The skeleton is the most common site of secondary disease in breast cancer and prostate cancer, with up to 80% of patients with advanced disease developing bone metastases (BM). The proportion is ...also substantial in advanced lung cancer (20%–40%). Because of the high prevalence of cancers of the breast, prostate and lung, these cancers account for more than 80% of cases of metastatic bone disease occurring in solid tumours.
Metastatic bone disease is associated with greatly increased bone resorption by osteoclasts, leading to moderate to severe pain and other skeletal complications, with major impact on quality of life (QoL). Skeletal Related Events (SREs) have been defined as: pathological long bone or vertebral fractures; spinal cord compression; need for radiation for pain relief or to prevent fracture/spinal cord compression, need for surgery to bone and hypercalcaemia. More recently, Symptomatic Skeletal Events (SSEs) have been defined to monitor QoL.
Although there are currently no curative treatments for metastatic bone disease, patients with breast or prostate cancer and BM are now surviving for several years and sometimes longer, and prevention of SREs is the key aim to optimization of QoL. Since their discovery 50 years ago and their introduction more than 30 years ago into the field of metastatic bone disease, a range of oral and intravenous bisphosphonate drugs have made a major contribution to prevention of SREs.
Large trials have clearly demonstrated the clinical value of different bisphosphonate-based drugs (including the oral drugs ibandronate and clodronate and intravenous agents such as zoledronate and pamidronate), in treatment of hypercalcaemia of malignancy and the reduction of SREs and SSEs in a range of cancers. Despite the success of denosumab in reducing osteolysis, bisphosphonates also remain mainstay drugs for treatment of metastatic bone disease. Recognizing the 50th Anniversary of the discovery of bisphosphonates, this review focuses on their continuing value in BM treatment and their future potential, for example in providing a bone-targeting vehicle for cytotoxic drugs.
•Metastasis to the skeleton is a major complication of solid tumours, including breast, prostate, lung and renal cancers.•Bisphosphonates have revolutionized the treatment and clinical outcomes of patients with metastatic bone disease.•Bisphosphonates can prevent/delay onset of skeletal related events (SREs), including hypercalcaemia.•Bisphosphonates improve patient quality of life, including reduction of bone pain.•Current research aims to use the bisphosphonate group to target anti-cancer drugs to bone.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Central compact objects (CCOs) are young neutron stars emitting thermal X-rays with bolometric luminosities
L
X
in the range of 10
32
–10
34
erg s
−1
. Gourgouliatos, Hollerbach, and Igoshev ...recently suggested that peculiar emission properties of CCOs can be explained by tangled magnetic field configurations formed in a stochastic dynamo during the proto–neutron star stage. In this case the magnetic field consists of multiple small-scale components with negligible contribution of global dipolar field. We study numerically three-dimensional magnetothermal evolution of tangled crustal magnetic fields in neutron stars. We find that all configurations produce complicated surface thermal patterns that consist of multiple small hot regions located at significant separations from each other. The configurations with initial magnetic energy of (2.5–10) × 10
47
erg have temperatures of hot regions that reach ≈ 0.2 keV, to be compared with the bulk temperature of ≈ 0.1 keV in our simulations with no cooling. A factor of two in temperature is also seen in observations of CCOs. The hot spots produce periodic modulations in light curve with typical amplitudes of ≤9%–11%. Therefore, the tangled magnetic field configuration can explain thermal emission properties of some CCOs.
The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). ...Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.
We report the realization of an acoustic capacitive microphone formed by graphene/poly(methyl methacrylate) (PMMA). It is the first time that the ultra-large graphene/PMMA membrane suspended fully ...over the cavity has been fabricated by releasing the silicon dioxide sacrificial layer underneath the membrane. The novelty in the fabrication method is that the silicon dioxide layer has been etched by hydrogen fluoride vapor from the back of the partly etched silicon substrate. Using the new process, the ultra-large graphene/PMMA membrane, with a diameter to thickness ratio of 7800, has been suspended over the cavity with a 2 μm air gap. The spacing of 2 μm is the minimum gap over the graphene-based acoustic capacitive microphones which have been reported so far. The static deformation of the suspended graphene/PMMA membrane after silicon dioxide has been etched is estimated to be 270 nm. The aspect ratio of the membrane’s diameter over its static deformation is around 13,000, which shows that the graphene/PMMA membrane with a diameter of a few millimeters can be transferred and suspended over the substrate with relatively small deformation by releasing the sacrificial silicon dioxide layer. The dynamic behavior of the device under electrostatic actuation has been characterized. The acoustic response of the graphene/PMMA capacitive microphone has been measured, and the sensitivity has been observed to be −47.5 dB V (4.22 mV/Pa) ± 10%. The strain in the graphene/PMMA membrane is estimated to be 0.034%.
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IJS, KILJ, NUK, PNG, UL, UM
Abstract Background and aim Little is known about the relationship between neurocognitive performance and functional outcome before the onset of frank psychosis. This longitudinal study aimed to ...investigate neurocognitive predictors of poor functional outcome in a group identified as ultra-high risk (UHR) for psychosis between two and 13 years prior. Method Individuals ( N = 230) identified as UHR for psychosis at the PACE Clinic in Melbourne completed assessment of psychopathology, functioning and neurocognition at baseline and follow-up. The mean length of follow-up was 7.26 years ( SD 3.05). Results Forty-one individuals with the poorest functional outcome were identified. Only 48.8% of this group had transitioned to psychosis. Poor functional outcome was associated with reduced performance at baseline in the specific neurocognitive domains of verbal learning and memory, processing speed and attention, and verbal fluency, but not global cognitive impairment. Reduced performance on a verbal story recall task, in combination with higher negative symptoms at baseline, was the best predictor of later poor outcome. Baseline positive psychotic symptoms and GAF scores were not associated with later poor outcome. Discussion To date, this is the longest follow-up study of an UHR sample. Poor functional outcome was associated with specific neurocognitive decrements, regardless of transition to psychosis. The detection of individuals with poor functioning at follow-up, against a background of previously identified risk factors for psychotic disorder, may yield a valid group in which to study biomarkers and treatment of schizophrenia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Interlocked molecules possess properties and functions that depend upon their intricate connectivity. In addition to the topologically trivial rotaxanes, whose structures may be captured by a planar ...graph, the topologically non-trivial knots and catenanes represent some of chemistry's most challenging synthetic targets because of the three-dimensional assembly necessary for their construction. Here we report the synthesis of a cyclic 3catenane, which consists of three mutually interpenetrating rings, via an unusual synthetic route. Five distinct building blocks self-assemble into a heteroleptic triangular framework composed of two joined Fe(II)3L3 circular helicates. Subcomponent exchange then enables specific points in the framework to be linked together to generate the cyclic 3catenane product. Our method represents an advance both in the intricacy of the metal-templated self-assembly procedure and in the use of selective imine exchange to generate a topologically complex product.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UL, UM, UPUK
Objective
Auditory verbal hallucinations (AVHs) are core features of psychotic illness and remain significant in predicting poor outcome and risk. There has been a wide range of approaches to ...understanding these experiences.
Method
A systematic literature review summarizing different methods of investigation and their results; phenomenology, descriptive psychopathology, psychological, cognitive neurobiology, and neuroimaging.
Results
A number of 764 papers and texts were screened and 113 reviewed. Phenomenological studies are comparably few in number, and psychopathology remains based on concepts defined in the early 20th century. Psychological models focus on voice content and emotional reaction, and suggest a continuum of AVHs from normal experience. Neuropsychological models include AVHs as misattribution of inner speech, whilst functional neuroimaging studies focus on the spontaneous activity and connectivity of auditory networks.
Conclusion
There has been a large growth in research on AVHs in recent decades dominated by neurobiological and neuroimaging studies. Future research should include focus on phenomenological aspects and AVHs change over the course of developing illness. Integration between branches of enquiry is needed, and the risk is that without this, models are proposed and investigated that bear scant relevance to the symptom itself.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Assessing the environmental impact of salmon farms on benthic systems is traditionally undertaken using biotic indices derived from microscopic analyses of macrobenthic infaunal (MI) communities. In ...this study, we tested the applicability of using foraminiferal-specific high-throughput sequencing (HTS) metabarcoding for monitoring these habitats. Sediment samples and physico-chemical data were collected along an enrichment gradient radiating out from three Chinook salmon (Oncorhynchus tshawytscha) farms in New Zealand. HTS of environmental DNA and RNA (eDNA/eRNA) resulted in 1,875,300 sequences that clustered into 349 Operational Taxonomic Units. Strong correlations were observed among various biotic indices calculated from MI data and normalized fourth-root transformed HTS data. Correlations were stronger using eRNA compared to eDNA data. Quantile regression spline analyses identified 12 key foraminiferal taxa that have potential to be used as bioindicator species. This study demonstrates the huge potential for using this method for biomonitoring of fish-farming and other marine industrial activities.
•Foraminiferal metabarcoding is a cost-effective tool for monitoring environmental impacts of fish farming.•Metabarcoding data correlate strongly with traditional biotic indices derived from macrobenthic infaunal community data.•Correlations are stronger using eRNA compared to eDNA data.•Quantile regression spline analysis identifies 12 key foraminiferal taxa that have potential to be used as bioindicator species.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Positron emission tomography using ligands targeting prostate specific membrane antigen has recently been introduced. Positron emission tomography imaging with 68Ga-PSMA-HBED-CC has been shown to ...detect metastatic prostate cancer lesions at a high rate. In this study we compare multiparametric magnetic resonance imaging and prostate specific membrane antigen positron emission tomography of the prostate with whole mount ex vivo prostate histopathology to determine the true sensitivity and specificity of these imaging modalities for detecting and locating tumor foci within the prostate.
In a prospective clinical trial setting 20 patients with localized prostate cancer and a planned radical prostatectomy were recruited. All patients underwent multiparametric magnetic resonance imaging and positron emission tomography before surgery, and whole mount histopathology slides were directly compared to the images. European Society of Urogenital Radiology guidelines for reporting magnetic resonance imaging were used as a template for regional units of analysis. The uropathologist and radiologists were blinded to individual components of the study, and the final correlation was performed by visual and deformable registration analysis.
A total of 50 clinically significant lesions were identified from the whole mount histopathological analysis. Based on regional analysis the sensitivity, specificity, positive predictive value and negative predictive value for multiparametric magnetic resonance imaging were 44%, 94%, 81% and 76%, respectively. With prostate specific membrane antigen positron emission tomography the sensitivity, specificity, positive predictive value and negative predictive value were 49%, 95%, 85% and 88%, respectively. Prostate specific membrane antigen positron emission tomography yielded a higher specificity and positive predictive value.
A significant proportion of cancers are potentially missed and underestimated by both imaging modalities. Prostate specific membrane antigen positron emission tomography may be used in addition to multiparametric magnetic resonance imaging to help improve local staging in those patients undergoing retropubic radical prostatectomy.
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