PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available

The burden of sickle cell disease in Cape Town

Background. South Africa has a low incidence of sickle cell disease (SCD). However, its demographics are changing because of immigration from sub-Saharan African countries where SCD is prevalent.Objectives. We aimed to determine the frequency of SCD presenting to the Haematology/Oncology Service at Red Cross War Memorial Children’s Hospital in Cape Town and to measure the associated disease burden.Methods. This was a retrospective cross-sectional study of patients first attending the Haematology Service between January 2001 and June 2010.Results. A total of 58 SCD patients were indentified, with an annual frequency that increased over the study period by 300 -400%. Up to 93.1% (n=54) were originally from other African countries, mainly the Democratic Republic of Congo (62.1%, n=36). One patient had sickle D-Punjab genotype, and all the other patients had the homozygous sickle cell anaemia genotype (Hb SS). Their haematological parameters  demonstrated a normocytic anaemia with high white cell counts. The mean number of clinic visits per patient per year was 22.2 (range 0 - 64), and the mean number of hospital admissions per patient per year was 1.2 (range 0 - 5). All the patients were on antibiotic prophylaxis. The majorityhad at least one blood transfusion (65.5%, n=38), and a significantproportion required intravenous analgesia on admission (29.3%, n=17) and hydroxyurea treatment (36.2%, n=21).Conclusions. Over the past 10 years the frequency of SCD has increased considerably, imposing a significant burden and new challenges to the health services in Cape Town

Democratization in a passive dendritic tree : an analytical investigation

One way to achieve amplification of distal synaptic inputs on a dendritic tree is to scale the amplitude and/or duration of the synaptic conductance with its distance from the soma. This is an example of what is often referred to as “dendritic democracy”. Although well studied experimentally, to date this phenomenon has not been thoroughly explored from a mathematical perspective. In this paper we adopt a passive model of a dendritic tree with distributed excitatory synaptic conductances and analyze a number of key measures of democracy. In particular, via moment methods we derive laws for the transport, from synapse to soma, of strength, characteristic time, and dispersion. These laws lead immediately to synaptic scalings that overcome attenuation with distance. We follow this with a Neumann approximation of Green’s representation that readily produces the synaptic scaling that democratizes the peak somatic voltage response. Results are obtained for both idealized geometries and for the more realistic geometry of a rat CA1 pyramidal cell. For each measure of democratization we produce and contrast the synaptic scaling associated with treating the synapse as either a conductance change or a current injection. We find that our respective scalings agree up to a critical distance from the soma and we reveal how this critical distance decreases with decreasing branch radius

633 Comparison of soluble proteins from skin sections of acne and TCA induced postinflammatory hyperpigmentation and erythema

Postinflammatory hyperpigmentation (PIH) is an acquired hypermelanosis occurring after cutaneous inflammation or injury that can arise in all skin types, but more frequently affects skin-of-color. The differences in the ethology of PIH and Postinflammatory erythema (PIE) in skin of color were evaluated from soluble protein extracts collected from skin section samples, using Somascan protein kit1.3 k (n=5). The skin samples were collected from selected gluteal TCA-induced lesions and truncal acne pustules, of either PIH or PIE, at day 28 post initial evaluation. Differences between proteins (FDR\u3c0.05) from PIH and PIE were analyzed with STRING version 11.5 and analysis points toward involvement of JAK/STAT signaling pathway and enhanced IL17 signaling in PIH compared to PIE lesions (OSM, CSF3, IL10RA, IL12RB2, IL10RB, IL3, CSF2, IL17D, IL17F, IFNA2, IFNA10, CRLF2, IL5RA, TYK2, IL12RB1, PRLR, GHR). The involvement of JAK/STAT signaling pathway has been described for some chronic cutaneous inflammatory conditions and acne. A higher occurrence of dermal remodeling proteases and inhibitors were found in PIE (MMP1, MMP2, MMP7, TIMP2) indicating a dermal remodeling phase at the time of excision. Concurrently, elevated levels of IL-1β, and TGF-β (critical for triggering and continuing differentiation programs of naïve CD4+ T cells to IL-17 secreting Th17 cells) in PIH samples suggests continuing promotion of macrophage infiltration and sustained inflammation. In addition to MMP13 and MMP16, the protein Keap1 was found to be increased in the PIH samples. Keap1, a repressor of master cellular defense against oxidative and electrophilic stresses, has been reported to be involved in the imbalance of proteolysis that can lead towards premature aging and in a senescent phenotype of endothelial cells. The sustained inflammation with excess of Keap1 protein might contribute to an altered proteostasis and ethology of PIH

The Murmur of the Sleeping Black Hole: Detection of Nuclear Ultraviolet Variability in LINER Galaxies

LINER nuclei, which are present in many nearby galactic bulges, may be the manifestation of low-rate or low-radiative-efficiency accretion onto supermassive central black holes. However, it has been unclear whether the compact UV nuclear sources present in many LINERs are clusters of massive stars, rather than being directly related to the accretion process. We have used HST to monitor the UV variability of a sample of 17 galaxies with LINER nuclei and compact nuclear UV sources. Fifteen of the 17 galaxies were observed more than once, with two to five epochs per galaxy, spanning up to a year. We detect significant variability in most of the sample, with peak-to-peak amplitudes from a few percent to 50%. In most cases, correlated variations are seen in two independent bands (F250W and F330W). Comparison to previous UV measurements indicates, for many objects, long-term variations by factors of a few over decade timescales. Variability is detected in LINERs with and without detected compact radio cores, in LINERs that have broad H-alpha wings detected in their optical spectra (``LINER 1's''), and in those that do not (``LINER 2s''). This variability demonstrates the existence of a non-stellar component in the UV continuum of all types, and sets a lower limit to the luminosity of this component. We note a trend in the UV color (F250W/F330W) with spectral type - LINER 1s tend to be bluer than LINER 2s. This trend may indicate a link between the shape of the nonstellar continuum and the presence or the visibility of a broad-line region. In one target, the post-starburst galaxy NGC 4736, we detect variability in a previously noted UV source that is offset by 2.5" (60 pc in projection) from the nucleus. This may be the nearest example of a binary active nucleus, and of the process leading to black hole merging.Comment: accepted to Ap

Direct path from microscopic mechanics to Debye shielding, Landau damping, and wave-particle interaction

The derivation of Debye shielding and Landau damping from the $N$-body description of plasmas is performed directly by using Newton's second law for the $N$-body system. This is done in a few steps with elementary calculations using standard tools of calculus, and no probabilistic setting. Unexpectedly, Debye shielding is encountered together with Landau damping. This approach is shown to be justified in the one-dimensional case when the number of particles in a Debye sphere becomes large. The theory is extended to accommodate a correct description of trapping and chaos due to Langmuir waves. Shielding and collisional transport are found to be two related aspects of the repulsive deflections of electrons, in such a way that each particle is shielded by all other ones while keeping in uninterrupted motion.Comment: arXiv admin note: substantial text overlap with arXiv:1310.3096, arXiv:1210.154

Overexpression of CD44 in acquired tamoxifen-resistant breast cancer cells augments their migratory response to heregulin beta 1

Background Acquired endocrine resistance in breast cancer cells is accompanied by altered growth factor receptor signalling [1] and a highly migratory cell phenotype [2]. Interestingly, in tamoxifen-resistant (TamR) MCF7 cells, our microarray analysis has demonstrated elevated levels of CD44, a transmembrane glycoprotein known to interact with, and modulate the function of, growth factor receptors [3]. Here we have explored the role of CD44 as a modulator of heregulin beta-1-induced migratory signalling in TamR cells. Methods Expression of CD44 (standard and v3 isoforms) were confirmed by RT-PCR and western blotting and their association with erbB family members determined by both immunofluorescence microscopy and immunoprecipitation. Activation of intracellular signalling following heregulin beta 1 treatment (10 ng/ml) in the presence or absence of CD44 (using siRNA-mediated inhibition) was determined by western blotting using phosphospecific antibodies. Cellular migration was determined by seeding cells (control and CD44 siRNA-treated) into fibronectin-coated transwell chambers (8.0 μm pore size) in the presence or absence of heregulin beta 1. After 24 hours, migratory cells were fixed, stained with crystal violet and counted. Results Both standard and v3 isoforms of CD44 were overexpressed in TamR cells at both gene and protein levels (mean fold increase in CD44s protein (TamR versus MCF7): 4.26 ± 1.2, P < 0.05). Moreover, CD44s and v3 colocalised with Her2 and Her3 receptors at the cell surface and were also detectable in Her2/Her3 cellular immunoprecipitates. Treatment of TamR cells with heregulin resulted in phosphorylation of erbB receptors together with a number of downstream signalling intermediates, including Akt, Src and FAK, and resulted in enhanced cellular migration. Significantly, heregulin-induced intracellular signalling was dramatically reduced in cells in which the expression of CD44 was suppressed (via siRNA), with a corresponding loss of heregulin-induced migratory behaviour (mean fold change in cell migration versus untreated control: 6.7 ± 1.1, P < 0.05 (heregulin beta 1); 1.8 ± 0.9 (CD44 siRNA); 1.47 ± 0.6, P < 0.05 (heregulin beta 1 + CD44 siRNA)). Conclusion These data demonstrate a role for CD44 as a modulator of erbB receptor function in endocrine-resistant breast cancer cells, where it augments heregulin beta 1 migratory signalling

Testing for sexually transmitted infections in a population-based sexual health survey: development of an acceptable ethical approach

Population-based research is enhanced by biological measures, but biological sampling raises complex ethical issues. The third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3) will estimate the population prevalence of five sexually transmitted infections (STIs) (Chlamydia trachomatis, Neisseria gonorrhoeae, human papillomavirus (HPV), HIV and Mycoplasma genitalium) in a probability sample aged 16e44 years. The present work describes the development of an ethical approach to urine testing for STIs, including the process of reaching consensus on whether to return results. The following issues were considered: (1) testing for some STIs that are treatable and for which appropriate settings to obtain free testing and advice are widely available (Natsal-3 provides all respondents with STI and healthcare access information), (2) limits on test accuracy and timeliness imposed by survey conditions and sample type, (3) testing for some STIs with unknown clinical and public health implications, (4) how a uniform approach is easier to explain and understand, (5) practical difficulties in returning results and cost efficiency, such as enabling wider STI testing by not returning results. The agreed approach, to perform voluntary anonymous testing with specific consent for five STIs without returning results, was approved by stakeholders and a research ethics committee. Overall, this was acceptable to respondents in developmental piloting; 61% (68 of 111) of respondents agreed to provide a sample. The experiences reported here may inform the ethical decision making of researchers, research ethics committees and funders considering population-based biological sampling