Summary
Background
Expression of P2X7, an ATP‐gated calcium channel, increases cancer cell proliferation and invasiveness. A variant of P2X7 (termed nfP2X7), in which a normally hidden epitope (E200) ...is exposed for antibody binding, is observed in a variety of different cancers.
Objectives
To investigate the safety, tolerability and pharmacokinetics and assess indicative efficacy of a novel antibody ointment as a therapeutic for basal cell carcinoma (BCC).
Methods
An open‐label, phase I clinical trial was undertaken at three dermatology clinics to evaluate the safety and tolerability of topical administration of an ointment containing 10% sheep polyclonal anti‐nfP2X7 antibodies (BIL010t) to primary BCC lesions twice daily for 28 days. Twenty‐one patients with primary BCC lesions at least 0·5 cm2 in area and less than 2·0 cm in diameter were enrolled. The primary end points were safety, tolerability and pharmacokinetics. Change in lesion size after treatment was determined and histology was performed on pretreatment and end‐of‐treatment (EOT) biopsies.
Results
Compliance was very high, with treatment being well tolerated. The most common adverse events were treatment site erythema, pruritus, dryness and pain. There was no evidence of systemic penetration of the sheep antibody. Lesions were measured prior to and after 28 days of treatment, with 65% of patients showing a reduction in lesion area, 20% showing no change and 15% showing an increase. Histopathology of post‐treatment excision of lesion sites showed eight patients with stable disease, nine with partial response and three with complete response.
Conclusions
Antibodies against nfP2X7 (BIL010t) provide a novel, safe and well‐tolerated treatment for BCC.
What's already known about this topic?
nfP2X7 is a form of the ATP‐gated P2X7 receptor in which the E200 epitope is exposed for antibody binding.
nfP2X7 is highly expressed in several cancers, including melanoma.
What does this study add?
A mouse model of melanoma is used to demonstrate that topical application of anti‐nfP2X7 antibodies is effective in reducing lesion size.
Expression of nfP2X7 in basal cell carcinoma is demonstrated by immunohistochemistry.
A phase I clinical trial demonstrates that topical application of an ointment containing anti‐nfP2X7 antibodies to basal cell carcinomas is well tolerated and provides early indications of efficacy.
Linked Comment: Stoff. Br J Dermatol 2017; 177:12–13
Plain language summary available online
The inherent and diverse capacity of dietary fibres, nondigestible oligosaccharides (NDOs) and prebiotics to modify the gut microbiota and markedly influence health status of the host has attracted ...rising interest. Research and collective initiatives to determine the composition and diversity of the human gut microbiota have increased over the past decade due to great advances in high-throughput technologies, particularly the 16S ribosomal RNA (rRNA) sequencing. Here we reviewed the application of 16S rRNA-based molecular technologies, both community wide (sequencing and phylogenetic microarrays) and targeted methodologies (quantitative PCR, fluorescent in situ hybridisation) to study the effect of chicory inulin-type fructans, NDOs and specific added fibres, such as resistant starches, on the human intestinal microbiota. Overall, such technologies facilitated the monitoring of microbiota shifts due to prebiotic/fibre consumption, though there are limited community-wide sequencing studies so far. Molecular studies confirmed the selective bifidogenic effect of fructans and galactooligosaccharides (GOS) in human intervention studies. Fructans only occasionally decreased relative abundance of Bacteroidetes or stimulated other groups. The sequencing studies for various resistant starches, polydextrose and beta-glucan showed broader effects with more and different types of gut microbial species being enhanced, often including phylotypes of Ruminococcaceae. There was substantial variation in terms of magnitude of response and in individual responses to a specific fibre or NDO which may be due to numerous factors, such as initial presence and relative abundance of a microbial type, diet, genetics of the host, and intervention parameters, such as intervention duration and fibre dose. The field will clearly benefit from a more systematic approach that will support defining the impact of prebiotics and fibres on the gut microbiome, identify biomarkers that link gut microbes to health, and address the personalised response of an individual’s microbiota to prebiotics and dietary fibres.
Hypoxia has become a world-wide phenomenon in the global coastal ocean and causes a deterioration of the structure and function of ecosystems. Based on the collective contributions of members of SCOR ...Working Group #128, the present study provides an overview of the major aspects of coastal hypoxia in different biogeochemical provinces, including estuaries, coastal waters, upwelling areas, fjords and semi-enclosed basins, with various external forcings, ecosystem responses, feedbacks and potential impact on the sustainability of the fishery and economics. The obvious external forcings include freshwater runoff and other factors contributing to stratification, organic matter and nutrient loadings, as well as exchange between coastal and open ocean water masses. Their different interactions set up mechanisms that drive the system towards hypoxia. Coastal systems also vary in their relative susceptibility to hypoxia depending on their physical and geographic settings. It is understood that coastal hypoxia has a profound impact on the sustainability of ecosystems, which can be seen, for example, by the change in the food-web structure and system function; other influences include compression and loss of habitat, as well as changes in organism life cycles and reproduction. In most cases, the ecosystem responds to the low dissolved oxygen in non-linear ways with pronounced feedbacks to other compartments of the Earth System, including those that affect human society. Our knowledge and previous experiences illustrate that there is a need to develop new observational tools and models to support integrated research of biogeochemical dynamics and ecosystem behavior that will improve confidence in remediation management strategies for coastal hypoxia.
We present a demonstration of delensing the observed cosmic microwave background (CMB) B-mode polarization anisotropy. This process of reducing the gravitational-lensing-generated B-mode component ...will become increasingly important for improving searches for the B modes produced by primordial gravitational waves. In this work, we delens B-mode maps constructed from multi-frequency SPTpol observations of a 90 deg2 patch of sky by subtracting a B-mode template constructed from two inputs: SPTpol E-mode maps and a lensing potential map estimated from the Herschel 500 m map of the cosmic infrared background. We find that our delensing procedure reduces the measured B-mode power spectrum by % in the multipole range this is shown to be consistent with expectations from simulations and to be robust against systematics. The null hypothesis of no delensing is rejected at . Furthermore, we build and use a suite of realistic simulations to study the general properties of the delensing process and find that the delensing efficiency achieved in this work is limited primarily by the noise in the lensing potential map. We demonstrate the importance of including realistic experimental non-idealities in the delensing forecasts used to inform instrument and survey-strategy planning of upcoming lower-noise experiments, such as CMB-S4.
The topoisomerase I (Top 1) poison irinotecan is an important component of the modern treatment of colorectal cancer. By stabilising Top 1-DNA complexes, irinotecan generates Top 1-linked DNA ...single-strand breaks that can evolve into double-strand breaks and ultimately cause cell death. However, cancer cells may overcome cell killing by releasing the stalled topoisomerase from DNA termini, thereby reducing the efficacy of Top 1 poisons in clinics. Thus, understanding the DNA repair mechanisms involved in the repair of Top 1-mediated DNA damage provides a useful tool to identify potential biomarkers that predict response to this class of chemotherapy. Furthermore, targeting these pathways could enhance the therapeutic benefits of Top 1 poisons. In this review, we describe the cellular mechanisms and consequences of targeting Top 1 activity in cells. We summarise preclinical data and discuss the potential clinical utility of small-molecule inhibitors of the key proteins.
With this document, we provide a standard for PET/(diagnostic) CT imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional ...innervation (4Is). This standard should be applied in clinical practice and integrated in clinical (multicenter) trials for optimal procedural standardization. A major focus is put on procedures using
18
FFDG, but 4Is PET radiopharmaceuticals beyond
18
FFDG are also described in this document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicenter trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Finally, PET/MR applications in 4Is cardiovascular diseases are also briefly described. Diagnosis and management of 4Is-related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/MR, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications.
Background
Since the very early days of surgical practice, surgeons have recognized the importance of considering that intestinal microbes might have a profound influence on recovery from surgical ...diseases such as appendicitis and peritonitis. Although the pathogenesis of surgical diseases such as cholelithiasis, diverticulosis, peptic ulcer disease and cancer have been viewed as disorders of host biology, they are emerging as diseases highly influenced by their surrounding microbiota.
Methods
This is a review of evolving concepts in microbiome sciences across a variety of surgical diseases and disorders, with a focus on disease aetiology and treatment options.
Results
The discovery that peptic ulcer disease and, in some instances, gastric cancer can now be considered as infectious diseases means that to advance surgical practice humans need to be viewed as superorganisms, consisting of both host and microbial genes. Applying this line of reasoning to the ever‐ageing population of patients demands a more complete understanding of the effects of modern‐day stressors on both the host metabolome and microbiome.
Conclusion
Despite major advances in perioperative care, surgeons today are witnessing rising infection‐related complications following elective surgery. Many of these infections are caused by resistant and virulent micro‐organisms that have emerged as a result of human progress, including global travel, antibiotic exposure, crowded urban conditions, and the application of invasive and prolonged medical and surgical treatment. A more complete understanding of the role of the microbiome in surgical disease is warranted to inform the path forward for prevention.
More important than many think
The new SARS-CoV-2 Omicron variant (B.1.1.529) has been recently declared a Variant of Concern due to a series of important mutations in the viral spike protein and especially in the receptor-binding ...domain. While investigations into the spread of this new variant are ongoing, the first cases have been detected in Switzerland. Important questions have been raised: (1) Will the PCR assays commonly used to detect SARS-CoV-2 still work for the Omicron variant? (2) Can specific PCR features, e.g. S-gene dropout, be used to identify potential Omicron samples? In this minireview we provide current knowledge on the Omicron variant and guidance on its PCR validation.
This review considers current Zr alloys and opportunities for advanced zirconium alloys to meet the demands of a structural material in fusion reactors. Zr based materials in the breeder blanket ...offer the potential to increase the tritium breeding ratio above that of Fe, Si and V based materials. Current commercial Zr alloys might be considered as a material in water-cooled breeder blanket designs, due to the similar operating temperature to fission power plants. For breeder blankets designed to operate at higher temperatures, current commercial Zr alloys will not meet the high temperature strength and thermal creep requirements. Hence, Zr alloys with an operational temperature capability beyond that of current commercial fission alloys have been reviewed, specifically: binary Zr alloy systems Zr-Al, Zr-Be, Zr-Cr, Zr-Nb Zr-Ti, Zr-Si, Zr-Sn, Zr-V and Zr-W; as well as higher order Zr alloys Zr-Mo-Ti, Zr-Nb-Ti, Zr-Ti-Al-V and Zr-Mo-Sn. It is concluded that, with further work, higher order Zr alloys could achieve the required high temperature strength, alongside ductility, while maintaining a low thermal neutron cross-section. However, there is limited data and uncertainty regarding the structural performance and microstructural stability of the majority of advanced Zr alloys for temperatures 500–700 °C, at which they would be expected to operate for helium- and liquid metal-cooled breeder blanket designs.
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