Photodynamic therapy in 3D cancer models and the utilisation of nanodelivery systems

Photodynamic therapy (PDT) is the subject of considerable research in experimental cancer models mainly for the treatment of solid cancerous tumours. Recent studies on the use of nanoparticles as photosensitiser carriers have demonstrated improved PDT efficacy in experimental cancer therapy. Experiments typically employ conventional monolayer cell culture but there is increasing interest in testing PDT using three dimensional (3D) cancer models. 3D cancer models can better mimic in vivo models than 2D cultures by for example enabling cancer cell interactions with a surrounding extracellular matrix which should enable the treatment to be optimised prior to in vivo studies. The aim of this review is to discuss recent research using PDT in different types of 3D cancer models, from spheroids to nano-fibrous scaffolds, using a range of photosensitisers on their own or incorporated in nanoparticles and nanodelivery systems

5 Gbps wireless transmission link with an optically pumped uni-traveling carrier photodiode mixer at the receiver

We report the first demonstration of a uni-traveling carrier photodiode (UTC-PD) used as a 5 Gbps wireless receiver. In this experiment, a 35.1 GHz carrier was electrically modulated with 5 Gbps non-return with zero on-off keying (NRZ–OOK) data and transmitted wirelessly over a distance of 1.3 m. At the receiver, a UTC-PD was used as an optically pumped mixer (OPM) to down-convert the received radio frequency (RF) signal to an intermediate frequency (IF) of 11.7 GHz, before it was down-converted to the baseband using an electronic mixer. The recovered data show a clear eye diagram, and a bit error rate (BER) of less than 10 −8 was measured. The conversion loss of the UTC-PD optoelectronic mixer has been measured at 22 dB. The frequency of the local oscillator (LO) used for the UTC-PD is defined by the frequency spacing between the two optical tones, which can be broadly tuneable offering the frequency agility of this photodiode-based receiver

Development of a score for assessment of radiologic damage in large-vessel vasculitis (Combined Arteritis Damage Score, CARDS)

OBJECTIVES: Outcome assessment in large-vessel vasculitis (LVV) remains challenging and this impairs patient management and the conduct of clinical studies. Previous proposals for outcome tools have not included imaging. This study aimed to develop an imaging score to quantify damage in LVV and to assess the difference between Takayasu (TAK) and giant cell arteritis (GCA). METHODS: Ninety-six patients (41 TAK, 55 GCA) were identified from local registries at two University Hospitals in the UK. Radiologic lesions including stenosis, occlusion and aneurysm were evaluated in 25 arterial regions by enhanced computed tomography or magnetic resonance angiography. Lesion correlation with combined damage assessment scores was employed in a multiple regression analysis to define the weight of individual lesions and develop a damage index. RESULTS: A numerical damage index was developed: the “Combined Arteritis Damage Score (CARDS)”. The index was derived from a formula: number of regions with mild stenosis × 0.6 + number of regions with moderate to severe stenosis × 1.2 + number with occlusions × 1.6 + number with aneurysms × 0.8 in 25 arterial regions. The median CARDS was higher in TAK than GCA (4.1 and 0.6, interquartile range 1.3-5.7 and 0-3, p<0.001). CONCLUSIONS: We have developed a damage assessment tool, CARDS, based on imaging in LVV of potential value to clinical studies and patient management. TAK and GCA differ in the radiologic severity of disease.Dr. Daiki Nakagomi is supported by the Japan College of Rheumatology and Shimoshizu Hospital, National Hospital Organization. This project was supported by the Cambridge Biomedical Research Centre

Evaluation of Risk-based Re-Authentication Methods

Risk-based Authentication (RBA) is an adaptive security measure that improves the security of password-based authentication by protecting against credential stuffing, password guessing, or phishing attacks. RBA monitors extra features during login and requests for an additional authentication step if the observed feature values deviate from the usual ones in the login history. In state-of-the-art RBA re-authentication deployments, users receive an email with a numerical code in its body, which must be entered on the online service. Although this procedure has a major impact on RBA's time exposure and usability, these aspects were not studied so far. We introduce two RBA re-authentication variants supplementing the de facto standard with a link-based and another code-based approach. Then, we present the results of a between-group study (N=592) to evaluate these three approaches. Our observations show with significant results that there is potential to speed up the RBA re-authentication process without reducing neither its security properties nor its security perception. The link-based re-authentication via "magic links", however, makes users significantly more anxious than the code-based approaches when perceived for the first time. Our evaluations underline the fact that RBA re-authentication is not a uniform procedure. We summarize our findings and provide recommendations.Comment: 14 pages, 5 figures. Paper accepted for IFIP SEC 2020. Keywords: Risk-based Authentication (RBA), Re-authentication, Usable Securit

The Effect of Blood Loss in the Presence and Absence of Severe Soft Tissue Injury on Hemodynamic and Metabolic Parameters; an Experimental study

Introduction: The effect of severe soft tissue injury on the severity of hemorrhagic shock is still unknown. Therefore, the present study was aimed to determine hemodynamic and metabolic changes in traumatic/hemorrhagic shock in an animal model. Methods: Forty male rats were randomly divided into 4 equal groups including sham, hemorrhagic shock, soft tissue injury, and hemorrhagic shock + soft tissue injury groups. The changes in blood pressure, central venous pressure (CVP) level, acidity (pH), and base excess were dynamically monitored and comparedsented. Results: Mean arterial blood pressure decreased significantly in hemorrhagic shock (df: 12; F=10.9; p&lt;0.001) and severe soft tissue injury + hemorrhagic shock (df: 12; F=11.7; p&lt;0.001) groups 15 minutes and 5 minutes after injury, respectively. A similar trend was observed in CVP in severe soft tissue injury + hemorrhagic shock group (df: 12; F=8.9; p&lt;0.001). After 40 minutes, pH was significantly lower in hemorrhagic shock (df: 12; F=6.8; p=0.009) and severe soft tissue injury + hemorrhagic shock (df: 12; F=7.9; p=0.003) groups. Base excess changes during follow ups have a similar trend. (df: 12; F=11.3; p&lt;0.001). Conclusion: The results of this study have shown that the effect of hemorrhage on the decrease of mean arterial blood pressure, CVP, pH, and base excess is the same in the presence or absence of soft tissue injury

Photobactericidal activity activated by thiolated gold nanoclusters at low flux levels of white light

The emergence of antibiotic resistant bacteria is a major threat to the practice of modern medicine. Photobactericidal agents have obtained significant attention as promising candidates to kill bacteria, and they have been extensively studied. However, to obtain photobactericidal activity, an intense white light source or UV-activation is usually required. Here we report a photobactericidal polymer containing crystal violet (CV) and thiolated gold nanocluster ([Au25(Cys)18]) activated at a low flux levels of white light. It was shown that the polymer encapsulated with CV do not have photobactericidal activity under white light illumination of an average 312 lux. However, encapsulation of [Au25(Cys)18] and CV into the polymer activates potent photobactericidal activity. The study of the photobactericidal mechanism shows that additional encapsulation of [Au25(Cys)18] into the CV treated polymer promotes redox reactions through generation of alternative electron transfer pathways, while it reduces photochemical reaction type-ІІ pathways resulting in promotion of hydrogen peroxide (H2O2) production

60 GHz Transmission Link using Uni-Travelling Carrier Photodiodes at the Transmitter and the Receiver

We present the first demonstration of a wireless transmission link based on uni-travelling carrier photodiodes (UTC-PDs) as transmitter and receiver. In this demonstration, a UTC-PD was used at the transmitter to generate a 1 Gbps on-off keying (OOK) data signal at a carrier frequency of 61.3 GHz by heterodyning two modulated optical tones originating from an optical frequency comb (OFC) system. The generated electrical heterodyne signal was transmitted, using a 25 dBi gain parabolic antenna. An identical antenna was used to detect the signal at the receiver, followed by an optically pumped UTC-PD mixer to down-convert the received RF signal to an intermediate frequency (IF) of 6.3 GHz, which, was subsequently amplified and acquired by a real-time oscilloscope (RTO) for offline processing. The recovered data showed an open eye diagram, and a bit error rate (BER) of the order of 10$_{-5}$ was measured. The receiver UTC-PD was characterized in terms of its conversion loss and noise figure (NF), and the overall NF of the receiver was measured at 21.5 dB

Impact of treatment on damage and hospitalization in elderly patients with microscopic polyangiitis and granulomatosis with polyangiitis

OBJECTIVE: Age is a risk factor for organ damage, adverse events, and mortality in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, the relationship between treatment and damage, hospitalizations, and causes of death in elderly patients is largely unknown. METHODS: Consecutive patients from Sweden, England, and the Czech Republic diagnosed between 1997 and 2013 were included. Inclusion criteria were a diagnosis of MPA or GPA and age 75 years or more at diagnosis. Treatment with cyclophosphamide, rituximab, and corticosteroids the first three months was registered. Outcomes up to two years from diagnosis included vasculitis damage index (VDI), hospitalization, and cause of death. RESULTS: Treatment data was available for 167 of 202 patients. At two years, 4% had no items of damage. There was a positive association between VDI score at two years and Birmingham Vasculitis Activity Score at onset, and a negative association with treatment using cyclophosphamide or rituximab. Intravenous methylprednisolone dose was associated with treatment-related damage. During the first year, 69% of patients were readmitted to hospital. MPO-ANCA positivity and lower creatinine levels decreased the odds for readmission. The most common cause of death was infection, and this was associated with cumulative oral prednisolone dose. CONCLUSION: Immunosuppressive treatment with cyclophosphamide or rituximab in elderly patients with MPA and GPA was associated with development of less permanent organ damage and was not associated with hospitalization. However, higher doses of corticosteroids during the first three months was associated with treatment-related damage and fatal infections

SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status

The Bcl-2 family of proteins is critical to the life and death of malignant B-lymphocytes. Interfering with their activity using small-molecule inhibitors (SMI) is being explored as a new therapeutic strategy for treating B-cell tumors. We evaluated the efficacy of TW-37, a non-peptidic SMI of Bcl-2 against a range spectrum of human B-cell lines, fresh patient samples and animal xenograft models. Multiple cytochemical and molecular approaches such as acridine orange/ethidium bromide assay for apoptosis, co-immunoprecipitation of complexes and western blot analysis, caspase luminescent activity assay and apoptotic DNA fragmentation assay were used to demonstrate the effect of TW-37 on different B-cell lines, patient derived samples, as well as in animal xenograft models. Nanomolar concentrations of TW-37 were able to induce apoptosis in both fresh samples and established cell lines with IC50 in most cases of 165–320 nM. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-XL and Bim-Mcl-1 heterodimerization and induced apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log10kill, when used at its maximum tolerated dose (40 mg/kg × 3 days) via tail vein. TW-37 failed to induce changes in the Bcl-2 proteins levels suggesting that assessment of baseline Bcl-2 family proteins can be used to predict response to the drug. These findings indicate activity of TW-37 across the spectrum of human B-cell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy regardless of the stage of B-cell differentiation