zostaje „małą narracją” „teatru potrzebnego”, wywodzącą się z wykluczonych, zapomnianych litot. Artykuł dokumentuje i analizuje tzw. teatr potrzebny na przykładzie działań Teatru Węgajty/ Projektu Terenowego w Domu Pomocy Społecznej w Jonkowie.
Sublokatorstwo jako kategoria kultury polskiej
Authors: Janicka Elżbieta , Tokarska-Bakir Joanna
Published: October 2014

Eng. title: Subtenancy as a category of Polish culture
Wytwarzanie „winy obojętności” oraz kategorii „obojętnego świadka” na przykładzie artykułu Jana Błońskiego „Biedni Polacy patrzą na getto”
Authors: Żukowski Tomasz
Published: October 2014

Producing the 'guilt of indifference' and the category of "indifferent witness". A case study of Jan Błoński’s 'Biedni Polacy patrzą na getto'Błoński’s article Biedni Polacy patrzą na getto (1987) is regarded as a milestone for the Polish awareness of the Holocaust. Błoński tried to tackle the issue of the Polish complicity, and his narration updated an important model in the Polish culture. It contained some facts about the wartime reality, but at the same time it overturned much of the knowledge about those times and rendered it mostly transparent. The analysis of Błoński’s article allowed me to elucidate the relation between the catharsis effect and the denial, which appeared as the effect of the article. The paper attempts at answering some important questions: What is the Polish complicity according to Błoński? What are the different perceptions of the relations between Poles and Jews? What is the perception of the majority? How the different opinions on the Polish complicity in the Holocaust are legitimised by the majority? How are they removed and delegitimised at the same time?[The article was prepared with financial support of the NPRH.] Wytwarzanie „winy obojętności” oraz kategorii „obojętnego świadka” na przykładzie artykułu Jana Błońskiego „Biedni Polacy patrzą na getto”Tekst Jana Błońskiego Biedni Polacy patrzą na getto (1987) uznaje się za przełomowy dla polskiej świadomości zbiorowej dotyczącej Zagłady. Błoński stawia w nim problem polskiej współwiny. Jego narracja aktualizuje ważny wzór polskiej kultury. Zawiera elementy wiedzy o wojennych realiach, a jednocześnie ją unieważnia i czyni w dużym stopniu niewidoczną. Analiza tekstu Błońskiego pozwala uchwycić związek między efektem przełomu i jednoczesnym wyparciem. Autor pyta, w jaki sposób Błoński stawia kwestię polskiej winy, jakie wyobrażenia relacji polsko-żydowskich jej towarzyszą, jaki jest obraz polskiej większości, wreszcie – jak głosy na temat polskiej roli w eksterminacji Żydów zyskują prawo istnienia w zbiorowej świadomości, stając się prawomocnymi narracjami o historii i jak są z niej – niemal jednocześnie – usuwane i delegitymizowane.[Artykuł powstał w ramach projektu Wobec Zagłady – w stronę demitologizacji kategorii opisu. Kategoria „obojętni świadkowie” finansowanego przez NPRH.]
Modernistyczny terror, czyli krótko o "tunnel vision" Jamesa C. Scotta
Authors: Pietryka Mateusz
Published: October 2014

The terror of modernism or Scott’s 'tunnel vision' The article analyses James C. Scott’s book Seeing Like a State: How Certain Schemes to Improve the Human Condition Have Failed. Scott’s book examines different aspects of a modern state’s activity and its methods of control over the population. Scott describes diverse failures in state planning and links them to the ideology of what he terms “high modernism”. Scott states that this ideology results in over confidence in scientific progress and omnipresent simplifications, since a modernist plan does not recognize the importance of local knowledge and tradition.Though the book clearly illustrates how the fore-mentioned centralist approach leads to failures, its methodology, however, lacks the critical analysis of the nature of governance and liberal economy. Furthermore, Scott offers no insight on the late capitalism nor legible solutions for the described issues. He seems to be unaware of constructing his own “tunnel vision” by selective case studies and building the narration on simplified oppositions. Modernistyczny terror, czyli krótko o tunnel vision Jamesa C. ScottaArtykuł jest analizą książki Jamesa Scotta, Seeing Like a State: How Certain Schemes to Improve the Human Condition Have Failed. Książka ta bada różnorodne aspekty aktywności współczesnego państwa i jego metody kontroli nad populacją. Autor opisuje rożnego typu niepowodzenia wynikające z państwowego planowania i wiąże je z ideologią nazwaną przez siebie „zaawansowanym modernizmem”. Scott twierdzi, że skutkuje ona pokładaniem nadmiernej wiary w postęp naukowy i wszechobecnymi uproszczeniami, ponieważ modernistyczny plan nie uznaje znaczenia lokalnej wiedzy i tradycji.Choć książka jasno pokazuje, jak wspomniane centralistyczne podejście kończy się porażkami, jej metodologii brakuje krytycznej analizy natury władzy i liberalnej ekonomii. Ponadto Scott pomija temat późnego kapitalizmu i jasnych rozwiązań opisywanych problemów. Wydaje się, iż poprzez selektywne studia przypadku i budowanie narracji na uproszczonych opozycjach nieświadomie konstruuje swoje własne tunnel vision.
Two Approaches for Statistical Prediction of Non-Gaussian Climate Extremes: A Case Study of Macao Hot Extremes during 1912–2012
Authors: Qian Cheng , Zhou Wen , Fong Soi Kun , Leong Ka Cheng
Published: October 2014

The Gaussian assumption has been widely used without testing in many previous studies on climate variability and change that have used traditional statistical methods to estimate linear trends, diagnose physical mechanisms, or construct statistical prediction/downscaling models. In this study, the authors carefully test the normality of two hot extreme indices in Macao, China, during the last 100 years based on consecutive daily temperature observational data and find that the occurrences of both hot day and hot night indices are non-Gaussian. Simple least squares fitting is shown to overestimate the linear trend when the Gaussian assumption is violated. Two approaches are further proposed to statistically predict non-Gaussian temperature extremes: one uses a multiple linear regression model after transforming the non-Gaussian predictant to a quasi-Gaussian variable and uses Pearson’s correlation test to identify potential predictors, and the other uses a generalized linear model when the transformation is difficult and uses a nonparametric Spearman’s correlation test to identify potential predictors. The annual occurrences of hot days and hot nights in Macao are used as examples of these two approaches, respectively. The physical mechanisms for these two hot extremes in Macao are also investigated, and the results show that both are related to the interannual and interdecadal variability of a coupled El Niño–Southern Oscillation (ENSO)–East Asian summer monsoon system. Finally, the authors caution other researchers to test the assumed distribution of climate extremes and to apply appropriate statistical approaches.