A Cyanobacteria Enriched Layer of Shark Bay Stromatolites Reveals a New Acaryochloris Strain Living in Near Infrared Light.

The genus Acaryochloris is unique among phototrophic organisms due to the dominance of chlorophyll d in its photosynthetic reaction centres and light-harvesting proteins. This allows Acaryochloris to capture light energy for photosynthesis over an extended spectrum of up to ~760 nm in the near infra-red (NIR) spectrum. Acaryochloris sp. has been reported in a variety of ecological niches, ranging from polar to tropical shallow aquatic sites. Here, we report a new Acarychloris strain isolated from an NIR-enriched stratified microbial layer 4-6 mm under the surface of stromatolite mats located in the Hamelin Pool of Shark Bay, Western Australia. Pigment analysis by spectrometry/fluorometry, flow cytometry and spectral confocal microscopy identifies unique patterns in pigment content that likely reflect niche adaption. For example, unlike the original A. marina species (type strain MBIC11017), this new strain, Acarychloris LARK001, shows little change in the chlorophyll d/a ratio in response to changes in light wavelength, displays a different Fv/Fm response and lacks detectable levels of phycocyanin. Indeed, 16S rRNA analysis supports the identity of the A. marina LARK001 strain as close to but distinct from from the A. marina HICR111A strain first isolated from Heron Island and previously found on the Great Barrier Reef under coral rubble on the reef flat. Taken together, A. marina LARK001 is a new cyanobacterial strain adapted to the stromatolite mats in Shark Bay

Systemic Treatments for Mesothelioma: Standard and Novel

Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes—epithelial, sarcomatoid, and biphasic—that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival. The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed

Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours

The aim of this open-label phase 1b study was to assess the safety and pharmacokinetics of motesanib in combination with gemcitabine in patients with advanced solid tumours. Eligible patients with histologically or cytologically documented solid tumours or lymphoma were enroled in three sequential, dose-escalating cohorts to receive motesanib 50 mg once daily (QD), 75 mg two times daily (BID), or 125 mg QD in combination with gemcitabine (1000 mg m−2). The primary end point was the incidence of dose-limiting toxicities (DLTs). Twenty-six patients were enroled and received motesanib and gemcitabine. No DLTs occurred. The 75 mg BID cohort was discontinued early; therefore, 125 mg QD was the maximum target dose. Sixteen patients (62%) experienced motesanib-related adverse events, most commonly lethargy (n=6), diarrhoea (n=4), fatigue (n=3), headache (n=3), and nausea (n=3). The pharmacokinetics of motesanib and of gemcitabine were not markedly affected after combination therapy. The objective response rate was 4% (1 of 26), and 27% (7 of 26) of patients achieved stable disease. In conclusion, treatment with motesanib plus gemcitabine was well tolerated, with adverse event and pharmacokinetic profiles similar to that observed in monotherapy studies

The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascular endothelial growth factor (VEGF) is a well-characterized mediator of tumor angiogenesis that functions primarily by binding and activating VEGF receptor 2 (VEGFR2). In this study, we evaluate the use of CT-322, a novel biologic (Adnectin). This small protein is based on a human fibronectin domain and has beneficial properties in that it is fully human, stable, and is produced in bacteria. CT-322 binds to and inhibits activation of VEGFR2.</p> <p>Methods</p> <p>The efficacy of CT-322 was evaluated <it>in vivo </it>using two orthotopic pancreatic tumor models. The first model was a human tumor xenograft where MiaPaCa-2 cells were injected into the tail of the pancreas of nude mice. The second model was a syngeneic tumor using Pan02 cells injected into pancreas of C57BL/6J mice. In both models, therapy was initiated once primary tumors were established. Mice bearing MiaPaCa-2 tumors were treated with vehicle or CT-322 alone. Gemcitabine alone or in combination with CT-322 was added to the treatment regimen of mice bearing Pan02 tumors. Therapy was given twice a week for six weeks, after which the animals were sacrificed and evaluated (grossly and histologically) for primary and metastatic tumor burden. Primary tumors were also evaluated by immunohistochemistry for the level of apoptosis (TUNEL), microvessel density (MECA-32), and VEGF-activated blood vessels (Gv39M).</p> <p>Results</p> <p>Treatment with CT-322 was effective at preventing pancreatic tumor growth and metastasis in orthotopic xenograft and syngeneic models of pancreatic cancer. Additionally, CT-322 treatment increased apoptosis, reduced microvessel density and reduced the number of VEGF-activated blood vessels in tumors. Finally, CT-322, in combination with gemcitabine was safe and effective at controlling the growth of syngeneic pancreatic tumors in immunocompetent mice.</p> <p>Conclusion</p> <p>We conclude that CT-322 is an effective anti-VEGFR2 agent and that further investigation of CT-322 for the treatment of pancreatic cancer is warranted.</p

A qualitative and quantitative model for climate-driven lake formation on carbonate platforms based on examples from the Bahamian archipelago

Lakes on carbonate platform islands such as the Bahamas display wide variability in morphometry, chemistry, and fauna. These parameters are ultimately driven by climate, sea level, and carbonate accumulation and dissolution. The authors propose a model that integrates climatological, geomorphological, and stratigraphic frameworks to understand processes of carbonate-hosted lake formation and limnological characteristics in modern day environments, with applications to carbonate lake sedimentary records. Fifty-two lakes from San Salvador Island and Eleuthera, Bahamas, were examined for water chemistry, basin morphology, conduit development, conductivity, and major ions. Using non-metric, multi-dimensional scaling ordination methods, the authors derived a model dividing lakes into either constructional or destructional formational modes. Constructional lakes were further divided into pre-highstand and highstand types based on whether their formation occurred during a marine regressive or transgressive phase. Destructional lakes are created continually by dissolution of bedrock at fresh/saline water interfaces and their formation is therefore related to changing climate and sea level. This model shows that lake formation is influenced by the hydrologic balance associated with climatic conditions that drives karst dissolution as well as the deposition of aeolian dune ridges that isolate basins due to sea-level fluctuations. It allows for testing and examining the climatic and hydrologic regime as related to carbonate accumulation and dissolution through time, and for an improved understanding of lake sensitivity and response to climate as preserved in the lacustrine sedimentary record

Understanding Palliative Cancer Chemotherapy: About Shared Decisions and Shared Trajectories

Most models of patient-physician communication take decision-making as a central concept. However, we found that often the treatment course of metastatic cancer patients is not easy to describe in straightforward terms used in decision-making models but is instead frequently more erratic. Our aim was to analyse these processes as trajectories. We used a longitudinal case study of 13 patients with metastatic colorectal and pancreatic cancer for whom palliative chemotherapy was a treatment option, and analysed 65 semi-structured interviews. We analysed three characteristics of the treatment course that contributed to the ‘erraticness’ of the course: (1) The treatment (with or without chemotherapy) contained many options; (2) these options were not stable entities to be decided upon, but changed identity over the course of treatment, and (3) contrary to the closure (option X means no option Y, Z, etc.) a decision implies, the treatment course was a continuous process in which options instead remained open. When the treatment course is characterised by these many and changeable options that do not result in closure, the shared decision-making model should take these into account. More attention needs to be paid to the erratic character of the process in which the doctor has to provide continuous information that is related to the changing situation of the patient; also, flexibility in dealing with protocols is warranted, as is vigilance about the overall direction of the process

Does clinical method mask significant VTE-related mortality and morbidity in malignant disease?

After more than 150 years of a recognised link between cancer and vascular thromboembolic events (VTE), and despite a greatly improved understanding of its pathophysiology, epidemiology and treatment, the management of patients with cancer and VTE is still limited. Limitations can be related to the thromboembolism itself, the underlying cancer, or to the management process. There is significant literature that deals with the first two, but very little regarding the systems we use, or how the inadequacies in documentation, identification and classification of VTE affect the cancer patients themselves. This review aims to raise awareness of this neglected area and stimulate research that may lead to improvements in patient care