Optical coherence tomography angiography (OCTA) has emerged as a novel, non-invasive imaging modality that allows the detailed study of flow within the vascular structures of the eye. Compared to ...conventional dye angiography, OCTA can produce more detailed, higher resolution images of the vasculature without the added risk of dye injection. In our review, we discuss the advantages and disadvantages of this new technology in comparison to conventional dye angiography. We provide an overview of the current OCTA technology available, compare the various commercial OCTA machines technical specifications and discuss some future software improvements. An approach to the interpretation of OCTA images by correlating images to other multimodal imaging with attention to identifying potential artefacts will be outlined and may be useful to ophthalmologists, particularly those who are currently still unfamiliar with this new technology. This review is based on a search of peer-reviewed published papers relevant to OCTA according to our current knowledge, up to January 2017, available on the PubMed database. Currently, many of the published studies have focused on OCTA imaging of the retina, in particular, the use of OCTA in the diagnosis and management of common retinal diseases such as age-related macular degeneration and retinal vascular diseases. In addition, we describe clinical applications for OCTA imaging in inflammatory diseases, optic nerve diseases and anterior segment diseases. This review is based on both the current literature and the clinical experience of our individual authors, with an emphasis on the clinical applications of this imaging technology.
Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently ...demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited.
This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH.
We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months 95% confidence interval 3.6–10.8 months. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation.
RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.
•Resistance is a major challenge in RET fusion-positive lung cancer treated with RET tyrosine kinase inhibitors (TKIs).•RET mutations involving the solvent front residue G810 are a recurrent yet infrequent mechanism of resistance to RET TKIs.•The majority of resistance to selective RET inhibition is driven by RET-independent resistance, such as MET amplification.•RET TKIs with potency against RET solvent front mutations and combination strategies are needed to overcome resistance.
There is compelling evidence that treponemes are involved in the etiology of several chronic diseases, including chronic periodontitis as well as other forms of periodontal disease. There are ...interesting parallels with other chronic diseases caused by treponemes that may indicate similar virulence characteristics. Chronic periodontitis is a polymicrobial disease, and recent animal studies indicate that co-infection of Treponema denticola with other periodontal pathogens can enhance alveolar bone resorption. The bacterium has a suite of molecular determinants that could enable it to cause tissue damage and subvert the host immune response. In addition to this, it has several non-classic virulence determinants that enable it to interact with other pathogenic bacteria and the host in ways that are likely to promote disease progression. Recent advances, especially in molecular-based methodologies, have greatly improved our knowledge of this bacterium and its role in disease.
The role of TGF-β signaling in tumorigenesis is paradoxical: it can be tumor suppressive or tumor promotional, depending on context. The metastatic regulator, Six1, was recently shown to mediate this ...switch, providing a novel means to explain this elusive 'TGF-β paradox'. Herein, we identify a mechanism by which Six1 activates the tumor promotional arm of TGF-β signaling, via its ability to upregulate the miR-106b-25 microRNA cluster, and further identify a novel function for this cluster of microRNAs. Although expression of the miR-106b-25 cluster is known to overcome TGF-β-mediated growth suppression via targeting p21 and BIM, we demonstrate for the first time that this same cluster can additionally target the inhibitory Smad7 protein, resulting in increased levels of the TGF-β type I receptor and downstream activation of TGF-β signaling. We further show that the miR-106b-25 cluster is sufficient to induce an epithelial-to-mesenchymal transition and a tumor initiating cell phenotype, and that it is required downstream of Six1 to induce these phenotypes. Finally, we demonstrate a significant correlation between miR-106b, Six1, and activated TGF-β signaling in human breast cancers, and further show that high levels of miR-106b and miR-93 in breast tumors significantly predicts shortened time to relapse. These findings expand the spectrum of oncogenic functions of miR-106b-25, and may provide a novel molecular explanation, through the Six1 regulated miR-106b-25 cluster, by which TGF-β signaling shifts from tumor suppressive to tumor promoting.
The Dexter “
S-value” (
S
gi) is a promising new indicator of soil physical quality (SPQ), but it is not well tested against established indicators, such as relative field capacity (RFC), ...plant-available water capacity (PAWC), air capacity (AC), macroporosity (
P
MAC), bulk density (BD), organic carbon content (OC), and structural stability index (SI). Furthermore, all SPQ indicators are direct or indirect expressions of pore volume and/or pore function, but optimal pore volume-function characteristics have not been identified. The objectives of this study were to: i) compare
S
gi to the other seven indicators for a range of rigid to moderately expansive soils and artificial porous media; ii) use the indicators to propose an optimal pore volume distribution and soil water release curve; and iii) assess the SPQ of a compost-amended soil using indicators, pore volume distributions and water release curves.
The indicators were measured in the laboratory on intact soil cores and grab samples collected from 13 soil-management combinations. Soil texture included clay loam, sandy clay loam, loam, sandy loam and sand; management included virgin soil, no-till cropping and mouldboard plough cropping. Also included were two artificial media consisting of glass beads and builders sand. Pore volume distributions and water release curves were determined by fitting the van Genuchten function to desorption data obtained from the soil cores and grab samples.
The
S
gi indicator gave correct SPQ designations for the structured loamy soils, but erroneous designations (
S
gi
>
0.035) for the structureless sands, glass beads and builders sand. The indicators suggested that four of the 13 soil-management combinations had optimal overall SPQ, and these combinations were used to define an optimal pore volume distribution and water release curve. Non-optimal soils with poor aeration (RFC
>
0.7, AC
<
0.14
m
3
m
−
3
) and poor structure (
P
MAC
<
0.07, SI
<
7%,
S
gi
<
0.035) had greater proportions of small pores and excessive water retention relative to optimal soils, while droughty soils (RFC
<
0.6, PAWC
≤
0.15
m
3
m
−
3
) had lower proportions of small pores and insufficient water retention. The indicators, pore volume distributions and release curves showed that adding 75
t ha
−
1
compost improved the SPQ and maize yield of a clay loam soil, but addition of 300
t ha
−
1
compost was required to achieve optimal SPQ and maximum measured yield.
It was concluded that the
S
gi indicator should be used judiciously and in concert with other indicators for assessing SPQ; and that the suite of eight indicators used in conjunction with an optimal pore volume distribution and water release curve are effective for quantifying the physical quality of rigid to moderately expansive agricultural soils.
Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, ...there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers.
The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC) were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration.
The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC.
This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective.
•Clinical adoption of NGS is heterogeneous in the APAC region due to diversity in access, practice guidelines, and funding.•The APODDC group recommends routine NGS testing for daily practice in patients presenting with advanced NSCLC.•Routine multigene NGS testing is not recommended in metastatic GC, cholangiocarcinoma, NPC, BC, and HCC.•In research centres with molecular screening programs, NGS can enhance understanding of promising targets in OC.•Allele-specific PCRs or a small-panel, multiplex-gene NGS testing was suggested to identify key alterations in CRC.
Conflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity.
We undertook large-scale observational and Mendelian randomisation (MR) analyses using UK ...Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase).
There were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1-9/day: OR 2.14, 95% CI 0.87 to 5.24; 10-19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72).
Congruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.
Glaucoma in myopia: diagnostic dilemmas Tan, Nicholas Y Q; Sng, Chelvin C A; Jonas, Jost B ...
British journal of ophthalmology,
10/2019, Letnik:
103, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Myopic eyes have an increased risk of glaucoma. However, glaucomatous changes in a myopic eye are often difficult to detect. Classic structural and functional investigations to diagnose glaucoma may ...be confounded by myopia. Here, we identify some of the common pitfalls in interpreting these structural parameters, and the possible solutions that could be taken to overcome them. For instance, in myopic eyes, we discuss the limitations and potential sources of error when using neuroretinal rim parameters, and retinal nerve fibre layer and ganglion cell-inner plexiform layer thickness measurements. In addition, we also review new developments and potential adjuncts in structural imaging such as the assessment of the retinal nerve fibre layer texture, and the examination of the microcirculation of the optic nerve head using optical coherence tomography angiography. For the functional assessment of glaucoma, we discuss perimetric strategies that may aid in detecting characteristic visual field defects in myopic glaucoma. Ultimately, the evaluation of glaucoma in myopia requires a multimodal approach, to allow correlation between structural and functional assessments. This review provides overview on how to navigate this diagnostic dilemma.
The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse ...stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patient's tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice-an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.
PDF
