Increasing the Efficacy of Oncolytic Adenovirus Vectors

Oncolytic adenovirus (Ad) vectors present a new modality to treat cancer. These vectors attack tumors via replicating in and killing cancer cells. Upon completion of the vector replication cycle, the infected tumor cell lyses and releases progeny virions that are capable of infecting neighboring tumor cells. Repeated cycles of vector replication and cell lysis can destroy the tumor. Numerous Ad vectors have been generated and tested, some of them reaching human clinical trials. In 2005, the first oncolytic Ad was approved for the treatment of head-and-neck cancer by the Chinese FDA. Oncolytic Ads have been proven to be safe, with no serious adverse effects reported even when high doses of the vector were injected intravenously. The vectors demonstrated modest anti-tumor effect when applied as a single agent; their efficacy improved when they were combined with another modality. The efficacy of oncolytic Ads can be improved using various approaches, including vector design, delivery techniques, and ancillary treatment, which will be discussed in this review

Evaporites and the salinity of the ocean during the Phanerozoic: Implications for climate, ocean circulation and life

A compilation of data on volumes and masses of evaporite deposits is used as the basis for reconstruction of the salinity of the ocean in the past. Chloride is tracked as the only ion essentially restricted to the ocean, and past salinities are calculated from reconstructed chlorine content of the ocean. Models for ocean salinity through the Phanerozoic are developed using maximal and minimal estimates of the volumes of existing evaporite deposits, and using constant and declining volumes of ocean water through the Phanerozoic. We conclude that there have been significant changes in the mean salinity of the ocean accompanying a general decline throughout the Phanerozoic. The greatest changes are related to major extractions of salt into the young ocean basins which developed during the Mesozoic as Pangaea broke apart. Unfortunately, the sizes of these salt deposits are also the least well known. The last major extractions of salt from the ocean occurred during the Miocene, shortly after the large scale extraction of water from the ocean to form the ice cap of Antarctica. However, these two modifications of the masses of H2O and salt in the ocean followed in sequence and did not cancel each other out. Accordingly, salinities during the Early Miocene were between 37‰ and 39‰. The Mesozoic was a time of generally declining salinity associated with the deep sea salt extractions of the North Atlantic and Gulf of Mexico (Middle to Late Jurassic) and South Atlantic (Early Cretaceous). The earliest of the major extractions of the Phanerozoic occurred during the Permian. There were few large extractions of salt during the earlier Palaeozoic. The models suggest that this was a time of relatively stable but slowly increasing salinities ranging through the upper 40‰'s into the lower 50‰'s. Higher salinities for the world ocean have profound consequences for the thermohaline circulation of the ocean in the past. In the modern ocean, with an average salinity of about 34.7‰, the density of water is only very slightly affected by cooling as it approaches the freezing point. Consequently, salinization through sea-ice formation or evaporation is usually required to make water dense enough to sink into the ocean interior. At salinities above about 40‰ water continues to become more dense as it approaches the freezing point, and salinization is not required. The energy-consuming phase changes involved in sea-ice formation and evaporation would not be required for vertical circulation in the ocean. The hypothesized major declines in salinity correspond closely to the evolution of both planktonic foraminifera and calcareous nannoplankton. Both groups were restricted to shelf regions in the Jurassic and early Cretaceous, but spread into the open ocean in the mid-Cretaceous. Their availability to inhabit the open ocean may be directly related to the decline in salinity. The Permian extraction may have created stress for marine organisms and may have been a factor contributing to the end-Permian extinction. The modeling also suggests that there was a major salinity decline from the Late Precambrian to the Cambrian, and it is tempting to speculate that this may have been a factor in the Cambrian explosion of life

Eine verbesserte Anpassung von Südamerika an Afrika : Ergebnisse einer Rekonstruktion der ursprünglichen Form von Rift-Becken

A method for palinspastic reconstruction of rift basins is described here. It is based on the assumption of isostatic equilibrium and calculated from the present topography and sediment thickness in a rift basin. Passive continental margins along eastern South America and western Africa were moved landward from the ocean-continent boundary approximately 100 km. When South America is rotated to Africa, a tight fit with Africa results along the northern and central margins of South America. The southern part of South America was rotated to fit against Africa based on the palinspastic reconstruction of the San Jorge, Colorado and Salado marginal rift basins in Argentina. The method could also be applied to passive margins to calculate the total amount of crustal stretching that occurred during continental extension and rifting. The pre-rift condition of passive margins could then be calculated for more accurate initial fits between conjugate passive margins

The role of salinity in circulation of the Cretaceous ocean

The density of seawater is a complex function of temperature, salinity, and pressure. Because of the non-linearity of the equation of state of seawater, the densities of sea waters having the same temperature and the same salinity differences (with respect to the mean salinity of the ocean) will vary with the mean salinity of the ocean. Although this strange property of seawater is evident in a plot of the equation of state, it has never been considered in trying to reconstruct ancient ocean circulation. These differences in the density field may have caused the ocean to respond differently to atmospheric forcing in the past. The different response may hold the key to understanding "ocean anoxic events" and episodes of large-scale burial of organic carbon and production of petroleum source rocks

Endoscopic Endonasal Transclival Approach versus Dual Transorbital Port Technique for Clip Application to the Posterior Circulation: A Cadaveric Anatomical and Cerebral Circulation Simulation Study

Purpose  Simulation training offers a useful opportunity to appreciate vascular anatomy and develop the technical expertise required to clip intracranial aneurysms of the posterior circulation. Materials and Methods  In cadavers, a comparison was made between the endoscopic transclival approach (ETA) alone and a combined multiportal approach using the ETA and a transorbital precaruncular approach (TOPA) to evaluate degrees of freedom, angles of visualization, and ergonomics of aneurysm clip application to the posterior circulation depending on basilar apex position relative to the posterior clinoids. Results  ETA alone provided improved access to the posterior circulation when the basilar apex was high riding compared with the posterior clinoids. ETA + TOPA provided a significantly improved functional working area for instruments and visualization of the posterior circulation for a midlevel basilar apex. A single-shaft clip applier provided improved visualization and space for instruments. Proximal and distal vascular control and feasibility of aneurysmal clipping were demonstrated. Conclusions  TOPA is a medial orbital approach to the central skull base; a transorbital neuroendoscopic surgery approach. This anatomical simulation provides surgical teams an alternative to the ETA approach alone to address posterior circulation aneurysms, and a means to preoperatively prepare for intraoperative anatomical and surgical instrumentation challenges

Endoscopic Management of Cavernous Carotid Surgical Complications: Evaluation of a Simulated Perfusion Model

Objective—Endoscopic surgical treatment of pituitary tumors, lateral invading tumors, or aneurysms requires surgeons to operate adjacent to the cavernous sinus. During these endoscopic endonasal procedures, the carotid artery is vulnerable to surgical injury at its genu. The objective of this simulation model was to evaluate trainees regarding management of a potentially lifethreatening vascular injury. Methods—Cadaveric heads were prepared in accordance with the Oregon Health & Science University body donation program. An endoscopic endonasal approach was used, and a perfusion pump with a catheter was placed in the ipsilateral common carotid artery at its origin in the neck. Learners used a muscle graft to establish vascular control and were evaluated over 3 training sessions. Simulation assessment, blood loss during sessions, and performance metric data were collected for learners. Results—Vascular control was obtained at a mean arterial pressure of 65 mm Hg using a muscle graft correctly positioned at the arteriotomy site. Learners improved over the course of training, with senior residents (n = 4) performing better across all simulation categories (situation awareness, decision making, communications and teamwork, and leadership); the largest mean difference was in communication and teamwork. Additionally, learner performance concerning blood loss improved between sessions (t = 3.667, P \u3c 0.01). Conclusions—In this pilot endoscopic endonasal simulation study, we successfully demonstrate a vascular complication perfusion model. Learners were able to gain direct applicable expertise in endoscopic endonasal techniques, instrumentation use, and teamwork required to optimize the technique. Learners gained skills of vascular complication management that transcend this model

A simpler plate-tectonic history for the Caribbean

Evolution of the Caribbean Plate can be modeled by motions about six successive rotation poles. Opening of Cayman Trough has occurred since 49.5 Ma through westward motion of the Caribbean Plate, eastern Greater Antilles and Chortis Block. Before 49.5 Ma, the eastern Greater-Antilles were west of Cuba, and the southeastern margins of Yucatan and the Nicaragua Rise (Chortis) were aligned. From 67.5 to 49.5 Ma the Caribbean Plate rotated clockwise, opening the Yucatan Basin. From 100 Ma to 67.5 Ma, the Caribbean Plate, with Cuba attached, moved along the southeastern margin of Yucatan-Chortis. At 130 Ma it was attached to northwestern South America

Preliminary reconstruction of the salinity of the ocean in the Cenozoic and Mesozoic

The salinity of the ocean in the past can be reconstructed by using knowledge of the existing evaporite deposits on land and in the offshore. We assume that evaporites on land follow the same rates of sedimentary cycling as other sedimentary materials to determine the flux of salts to the sea. However, the salt can be stored in the ocean until conditions appropriate for deposition occur. We assume that salt removals into the deep offshore, continental margin and marginal sea deposits, are not yet part of the recycling system. We conclude that during most of the Cenozoic salinities have been higher than they are today. Each of the major salt extractions into the offshore has caused a rapid decrease of oceanic salinity by a few per mille. In the Early Cretaceous mean ocean salinities ranged between 38 and 42‰, and the Jurassic and Triassic they were between 43 and 53‰