Systematic Review and Cumulative Analysis of Oncologic and Functional Outcomes After Robot-assisted Radical Cystectomy

CONTEXT Although open radical cystectomy (ORC) is still the standard approach, laparoscopic radical cystectomy (LRC) and robot-assisted radical cystectomy (RARC) are increasingly performed. OBJECTIVE To report on a systematic literature review and cumulative analysis of pathologic, oncologic, and functional outcomes of RARC in comparison with ORC and LRC. EVIDENCE ACQUISITION Medline, Scopus, and Web of Science databases were searched using a free-text protocol including the terms robot-assisted radical cystectomy or da Vinci radical cystectomy or robot* radical cystectomy. RARC case series and studies comparing RARC with either ORC or LRC were collected. A cumulative analysis was conducted. EVIDENCE SYNTHESIS The searches retrieved 105 papers, 87 of which reported on pathologic, oncologic, or functional outcomes. Most series were retrospective and had small case numbers, short follow-up, and potential patient selection bias. The lymph node yield during lymph node dissection was 19 (range: 3-55), with half of the series following an extended template (yield range: 11-55). The lymph node-positive rate was 22%. The performance of lymphadenectomy was correlated with surgeon and institutional volume. Cumulative analyses showed no significant difference in lymph node yield between RARC and ORC. Positive surgical margin (PSM) rates were 5.6% (1-1.5% in pT2 disease and 0-25% in pT3 and higher disease). PSM rates did not appear to decrease with sequential case numbers. Cumulative analyses showed no significant difference in rates of surgical margins between RARC and ORC or RARC and LRC. Neoadjuvant chemotherapy use ranged from 0% to 31%, with adjuvant chemotherapy used in 4-29% of patients. Only six series reported a mean follow-up of >36 mo. Three-year disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates were 67-76%, 68-83%, and 61-80%, respectively. The 5-yr DFS, CSS, and OS rates were 53-74%, 66-80%, and 39-66%, respectively. Similar to ORC, disease of higher pathologic stage or evidence of lymph node involvement was associated with worse survival. Very limited data were available with respect to functional outcomes. The 12-mo continence rates with continent diversion were 83-100% in men for daytime continence and 66-76% for nighttime continence. In one series, potency was recovered in 63% of patients who were evaluable at 12 mo. CONCLUSIONS Oncologic and functional data from RARC remain immature, and longer-term prospective studies are needed. Cumulative analyses demonstrated that lymph node yields and PSM rates were similar between RARC and ORC. Conclusive long-term survival outcomes for RARC were limited, although oncologic outcomes up to 5 yr were similar to those reported for ORC. PATIENT SUMMARY Although open radical cystectomy (RC) is still regarded as the standard treatment for muscle-invasive bladder cancer, laparoscopic and robot-assisted RCs are becoming more popular. Templates of lymph node dissection, lymph node yields, and positive surgical margin rates are acceptable with robot-assisted RC. Although definitive comparisons with open RC with respect to oncologic or functional outcomes are lacking, early results appear comparable.

Are Selective Serotonin Reuptake Inhibitors Associated With Hepatocellular Carcinoma in Patients With Hepatitis C?

BACKGROUND AND AIMS: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for patients with chronic hepatitis C virus (HCV) infection. Research suggests that serotonin promotes the development and growth of hepatocellular carcinoma (HCC). We tested the hypothesis whether exposure to SSRIs is associated with an increased risk of HCC in HCV patients. METHOD: Patients who entered the United States Veterans Affairs (VA) Hepatitis C Clinical Case Registry in 2000 to 2009 were analyzed. During the 8 years of follow-up, 36,192 patients filled at least 1 SSRI prescription. Cases of HCC were identified by diagnosis codes (ICD-9 155.0). Multivariable Cox regression analyses estimated adjusted HCC hazard ratios (HRs) for SSRI-exposed versus SSRI-unexposed subjects and categories of average SSRI doses. RESULTS: The annual incidence of HCC in the VA registry cohort of 109,736 patients was 0.5% and significantly greater in the 8% with cirrhosis at baseline (HR = 5.2; 95% CI, 4.7-5.7). There was no evidence for significant interactions between the effect of SSRI-exposure and cirrhosis. Baseline characteristics of the exposed (n = 36,192) and unexposed (n = 73,544) subjects were similar. The median (interquartile range [IQR]) follow-up period after SSRI-exposure began was 44 (20-74) months with 18 (3-49) months between the first and last prescription. The median average SSRI dose during follow-up expressed as a fraction of initial recommended doses for depression was 0.94 (IQR, 0.5 to 1.3). The risk of HCC was not significantly increased after SSRI exposure (HR = 0.96; 95% CI, 0.87-1.05) or with increasing SSRI doses. CONCLUSIONS: Analysis of a large cohort of HCV patients did not support the hypothesis that SSRIs increase the risk of developing HCC.

Pulse-shaping assisted multidimensional coherent electronic spectroscopy

Understanding nuclear and electronic dynamics of molecular systems has advanced considerably by probing their nonlinear responses with a suitable sequence of pulses. Moreover, the ability to control crucial parameters of the excitation pulses, such as duration, sequence, frequency, polarization, slowly varying envelope, or carrier phase, has led to a variety of advanced time-resolved spectroscopic methodologies. Recently, two-dimensional electronic spectroscopy with ultrashort pulses has become a more and more popular tool since it allows to obtain information on energy and coherence transfer phenomena, line broadening mechanisms, or the presence of quantum coherences in molecular complexes. Here, we present a high fidelity two-dimensional electronic spectroscopy setup designed for molecular systems in solution. It incorporates the versatility of pulse-shaping methods to achieve full control on the amplitude and phase of the individual exciting and probing pulses. Selective and precise amplitude- and phase-modulation is shown and applied to investigate electronic dynamics in several reference molecular systems.

Canopy gaps promote selective stem-cutting by small mammals of two dominant tree species in an African lowland forest: the importance of seedling chemistry

Small mammals can impede tree regeneration by injuring seedlings and saplings in several ways. One fatal way is by severing their stems, but apparently this type of predation is not well-studied in tropical rain forest. Here, we report on the incidence of 'stem-cutting' to new, wild seedlings of two locally dominant, canopy tree species monitored in 40 paired forest understorey and gap-habitat areas in Korup, Cameroon following a 2007 masting event. In gap areas, which are required for the upward growth and sapling recruitment of both species, 137 seedlings of the long-lived, light-demanding, fast-growing large tropical tree (Microberlinia bisulcata) were highly susceptible to stem-cutting (83% of deaths) - it killed 39% of all seedlings over a c. 2-y period. In stark contrast, seedlings of the more shade-tolerant, slower-growing tree species (Tetraberlinia bifoliolata) were hardly attacked (4.3%). In the understorey, however, stem-cutting was virtually absent. Across the gap areas, the incidence of stem-cutting of M. bisulcata seedlings showed significant spatial variation that could not be explained significantly by either canopy openness or Janzen-Connell type effects (proximity and basal area of conspecific adult trees). To examine physical and chemical traits that might explain the species difference to being cut, bark and wood tissues were collected from a separate sample of seedlings in gaps (i.e. not monitored for stem-cutting). These analyses suggested that, compared with T. bifoliolata, the lower stem density, higher Mg and K and fatty acid concentrations in bark, and fewer phenolic and terpene compounds in M. bisulcata seedlings made them more palatable and attractive to small-mammal predators, likely rodents. We conclude that selective stem-cutting is a potent countervailing force to the current local canopy dominance of the grove-forming M. bisulcata by limiting the recruitment and abundance of its saplings. Given the ubiquity of gaps and ground-dwelling rodents in pantropical forests, it would be surprising if this form of lethal browsing was restricted to Korup.

Automatic assessment of time-resolved OCT images for selective retina therapy

Purpose In recent years, selective retina laser treatment (SRT), a sub-threshold therapy method, avoids widespread damage to all retinal layers by targeting only a few. While these methods facilitate faster healing, their lack of visual feedback during treatment represents a considerable shortcoming as induced lesions remain invisible with conventional imaging and make clinical use challenging. To overcome this, we present a new strategy to provide location-specific and contact-free automatic feedback of SRT laser applications. Methods We leverage time-resolved optical coherence tomography (OCT) to provide informative feedback to clinicians on outcomes of location-specific treatment. By coupling an OCT system to SRT treatment laser, we visualize structural changes in the retinal layers as they occur via time-resolved depth images. We then propose a novel strategy for automatic assessment of such time-resolved OCT images. To achieve this, we introduce novel image features for this task that when combined with standard machine learning classifiers yield excellent treatment outcome classification capabilities. Results Our approach was evaluated on both ex vivo porcine eyes and human patients in a clinical setting, yielding performances above 95 % accuracy for predicting patient treatment outcomes. In addition, we show that accurate outcomes for human patients can be estimated even when our method is trained using only ex vivo porcine data. Conclusion The proposed technique presents a much needed strategy toward noninvasive, safe, reliable, and repeatable SRT applications. These results are encouraging for the broader use of new treatment options for neovascularization-based retinal pathologies.

Implications of Longterm Diameter-Limit Harvesting: Effects on Radial Growth of Red Spruce (Picea rubens) and Genetic Diversity of White Pine (Pinus strobus)

For over 3 centuries, diameter-limit harvesting has been a predominant logging method in the northeastern United States. Silvicultural theory asserts that such intensively selective harvesting can lead to genetic degradation. A decrease in softwood productivity has recently been reported in Maine - has a long history of dysgenic selection degraded the genetic resources of Maine softwoods, contributing to a decrease in growth and productivity? This study examines two aspects of potential implications of diameter-limit harvesting: effects on residual phenotypes of red spruce and impacts on genetic diversity of white pine. Radial growth of residual red spruce trees in stands experiencing 50 years of fixed diameter-limit harvesting was measured using annual increment rings and compared with residual red spruce trees in positive selection stands. Trees remaiaing after several rounds of diameter-limit harvesting exhibited sigdicantl y smaller radial sizes throughout their lives, and displayed significantly slower growth rates for the first 80 years of measured growth. These results strongly suggest that the largest and fastest-growing genotypes and their respective gene complexes determining good radial growth have been removed from the diameter-limit stand. Dysgenic selection can be observed in fixed diarneter-limit stands, resulting in a diminished genetic resource and decreased residual stand value. To examine more direct genetic implications of long-term diameter-limit harvesting, microsatellite DNA markers were implemented to study genetic diversity of eastern white pine in Maine. Three age groups of trees were studied: mature trees older than 200 years, juvenile trees 5-30 years old, and embryos. Trees were genotyped at 10 microsatellite loci. Overall genetic diversity levels of eastern white pine in Maine were extremely high, with an average observed heterozygosity of 0.762. Genetic differentiation was minimal among and between all three age groups, although an excess of heterozygotes was shown in the mature and juvenile groups that was not reflected in the embryo group, which actually had a slight heterozygote deficiency. Allele frequencies did not differ significantly between age groups, but did reveal more rare and low frequency alleles in the embryo groups than in the mature group. Overall, low frequency alleles comprise the largest portion of alleles in the sample population, with no common alleles evident overall. These results suggest that significant genetic degradation has either not occurred for white pine, or that the results of dysgenic selection have not yet emerged. It is clear, however, that selective harvesting could result in a loss of low frequency alleles, which are a primary reserve of evolutionary potential in a species. Implications of these studies affect industrial forestry, regional economics, and ecological concerns for the northeast. Long-term diameter-limit harvesting can lead to a degradation of residual phenotypes, and an overall decrease in stand quality. Potentially, a loss of low frequency, locally adapted alleles could result in a decrease of allelic richness and degradation of the regidnal genetic resource. Decreased genetic variation can lead to seriously limited evolutionary potential of species and ecosystems, particularly in rapidly changing environments. Based on these findings, I recommend a reassessment of any harvesting prescription that includes fixed diameter-limit removals, particularly for species that have low natural genetic diversity levels or a limited natural range, such as red spruce. Maintenance of a healthy genetic reserve can avoid effects of dysgenic harvesting.

Measuring College Student Satisfaction: A Multi-Year Study of the Factors Leading to Persistence

Using Tinto's (1987) social integration theory as a framework, this study measured student satisfaction in six transformative areas: educational experience, skills development, faculty interaction, personal growth, sense of community, and overall expectations. Emerging as a strategic planning process priority, this project sought to identify those areas where students succeeded or were at risk. Employing a three-phase mixed methods approach, this descriptive, longitudinal study was conducted from 1990-2004 at a highly selective specialized college and assisted college administrators in developing or modifying programs that would enhance student satisfaction to ensure degree completion.

Near infra-red-activatable nanocarriers for selective cancer diagnosis and treatment

Standard treatment strategies for cancer patients include surgery, radiation therapy, and chemotherapy. Although these strategies have been proven effective, they also have associated limitations. An attractive and innovative approach that can be used alone or in combination with the above modalities is based on the systemic or topical administration of a nanomaterial-based photoactive compound. Interaction with light in the near infrared (NIR) region results in either emission of fluorescence, which can be used for photodetection, or absorption of light which results in phototherapy. Nanomaterials have the advantage of providing multi-functional and unique properties in a single device that cannot be readily acquired with conventional small molecular weight compounds. ^ In this study, three different novel nanocarrier systems were designed and evaluated in mediating photodetection and phototherapy in the NIR. The first compound synthesized was a dual-labeled magnetic resonance/optical imaging agent for sentinel lymph node mapping and biopsy. This dual-labeled agent combines the high resolution of magnetic resonance imaging with the highly sensitive detection of optical imaging. The second imaging agent was an activatable optical imaging agent used to monitor cathepsin B activity in vivo and to probe the degradation of poly(L-glutamic acid). This polymeric nanocarrier offers highly sensitive technique for the detection of enzymatic activity, with is not yet possible with small molecular weight compounds. The third agent was a C225-conjugated hollow nanoshell that is targeted to epidermal growth factor receptors. This targeting agent has been demonstrated to mediate photothermal therapy both in vitro and in vivo. ^ These nanocarrier systems are an invaluable tool for the detection of cancer and many other diseases. With improved targeted delivery of these agents, the ability to diagnose diseases will become more sensitive and more specific. Finally, when designed properly, these agents would allow concurrent diagnosis and treatment of patients of various diseases. ^

Roles of insulin-like growth factor binding protein-3 in gastrointestinal stromal tumors

Imatinib mesylate, a selective inhibitor of KIT, PDGFR, and Abl kinases, has shown significant success as a therapy for patients with advanced gastrointestinal stromal tumors (GISTs). However, the underlying mechanisms of imatinib-induced cytotoxicity are not well understood. Using gene expression profiling and real-time PCR for target validation, we identified insulin-like growth factor binding protein-3 (IGFBP3) to be to be up-regulated after imatinib treatment in imatinib-sensitive GISTs. IGFBP3 is a multifunctional protein that regulates cell proliferation and survival and mediates the effects of a variety of anti-cancer agents through IGF-dependent and IGF-independent mechanisms. Therefore, we hypothesized that IGFBP3 mediates GIST cell response to imatinib. To test this hypothesis, we manipulated IGFBP3 protein levels in two KIT mutant, imatinib-sensitive GIST cell lines and assessed the resultant changes in cell viability, survival, and imatinib sensitivity. In GIST882 cells, endogenous IGFBP3 was required for cell viability. However, inhibiting imatinib-induced IGFBP3 up-regulation by RNA interference or neutralization resulted in reduced drug sensitivity, suggesting that IGFBP3 sensitizes GIST882 cells to imatinib. GIST-T1 cells, on the other hand, had no detectable levels of endogenous IGFBP3, nor did imatinib induce IGFBP3 up-regulation, in contrast to our previous findings. IGFBP3 overexpression in GIST-T1 cells reduced viability but did not induce cell death; rather, the cells became polyploid through a mechanism that may involve attenuated Cdc20 expression and securin degradation. Moreover, IGFBP3 overexpression resulted in a loss of KIT activation and decreased levels of mature KIT. Consistent with this, GIST-T1 cells overexpressing IGFBP3 were less sensitive to imatinib. Furthermore, as neither GIST882 cells nor GIST-T1 cells expressed detectable levels of IGF-1R, IGFBP3 is likely not exerting its effects by modulating IGF signaling through IGF-1R or IR/IGF-1R hybrid receptors in these cell lines. Collectively, these findings demonstrate that IGFBP3 has cell-dependent effects and would, therefore, not be an ideal marker for identifying imatinib response in GISTs. Nevertheless, our results provide preliminary evidence that IGFBP3 may have some therapeutic benefits in GISTs. ^

CHARACTERIZATION OF SELECTIVE INHIBITION OF ADENYLYL CYCLASE ACTIVITY BY SMALL MOLECULE INHIBITOR NKY80

The nine membrane-bound isoforms of adenylyl cyclase (AC), via synthesis of the signaling molecule cyclic AMP (cAMP), are involved in many isoform specific physiological functions. Decreasing AC5 activity has been shown to have potential therapeutic benefit, including reduced stress on the heart, pain relief, and attenuation of morphine dependence and withdrawal behaviors. However, AC structure is well conserved, and there are currently no isoform selective AC inhibitors in clinical use. P-site inhibitors inhibit AC directly at the catalytic site, but with an uncompetitive or noncompetitive mechanism. Due to this mechanism and nanomolar potency in cell-free systems, attempts at ligand-based drug design of novel AC inhibitors frequently use P-site inhibitors as a starting template. One small molecule inhibitor designed through this process, NKY80, is described as an AC5 selective inhibitor with low micromolar potency in vitro. P-site inhibitors reveal important ligand binding “pockets” in the AC catalytic site, but specific interactions that give NKY80 selectivity are unclear. Identifying and characterizing unique interactions between NKY80 and AC isoforms would significantly aid the development of isoform selective AC inhibitors. I hypothesized that NKY80’s selective inhibition is conferred by AC isoform specific interactions with the compound within the catalytic site. A structure-based virtual screen of the AC catalytic site was used to identify novel small molecule AC inhibitors. Identified novel inhibitors are isoform selective, supporting the catalytic site as a region capable of more potent isoform selective inhibition. Although NKY80 is touted commercially as an AC5 selective inhibitor, its characterization suggests strong inhibition of both AC5 and the closely related AC6. NKY80 was also virtually docked to AC to determine how NKY80 binds to the catalytic site. My results show a difference between NKY80 binding and the conformation of classic P-site inhibitors. The selectivity and notable differences in NKY80 binding to the AC catalytic site suggest a catalytic subregion more flexible in AC5 and AC6 that can be targeted by selective small molecule inhibitors.

Selective mortality associated with variation in CO2 tolerance in a marine fish

Predicted future CO2 levels can affect reproduction, growth, and behaviour of many marine organisms. However, the capacity of species to adapt to predicted changes in ocean chemistry is largely unknown. We used a unique field-based experiment to test for differential survival associated with variation in CO2 tolerance in a wild population of coral-reef fishes. Juvenile damselfish exhibited variation in their response to elevated (700 µatm) CO2 when tested in the laboratory and this influenced their behaviour and risk of mortality in the wild. Individuals that were sensitive to elevated CO2 were more active and move further from shelter in natural coral reef habitat and, as a result, mortality from predation was significantly higher compared with individuals from the same treatment that were tolerant of elevated CO2. If individual variation in CO2 tolerance is heritable, this selection of phenotypes tolerant to elevated CO2 could potentially help mitigate the effects of ocean acidification.

Data base on pelagic ciliates grazing and growth rate as a function of size, prey size and type compiled from the literature

Microzooplankton (the 20 to 200 µm size class of zooplankton) is recognised as an important part of marine pelagic ecosystems. In terms of biomass and abundance pelagic ciliates are one of the important groups of organism in microzooplankton. However, their rates - grazing and growth - , feeding behaviour and prey preferences are poorly known and understood. A set of data was assembled in order to derive a better understanding of pelagic ciliates rates, in response to parameters such as prey concentration, prey type (size and species), temperature and their own size. With these objectives, literature was searched for laboratory experiments with information on one or more of these parameters effect studied. The criteria for selection and inclusion in the database included: (i) controlled laboratory experiment with a known ciliates feeding on a known prey; (ii) presence of ancillary information about experimental conditions, used organisms - cell volume, cell dimensions, and carbon content. Rates and ancillary information were measured in units that meet the experimenter need, creating a need to harmonize the data units after collection. In addition different units can link to different mechanisms (carbon to nutritive quality of the prey, volume to size limits). As a result, grazing rates are thus available as pg C/(ciliate*h), µm**3/(ciliate*h) and prey cell/(ciliate*h); clearance rate was calculated if not given and growth rate is expressed as the growth rate per day.

InN/GaN heterojunction electrical behavior

Indium nitride (InN) has been the subject of intense research in recent years. Some of its most attractive features are its excellent transport properties such as its small band edge electron effective mass, high electron mobilities and peak drift velocities, and high frequency transient drift velocity oscillations [1]. These suggest enormous potential applications for InN in high frequency electronic devices. But to date the high unintentional bulk electron concentration (n~1018 cm-3) of undoped InN samples and the surface electron accumulation layer make it a hard task to create a reliable metalsemiconductor Schottky barrier. Some attempts have been made to overcome this problem by means of material oxidation [2] or deposition of insulators [3]. In this work we present a way to obtain an electrical rectification behaviour by means of heterojunction growth. Due to the big band gap differences among nitride semiconductors, it’s possible to create a structure with high band offsets. In InN/GaN heterojunctions, depending on the GaN doping, the magnitude of conduction and valence band offset are critical parameters which allow distinguishing among different electrical behaviours. The earliest estimate of the valence band offset at an InN–GaN heterojunction in a wurtzite structure was measured to be ~0.85 eV [4], while the Schottky barrier heights were determined to be ~ 1,4 eV [5].We grew In-face InN layer with varying thickness (between 150 nm and 1 mm) by plasma assisted molecular beam epitaxy (PA-MBE) on GaNntemplates (GaN/Al2O3), with temperatures ranging between 300°C and 450°C. The different doping in GaN template (Si doping, Fe doping and Mg doping) results in differences in band alignments of the two semiconductors changing electrical barriers for carriers and consequently electrical conduction behaviour. The processing of the devices includes metallization of the ohmic contacts on InN and GaN, for which we used Ti/Al/Ni/Au. Whereas an ohmic contact on InN is straightforward, the main issue was the fabrication of the contact on GaN due to the very low decomposition temperature of InN. A standard ohmic contact on GaN is generally obtained by high temperature rapid thermal annealing (RTA), typically done between 500ºC and 900ºC[6]. In this case, the limitation due to the presence of In-face InN imposes an upper limit on the temperature for the thermal annealing process and ohmic contact formation of about 450°C. We will present results on the morphology of the InN layers by X-Ray diffraction and SEM, and electrical measurements, in particular current-voltage and capacitance-voltage characteristics.

Modulation-mode assignment in SVD-assisted multiuser MIMO-OFDM systems

In order to comply with the demand on increasing available data rates in particular in wireless technologies, systems with multiple transmit and receive antennas, also called MIMO (multiple-input multiple-output) systems, have become indispensable for future generations of wireless systems. Due to the strongly increasing demand in high-data rate transmission systems, frequency non-selective MIMO links have reached a state of maturity and frequency selective MIMO links are in the focus of interest. In this field, the combination of MIMO transmission and OFDM (orthogonal frequency division multiplexing) can be considered as an essential part of fulfilling the requirements of future generations of wireless systems. However, single-user scenarios have reached a state of maturity. By contrast multiple users’ scenarios require substantial further research, where in comparison to ZF (zero-forcing) multiuser transmission techniques, the individual user’s channel characteristics are taken into consideration in this contribution. The performed joint optimization of the number of activated MIMO layers and the number of transmitted bits per subcarrier along with the appropriate allocation of the transmit power shows that not necessarily all user-specific MIMO layers per subcarrier have to be activated in order to minimize the overall BER under the constraint of a given fixed data throughput.