DNA barcoding and taxonomy: dark taxa and dark texts Page, Roderic D. M.
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
09/2016, Volume:
371, Issue:
1702
Journal Article
Peer reviewed
Open access
Both classical taxonomy and DNA barcoding are engaged in the task of digitizing the living world. Much of the taxonomic literature remains undigitized. The rise of open access publishing this century ...and the freeing of older literature from the shackles of copyright have greatly increased the online availability of taxonomic descriptions, but much of the literature of the mid- to late-twentieth century remains offline (‘dark texts’). DNA barcoding is generating a wealth of computable data that in many ways are much easier to work with than classical taxonomic descriptions, but many of the sequences are not identified to species level. These ‘dark taxa’ hamper the classical method of integrating biodiversity data, using shared taxonomic names. Voucher specimens are a potential common currency of both the taxonomic literature and sequence databases, and could be used to help link names, literature and sequences. An obstacle to this approach is the lack of stable, resolvable specimen identifiers. The paper concludes with an appeal for a global ‘digital dashboard’ to assess the extent to which biodiversity data are available online.
This article is part of the themed issue ‘From DNA barcodes to biomes’.
Immune modulation for cancer therapy NAIDOO, J; PAGE, D. B; WOLCHOK, J. D
British journal of cancer,
12/2014, Volume:
111, Issue:
12
Journal Article
Peer reviewed
Open access
Immune modulation in cancer refers to a range of treatments aimed at harnessing a patient's immune system to achieve tumour control, stabilisation, and potential eradication of disease. A novel ...therapeutic drug class called immune checkpoint-blocking antibodies modulate T-cell pathways that regulate T cells and have the potential to reinvigorate an antitumour immune response. Ipilimumab was the first FDA-approved immune checkpoint antibody licensed for the treatment of metastatic melanoma (MM) and blocks a checkpoint molecule called cytotoxic T-lymphocyte antigen 4 (CTLA-4).
Herein we review the preclinical and clinical development of ipilimumab. We outline the mode of action of these agents and other immune checkpoint inhibitors, the management of their toxicities, and how to adequately assess response to treatment.
As a result of these data, a number of other antibodies that block novel checkpoint molecules including programmed death-1 (PD-1), and corresponding ligands such as programmed death ligand-1 (PD-L1) are under preclinical and clinical development, and have demonstrated activity in multiple tumour types.
This review will summarise the mechanism of action and clinical development of immune checkpoint antibodies, as well as lessons learned in the management and assessment of patients receiving these agents.
Immune checkpoint antibodies that augment the programmed cell death protein 1 (PD-1)/PD-L1 pathway have demonstrated antitumor activity across multiple malignancies, and gained recent regulatory ...approval as single-agent therapy for the treatment of metastatic malignant melanoma and nonsmall-cell lung cancer. Knowledge of toxicities associated with PD-1/PD-L1 blockade, as well as effective management algorithms for these toxicities, is pivotal in order to optimize clinical efficacy and safety. In this article, we review selected published and presented clinical studies investigating single-agent anti-PD-1/PD-L1 therapy and trials of combination approaches with other standard anticancer therapies, in multiple tumor types. We summarize the key adverse events reported in these studies and their management algorithms.
Summary Objectives Chronic pulmonary aspergillosis (CPA) is estimated to affect 3 million persons worldwide. Aspergillus -specific IgG is a key component in CPA diagnosis. We aimed to establish the ...optimal diagnostic cut offs for CPA and the comparative performance of six assays in this context. Methods Sera from 241 patients with CPA and 100 healthy blood donors were tested using five Aspergillus -specific IgG assays plus precipitin testing using Microgen Aspergillus antigens. Results Receiver operating characteristic (ROC) curve area under the curve (AUC) results were as follows: ThermoFisher Scientific ImmunoCAP 0.996 (95% confidence interval 0.992–1), Siemens Immulite 0.991 (0.982–1), Serion 0.973 (0.960–0.987), Dynamiker 0.918 (0.89–0.946) and Genesis 0.902 (0.871–0.933). Optimal CPA diagnostic cut-offs were; ImmunoCAP 20 mg/L (96% sensitivity, 98% specificity), Immulite 10 mg/L (96% sensitivity, 98% specificity), Serion 35 U/ml (90% sensitivity, 98% specificity), Dynamiker 65 AU/ml (77% sensitivity, 97% specificity) and Genesis 20 U/ml (75% sensitivity, 99% specificity). The precipitin test was 59% sensitive and 100% specific. Conclusions ImmunoCAP and Immulite were statistically significantly superior to the other assays. Precipitins testing performed poorly. The currently accepted ImmunoCAP cut-off of 40 mg/L appears sub-optimal for CPA diagnosis and may require revision in this context.
Computer-aided lead optimization derives a unique, orally bioavailable inhibitor of the signal transducer and activator of transcription (Stat)3 Src homology 2 domain. BP-1-102 binds Stat3 with an ...affinity (K D) of 504 nM, blocks Stat3–phospho-tyrosine (pTyr) peptide interactions and Stat3 activation at 4–6.8 μM, and selectively inhibits growth, survival, migration, and invasion of Stat3-dependent tumor cells. BP-1-102–mediated inhibition of aberrantly active Stat3 in tumor cells suppresses the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, VEGF, and Krüppel-like factor 8, which is identified as a Stat3 target gene that promotes Stat3-mediated breast tumor cell migration and invasion. Treatment of breast cancer cells with BP-1-102 further blocks Stat3–NF-κB cross-talk, the release of granulocyte colony-stimulating factor, soluble intercellular adhesion molecule 1, macrophage migration-inhibitory factor/glycosylation-inhibiting factor, interleukin 1 receptor antagonist, and serine protease inhibitor protein 1, and the phosphorylation of focal adhesion kinase and paxillin, while enhancing E-cadherin expression. Intravenous or oral gavage delivery of BP-1-102 furnishes micromolar or microgram levels in tumor tissues and inhibits growth of human breast and lung tumor xenografts.
Early recognition and diagnosis of allergic bronchopulmonary aspergillosis (ABPA) is critical to improve patient symptoms, and antifungal therapy may prevent or delay progression of bronchiectasis ...and development of chronic pulmonary aspergillosis.
A recently commercialized lateral flow assay (Aspergillus ICT) (LDBio Diagnostics, Lyons, France) detects Aspergillus-specific antibodies in <30 minutes, requiring minimal laboratory equipment. We evaluated this assay for diagnosis of ABPA compared to diseased (asthma and/or bronchiectasis) controls.
ABPA and control sera collected at the National Aspergillosis Centre (Manchester, UK) and/or from the Manchester Allergy, Respiratory and Thoracic Surgery research biobank were evaluated using the Aspergillus ICT assay. Results were read both visually and digitally (using a lateral flow reader). Serological Aspergillus-specific IgG and IgE, and total IgE titres were measured by ImmunoCAP.
For 106 cases of ABPA versus all diseased controls, sensitivity and specificity for the Aspergillus ICT were 90.6% and 87.2%, respectively. Sensitivity for 'proven' ABPA alone (n = 96) was 89.8%, and 94.4% for 'presumed' ABPA (n = 18). 'Asthma only' controls (no bronchiectasis) and 'bronchiectasis controls' exhibited 91.4% and 81.7% specificity, respectively. Comparison of Aspergillus ICT result with Aspergillus-specific IgG and IgE titres showed no evident immunoglobulin isotype bias. Digital measurements displayed no correlation between ImmunoCAP Aspergillus-specific IgE level and ICT test line intensity.
The Aspergillus ICT assay exhibits good sensitivity for ABPA serological screening. It is easy to perform and interpret, using minimal equipment and resources; and provides a valuable simple screening resource to rapidly distinguish more serious respiratory conditions from Aspergillus sensitization alone.
Youth and young adult use of e-cigarette products continues to remain high despite regulatory approaches to reduce youth access. This study sought to examine TikTok content regarding the sale and ...distribution of e-cigarettes.
TikTok videos (n = 475) and metadata posted between June 2022 and August 2023 were scraped using a TikTok application programming interface and popular hashtags used to sell vaping products (ie, #discreetshipping 40.8 million, #puffbundle 14.8 million, #hiddennic 1.0 million). After watching the 25 most viewed videos (39 600-868 800 views), a codebook was developed. All metadata were annotated using 11 unique codes: Small business, brand, cannabis, bundled, hidden, fake, international sales, no ID, order via Instagram, order via another method, and cost.
Overall, 367 videos (with an average of 2017 likes) were deemed relevant. Videos advertised popular vaping brands (50.4%) that included cannabis products (45%). Products were described as bundled (28.6%), hidden (8.7%), and able to be shipped internationally (6%) without age verification (45.2%). Some videos (8.2%) evaded algorithms' detection of illegal activity by describing the post as "Fake." Customers were directed to other social media platforms (most often Instagram, 57.5%) and/or other websites/links (58.3%) to purchase products; 22.1% advertised discounts, free shipping, or low costs (ranging from $25-$35).
Social media platforms, such as TikTok and Instagram, are being used to circumvent e-cigarette regulatory policies. Regulatory agencies should expand enforcement strategies to include social media platforms where users are illegally selling and distributing e-cigarettes internationally to young audiences.
TikTok users across the globe are violating local, state, and federal laws by selling e-cigarettes concealed inside other products or bundled in packages that avoid detection. TikTok videos posted by self-proclaimed small business owners advertise discreet shipping practices that evade age verification in order to sell nicotine and cannabis bundles worldwide. Accounts used phrases describing the post to be "fake" to avoid detection by algorithms or TikTok administrators. E-cigarette regulatory agencies can partner with social media platforms to close regulatory gaps.
Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of ...clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen-deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.
MHealth interventions are extensively used to inform and remind women about cervical cancer and their upcoming screening appointments. Our scoping review aims to examine the effectiveness these ...interventions targeted to increase the uptake of cervical cancer screening along with its barriers and facilitators. We searched 4 databases (PsycINFO. PUBMED, CINAHL, and MEDLINE) for studies that were published between January 1, 2009 and October 2019. References were further screened manually for additional papers. Studies were included in the review if they used interventions including phone calls, text messages and mobile applications as their primary strategy to contact women. We identified 12 unique studies that met the inclusion criteria; seven were international studies. Most studies sent multiple messages (informative and reminder) and/or made numerous phone calls (manual/automated) to inform participants about cervical cancer screening, their nearest screening clinic, and their upcoming appointments. Five studies documented a significant increase in the uptake of cervical cancer screenings during the follow-ups conducted within 12 months. Qualitative studies suggested participants prefer particular communication mediums, and they were concerned about privacy and confidentiality issues when text messages were sent with their health information. Findings suggest mHealth interventions may be an effective strategy to reach women for improving their cervical cancer uptake. Barriers including transportation cost, inaccessibility, and inability to come for walk-in appointments in the health clinics need to be addressed, beyond reminders, in mobile phone-based interventions to facilitate their presence in their next appointment.
•MHealth strategies are widely used to reach target population living with chronic illness including cervical cancer.•Text messages, phone calls and mobile applications are used as a reminder strategy.•Barriers including transportation and inaccessibility to clinics need to be addressed to better facilitate their screening.
Macrophage fusion resulting in the formation of multinucleated giant cells occurs in a variety of chronic inflammatory diseases, yet the mechanism responsible for initiating this process is unknown. ...Here, we used live cell imaging to show that actin-based protrusions at the leading edge initiate macrophage fusion. Phase-contrast video microscopy demonstrated that in the majority of events, short protrusions (∼3 µm) between two closely apposed cells initiated fusion, but occasionally we observed long protrusions (∼12 µm). Using macrophages isolated from LifeAct mice and imaging with lattice light sheet microscopy, we further found that fusion-competent protrusions formed at sites enriched in podosomes. Inducing fusion in mixed populations of GFP- and mRFP-LifeAct macrophages showed rapid spatial overlap between GFP and RFP signal at the site of fusion. Cytochalasin B strongly reduced fusion and when rare fusion events occurred, protrusions were not observed. Fusion of macrophages deficient in Wiskott-Aldrich syndrome protein and Cdc42, key molecules involved in the formation of actin-based protrusions and podosomes, was also impaired both in vitro and in vivo. Finally, inhibiting the activity of the Arp2/3 complex decreased fusion and podosome formation. Together these data suggest that an actin-based protrusion formed at the leading edge initiates macrophage fusion.
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