Microscopic Visualization of Metabotropic Glutamate Receptors on the Surface of Living Cells Using Bifunctional Magnetic Resonance Imaging Probes

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Cover Image,Volume 40, Issue 4

The abysmal success rate of anticancer drugs in clinical trials, is in part, attributable to discordance between cultured cancer cells and patient tumors. While tumors in vivo, display a lower mitotic index, patient tumors portray much higher centrosomal aberrations, relative to in vitro cultured cells. The microenvironment too differs considerably between the in vitro and in vivo scenarios. Notably, another hallmark of cancer, hypoxia, is not recapitulated in cell lines cultured under normoxic conditions. These observations raise the possibility that hypoxia may be the missing link that explains the discordance between cell biological phenomena in vitro versus physiological conditions. Further, the interplay between hypoxia and centrosome amplification (CA) is relatively understudied. Recent research from our laboratory, geared toward examining the biological link between the two, has uncovered that hypoxia induces the expression of proteins (Plk4, Aurora A, Cyclin D) implicated in CA, in a hypoxia-inducible factor 1α (HIF-1α)-dependent context. Our studies evidence that hypoxia fuels CA that underlie intratumoral heterogeneity and metastatic potential of cancer cells. Given the advent of HIF-1α inhibitors, this research has ramifications in aiding patient risk stratification and designing new cancer drug therapies to facilitate clinical decision-making.     

Secondary Creep Analysis of FG Rotating Cylinder with Exponential,Linear and Quadratic Volume Reinforcement

Creep is an irreversible time-dependent deformation in which a material under constant mechanical stress and elevated temperature for a considerably prolonged period of time, starts to undergo permanent deformation. Creep deformation occurs in three stages namely, primary, secondary and tertiary. Out of these three stages, secondary or steady state creep is particularly an area of engineering interest as it has almost a constant creep rate. Creep deformation plays a significant role in understanding effective service life of an engineering component working under high temperature conditions as such components such as super-heater and re-heater tubes and headers in a boiler, jet engines operating at temperature as high as 1200 ∘C, usually experience a failure or rupture due to creep phenomenon. Design engineers keep a close attention on working stress conditions and elevated temperature under which an engineering component is expected to work as these conditions determine the onset of creep behavior in an engineering component. By recognizing the parameters of material response to creep behavior, engineers can analyse the useful service life and hazardous working conditions for an engineering components. Recognizing the creep phenomenon as high temperature design limitation, ASME Boiler and Pressure Vessel Code have provided guidelines on maximum allowable stresses for materials to be used in creep range. One of the criteria for determination of allowable stresses is 1% creep deformation of material in 100,000 h of service. Thus, the study of creep behavior in engineering components pertaining to high stress and temperature working conditions is very important as it affects the reliability and performance of the engineering components. The aim of our study is to understand the behavior of secondary creep deformation so that an advanced reinforced functionally graded material with better creep resistance, can be designed. In this paper, a secondary creep analysis of functionally graded (FG) thick-walled rotating cylinder under internal and external pressure is conducted. The novelty of the model intends to specify secondary creep stresses and strains by employing exponential, linear and quadratic volume reinforcement for SiCp ceramic in Al metal matrix in radial direction. This will help us to understand the effect of volume reinforcement in FG cylinder under internal/external pressure and rotating centrifugal body force by obtaining secondary creep stresses and strains. The response of the FG cylinder with isotropic material is analyzed and the solution for stress–strain rates in radial and tangential directions are obtained in closed form. Comparison of steady state creep stresses and strains under exponential, linear and quadratic volume reinforcement profiles are discussed and presented graphically.     

Intraperitoneal cisplatin and paclitaxel versus intravenous carboplatin and paclitaxel chemotherapy for Stage III ovarian cancer: a cost-effectiveness analysis

OBJECTIVE: To evaluate the cost-effectiveness of intraperitoneal cisplatin and paclitaxel chemotherapy as front-line treatment for patients with Stage III epithelial ovarian cancer following optimal primary cytoreductive surgery. METHODS: Based on Gynecologic Oncology Group protocols #172 and #158, a decision analysis model was created to compare two treatment strategies for patients with optimal residual disease Stage III ovarian cancer: (1) inpatient intravenous paclitaxel (24 h) and intraperitoneal cisplatin plus outpatient intraperitoneal paclitaxel chemotherapy (IP/IV), and (2) outpatient intravenous paclitaxel (3 h) and carboplatin chemotherapy (IV/IV). The cost-effectiveness of each strategy was evaluated from the perspective of society. RESULTS: Cost-effectiveness analysis revealed that the strategy of IP/IV chemotherapy had an overall cost per patient of $39,861 and effectiveness of 5.16 QALYs compared to $18,822 and 4.59 QALYs for IV/IV chemotherapy. The IP/IV chemotherapy strategy was associated with an additional 0.56 QALYs at an incremental cost of $21,039. The incremental C/E ratio for IP/IV chemotherapy was $37,454/QALY. Inpatient treatment accounted for 43.2% of the cost of IP/IV chemotherapy. Sensitivity analysis testing confirmed the robustness of the model. CONCLUSIONS: In this model, IP/IV chemotherapy was associated with a modest extension in quality-adjusted survival time but was also more costly than IV/IV chemotherapy. On balance, the IP/IV strategy can be considered a good healthcare value. However, these data also suggest that efforts to reduce the cost of IP/IV chemotherapy, such as through development of an ambulatory regimen with equivalent therapeutic efficacy but an improved toxicity profile, would improve the overall value of this adjuvant treatment program.     

Patterns of attendances to the hospital emergency eye care service: a multicentre study in England

Background/ObjectivesTo characterise the patterns of presentation and diagnostic frequencies in Hospital Emergency Eye Care Services (HEECS) across 13 hospitals in England.MethodsRetrospective, cross-sectional, observational multi-centre (n = 13) study to assess HEECS attendances over a 28-day study period. Data derived included: number of consecutive attendances, patient demographics and diagnoses. Age and gender variations, the impact of day of the week on attendance patterns, diagnostic frequencies and estimates of the annual incidence and attendance rates were evaluated.ResultsA total of 17,667 patient (mean ± standard deviation age = 49.6 ± 21.8 years) attendances were identified with an estimated HEECS annual new attendance rate of 31.0 per 1,000 population. Significantly more females (53%) than males (47%) attended HEECS (p < 0.001). Female attendances were 13% higher in those ≥50 years of age. Weekends were associated with a significant reduction in attendances compared to weekdays (χ² = 6.94, p < 0.001). Among weekdays, Mondays and Fridays were associated with significantly higher attendances compared with midweek (χ² = 2.20, p = 0.032). Presenting pathologies involving the external eye, cornea and conjunctiva accounted for 28.6% of the caseload.ConclusionThis is the largest multicentre study assessing attendance patterns in HEECS in England. We have, for the first time, observed a “weekend effect” in relation to attendance to HEECS. Differences in health-seeking behaviour and lack of awareness of HEECS weekend services may be partly attributed to the differences observed. Our findings, along with the type of presentations, have the potential to guide commissioners with future planning of HEECS.Subject terms: Epidemiology, Epidemiology     

Imatinib-Induced Hypogammaglobulinemia in Children and Adolescents with Chronic Myeloid Leukemia

Abstract

Imatinib-induced tyrosine kinase inhibition extends beyond the BCR-ABL mutation, resulting in adverse effects. We evaluated hypogammaglobulinemia as a potential ‘off-target’ action of imatinib in children with CML. A cross-sectional, observational study was performed. Patients with CML in chronic phase, age <18-years at diagnosis, receiving imatinib for a duration exceeding 6-months were enrolled. Serum immunoglobulin G, A, and M were measured by end-point nephelometry. Thirty patients were enrolled. The mean age at diagnosis was 10.4?±?3.1?years (range: 5-18). The mean age at enrollment was 16.4?±?4.1?years (range: 9-23). The median dose of imatinib was 287.5?mg/m² (IQR: 267.3, 345.0). The median duration of imatinib-therapy was 6-years (IQR: 3.0, 10.3). The median (IQR) normalized levels of IgG, IgA, and IgM were 33.0% (IQR: ?12.8, 58.7), 28.1% (IQR: ?17.0, 90.1) and 15.9% (IQR: ?9.3, 40.5), respectively. The IgG, IgA, and IgM levels were reduced in 9 (30%), 8 (27%), and 10 (33%) patients, respectively. Five (17%) patients had pan-hypogammaglobulinemia. We suggest checking immunoglobulin levels in patients with CML receiving imatinib with recurrent/unusual infections.     

Limited utility of conventional criteria for predicting unresectable disease in patients with advanced stage epithelial ovarian cancer

ObjectiveTo compare the overall survival of patients with cervical cancer treated exclusively with radiotherapy with that of patients treated with a combination of radio and chemotherapy.Material and methodsRetrospective analysis of all cases of cervical cancer registered at the Brazilian National Cancer Institute between 1999 and 2004, treated with radiotherapy exclusively or in combination with chemotherapy. The Kaplan–Meier curve and the log-rank test were used to assess overall survival. The Cox model and the propensity score were used for multivariate analysis.ResultsA total of 2584 patients were studied, and the clinical and epidemiological characteristics of the cohort were described. The combination of chemotherapy with radiotherapy provided an improvement in survival when compared with radiotherapy exclusively (HR-0.69; p < 0.001), which persisted after multivariate analysis (HR-0.72; p < 0.001).ConclusionThere was a beneficial effect of adding chemotherapy to radiotherapy on this cohort.     

Protective effects of Terminalia arjuna against Doxorubicin-induced cardiotoxicity

Terminalia arjuna has been marked as a potential cardioprotective agent since vedic period. The present study was aimed to investigate the effects of butanolic fraction of Terminalia arjuna bark (TA-05) on Doxorubicin (Dox)-induced cardiotoxicity. Male wistar rats were used as in vivo model for the study. TA-05 was administered orally to Wistar rats at different doses (0.42 mg/kg, 0.85 mg/kg, 1.7 mg/kg, 3.4 mg/kg and 6.8 mg/kg) for 6 days/week for 4 weeks. Thereafter, all the animals except saline and TA-05-treated controls were administered 20 mg/kg Dox intraperitonially. There was a significant decrease in myocardial superoxide dismutase (38.94%) and reduced glutathione (23.84%) in animals treated with Dox. Concurrently marked increase in serum creatine kinase-MB (CKMB) activity (48.11%) as well as increase in extent of lipid peroxidation (2.55-fold) was reported. Co-treatment of TA-05 and Dox resulted in an increase in the cardiac antioxidant enzymes, decrease in serum CKMB levels and reduction in lipid peroxidation as compared to Dox-treated animals. Electron microscopic studies in Dox-treated animals revealed mitochondrial swelling, Z-band disarray, focal dilatation of smooth endoplasmic reticulum (SER) and lipid inclusions, whereas the concurrent administration of TA-05 led to a lesser degree of Dox-induced histological alterations. These findings suggest that butanolic fraction of Terminalia arjuna bark has protective effects against Dox-induced cardiotoxicity and may have potential as a cardioprotective agent.