tbuckley/cabot-search huggingface dataset:
Monitoring Insect Transposable Elements in Large Double-Stranded DNA Viruses Reveals Host-to-Virus and Virus-to-Virus Transposition
Authors: Vincent Loiseau, Jean Peccoud, Clémence Bouzar, Sandra Guillier, Jiangbin Fan, Gianpiero Gueli Alletti, Carine Meignin, Elisabeth A Herniou, Brian A Federici, Jörg T Wennmann, Johannes A Jehle, Richard Cordaux, Clément Gilbert
Journal: Molecular Biology and Evolution (2021)

Abstract The mechanisms by which transposable elements (TEs) can be horizontally transferred between animals are unknown, but viruses are possible candidate vectors. Here, we surveyed the presence of host-derived TEs in viral genomes in 35 deep sequencing data sets produced from 11 host–virus systems, encompassing nine arthropod host species (five lepidopterans, two dipterans, and two crustaceans) and six different double-stranded (ds) DNA viruses (four baculoviruses and two iridoviruses). We found evidence of viral-borne TEs in 14 data sets, with frequencies of viral genomes carrying a TE ranging from 0.01% to 26.33% for baculoviruses and from 0.45% to 7.36% for iridoviruses. The analysis of viral populations separated by a single replication cycle revealed that viral-borne TEs originating from an initial host species can be retrieved after viral replication in another host species, sometimes at higher frequencies. Furthermore, we detected a strong increase in the number of integrations in a viral population for a TE absent from the hosts’ genomes, indicating that this TE has undergone intense transposition within the viral population. Finally, we provide evidence that many TEs found integrated in viral genomes (15/41) have been horizontally transferred in insects. Altogether, our results indicate that multiple large dsDNA viruses have the capacity to shuttle TEs in insects and they underline the potential of viruses to act as vectors of horizontal transfer of TEs. Furthermore, the finding that TEs can transpose between viral genomes of a viral species sets viruses as possible new niches in which TEs can persist and evolve.
Azithromycin or Doxycycline for Asymptomatic Rectal <i>Chlamydia trachomatis</i>
Authors: Andrew Lau, Fabian Y.S. Kong, Christopher K. Fairley, David J. Templeton, Janaki Amin, Samuel Phillips, Matthew Law, Marcus Y. Chen, Catriona S. Bradshaw, Basil Donovan, Anna McNulty, Mark A. Boyd, Peter Timms, Eric P.F. Chow, David G. Regan, Carole Khaw, David A. Lewis, John Kaldor, Mahesh Ratnayake, Natalie Carvalho, Jane S. Hocking
Journal: New England Journal of Medicine (2021)

Rectal chlamydia is a common bacterial sexually transmissible infection among men who have sex with men. Data from randomized, controlled trials are needed to guide treatment.In this double-blind trial conducted at five sexual health clinics in Australia, we randomly assigned men who have sex with men and who had asymptomatic rectal chlamydia to receive doxycycline (100 mg twice daily for 7 days) or azithromycin (1-g single dose). Asymptomatic chlamydia was selected as the trial focus because more than 85% of men with rectal chlamydia infection are asymptomatic, and clinical guidelines recommend a longer treatment course for symptomatic infection. The primary outcome was a negative nucleic acid amplification test for rectal chlamydia (microbiologic cure) at 4 weeks.From August 2016 through August 2019, we enrolled 625 men (314 in the doxycycline group and 311 in the azithromycin group). Primary outcome data were available for 290 men (92.4%) in the doxycycline group and 297 (95.5%) in the azithromycin group. In the modified intention-to-treat population, a microbiologic cure occurred in 281 of 290 men (96.9%; 95% confidence interval [CI], 94.9 to 98.9) in the doxycycline group and in 227 of 297 (76.4%; 95% CI, 73.8 to 79.1) in the azithromycin group, for an adjusted risk difference of 19.9 percentage points (95% CI, 14.6 to 25.3; P<0.001). Adverse events that included nausea, diarrhea, and vomiting were reported in 98 men (33.8%) in the doxycycline group and in 134 (45.1%) in the azithromycin group (risk difference, -11.3 percentage points; 95% CI, -19.5 to -3.2).A 7-day course of doxycycline was superior to single-dose azithromycin in the treatment of rectal chlamydia infection among men who have sex with men. (Funded by the National Health and Medical Research Council; RTS Australian New Zealand Clinical Trials Registry number, ACTRN12614001125617.).
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV): Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics
Authors: Lisa LaVange, Stacey J. Adam, Judith S. Currier, Elizabeth S. Higgs, Lora A. Reineck, Eric A. Hughes, Sarah W. Read
Journal: Annals of Internal Medicine (2021)

Working in an unprecedented time frame, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership developed and launched 9 master protocols between 14 April 2020 and 31 May 2021 to allow for the coordinated and efficient evaluation of multiple investigational therapeutic agents for COVID-19. The ACTIV master protocols were designed with a portfolio approach to serve the following patient populations with COVID-19: mild to moderately ill outpatients, moderately ill inpatients, and critically ill inpatients. To facilitate the execution of these studies and minimize start-up time, ACTIV selected several existing networks to launch the master protocols. The master protocols were also designed to test several agent classes prioritized by ACTIV that covered the spectrum of the disease pathophysiology. Each protocol, either adaptive or pragmatic, was designed to efficiently select those treatments that provide benefit to patients while rapidly eliminating those that were either ineffective or unsafe. The ACTIV Therapeutics-Clinical Working Group members describe the process by which these master protocols were designed, developed, and launched. Lessons learned that may be useful in meeting the challenges of a future pandemic are also described.
Glutamine-Dependence Targeting By Asparaginase Significantly Increases Anti-Myeloma Activity of Proteasome Inhibitors
Authors: Paola Minetto, Debora Soncini, Antonia Cagnetta, Fabio Guolo, Veronica Retali, Giulia Rivoli, Nadia Bisso, Nikki Di Felice, Maurizio Miglino, Letizia Canepa, Roberto Massimo Lemoli, Marco Gobbi, Michele Cea
Journal: Blood (2017)
Henrik Sjögren (1899–1986): the syndrome and his legacy
Authors: Roland Jonsson
Journal: Annals of the Rheumatic Diseases (2021)

Henrik Samuel Conrad Sjogren was born on 23 July 1899 in the small city of Koping, in the county of Vastmanland, Sweden. He studied medicine at the Karolinska Institute and received his license as an authorised doctor in 1927 (figure 1). Henrik Sjogren’s biography has been highlighted previously; one was in connection with the scientific meeting in Jonkoping, Sweden celebrating the 100-year anniversary of his birth in 1999.1 



Figure 1 
Portrait of Henrik Sjogren.



In January 1930, at the Serafimer Hospital in Stockholm, Henrik Sjogren met a 49-year-old female patient who had suffered for about 6 years from pain in different joints, especially in her hands. However, the visit to Dr Sjogren was due to irritation of her eyes. Further, she reported problem about difficulties in eating and swallowing, due to lack of saliva. He had previously observed similar cases and that year he published in Hygiea, the Proceedings of the Swedish Medical Association, a paper in which he described another four cases.2 In that article, he coined the symptom ‘keratoconjunctivitis sicca’ and where he also carefully described the method to stain the damaged cells in the conjunctiva and cornea by using 1% Bengal rose. The staining was similar to that seen in ‘keratitis filiformis’.

At this time, Sjogren was well aware of that each …
Abstract 2638: Developing 3d hydrogel model for patient-derived organoids of metastatic colorectal cancer
Authors: He Wei, Eveliina Karelehto, Karen Dubbin, Aimy Sebastian, Robert Warren, Monica Moya, Gaby Loots, Elizabeth Wheeler, Matthew Coleman
Journal: Cancer Research (2021)

Abstract The advances in the development of preclinical models for various cancers have tremendously helped study of the biology and genetics of human cancers as well as for development of therapeutics. Recently, patient-derived organoids (PDOs) have emerged as a robust preclinical platform that can provide insight into the patient specific genetic mechanisms, cancer progression and drug susceptibility. We have developed a novel PDO platform by embedding patient-derived organoids in a 3D hydrogel suspension culture. Our previous studies have shown that, when cultured in hydrogel, spheroids derived from cancer cell lines demonstrated upregulated gene expression signatures in relation to migration and angiogenesis compared to cultures in media, suggesting a more hypoxic, nutrient deficient environment. Given that hypoxia and nutrient deficiency are important feathers of solid tumors, the hydrogel environment could provide a good platform for in vitro study of tumor development and resistance to treatment. In the current study, we embedded PDOs derived from liver metastasis of colorectal cancer into the 3D suspension hydrogel culture. The PDOs adapted well in the hydrogel gel environment. We assessed the response of PDOs in hydrogel to anticancer agents, and compared that to those cultured in media. The PDOs cultured in hydrogel showed significantly elevated resistance to the treatments. The IC50s of chemotherapeutic drugs 5-fluorouracil and oxaliplatin are increased by ~5-10 fold when cultured in hydrogel compared to those in media. Further studies through RNAseq analysis revealed differentially activated signaling pathways. In particular, the levels of the CXC ligand family chemokines are significantly up-regulated in the PDOs cultured in the hydrogel. The CXC ligand family chemokines are important immune stimulants that are known to play key role in the chemotaxis and tumor recruitment of immune cells including neutrophil, T-cell and B-cells. Interestingly, the elevated levels of CXC-ligands have been shown to relate to resistance of colorectal cancer against drug treatment such as 5-fluorouracil. Our hydrogel model could help elucidate the mechanisms behind such resistance. Future study will focus on evaluating how well the hydrogel PDO platform can recapitulate tumor microenvironment and its potential in screening for personalized medicine. Citation Format: He Wei, Eveliina Karelehto, Karen Dubbin, Aimy Sebastian, Robert Warren, Monica Moya, Gaby Loots, Elizabeth Wheeler, Matthew Coleman. Developing 3d hydrogel model for patient-derived organoids of metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2638.
Evaluating medical student assessment of common dermatologic conditions across Fitzpatrick phototypes and skin of color
Authors: Andrina Mamo, Mindy D. Szeto, Hope Rietcheck, Stephanie Yu, Khyla Burrows, Jadesola T. Olayinka, Pratibha Anand, Robert P. Dellavalle, Cory A. Dunnick
Journal: Journal of the American Academy of Dermatology (2021)
Recent strategies for nano-based PTT combined with immunotherapy: from a biomaterial point of view
Authors: Xingyue Huang, Yang Lu, Mingxue Guo, Shouying Du, Ning Han
Journal: Theranostics (2021)

Cancer has been a great threat to humans for decades. Due to the limitations of monotherapy, combinational therapies such as photothermal therapy (PTT) and immunotherapy have gained increasing attention with expectation to overcome the shortfalls of each other and obtain satisfactory therapeutic outcomes. PTT can inhibit primary tumors by thermal ablation but usually fails to achieve complete eradication and cannot prevent metastasis and recurrence. Meanwhile, the efficacy of immunotherapy is usually attenuated by the weak immunogenicity of tumor and the immunosuppressive tumor microenvironment (ITM). Therefore, many recent studies have attempted to synergize PTT with immunotherapy in order to enhance the therapeutic efficacy. In this review, we aim to summarize the cutting-edge strategies in combining nano-based PTT with immunotherapy for cancer treatment. Herein, the combination strategies were mainly classified into four categories, including 1) nano-based PTT combined with antigens to induce host immune responses; 2) nano-based PTT in combination with immune adjuvants acting as
Loss of Optineurin Drives Cancer Immune Evasion via Palmitoylation-Dependent IFNGR1 Lysosomal Sorting and Degradation
Authors: Wan Du, Fang Hua, Xiong Li, Jian Zhang, Shasha Li, Weichao Wang, Jiajia Zhou, Weimin Wang, Peng Liao, Yijian Yan, Gaopeng Li, Shuang Wei, Sara Grove, Linda Vatan, Witold Zgodziński, Marek Majewski, Grzegorz Wallner, Haoyan Chen, Ilona Kryczek, Jing-Yuan Fang, Weiping Zou
Journal: Cancer Discovery (2021)

Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal cancer infrequently exhibit IFN and MHC signaling gene mutations and are generally resistant to immunotherapy. In exploring the integrity of IFN and MHC signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways and predicted colorectal cancer patient outcome. Loss of optineurin occurs in early-stage human colorectal cancer. Immunologically, optineurin deficiency was shown to attenuate IFNGR1 and MHC-I expression, impair T-cell immunity, and diminish immunotherapy efficacy in murine cancer models and patients with cancer. Mechanistically, we observed that IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated IFNGR1 lysosomal sorting and degradation, thereby maintaining IFNγ and MHC-I signaling integrity. Furthermore, pharmacologically targeting IFNGR1 palmitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer. SIGNIFICANCE: Loss of optineurin impairs the integrity of both IFNγ and MHC-I signaling pathways via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation, thereby driving immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Our work suggests that pharmacologically targeting IFNGR1 palmitoylation can stabilize IFNGR1, enhance T-cell immunity, and sensitize checkpoint therapy in colorectal cancer.See related commentary by Salvagno and Cubillos-Ruiz, p. 1623.This article is highlighted in the In This Issue feature, p. 1601.
Intraoperative Scintigraphy With Portable Gamma Camera for the Localization of Interaortocaval Paraganglioma
Authors: Leticia Pérez-Santiago, Norberto Cassinello-Fernández, Raquel Alfonso-Ballester, Rafael Díaz-Expósito, Anaïs Moscardó-Navarro, Joaquín Ortega-Serrano
Journal: Clinical Nuclear Medicine (2021)

Abstract A 15-year-old adolescent girl diagnosed of interaortocaval paraganglioma with a positive 123 I-MIGB SPECT/CT and 1 unsuccessful prior surgery was operated on with the assistance of a handheld gamma camera. Once the lesion was located and removed, 2 images were taken, one of the surgical field (without 123 I-MIGB uptake) and another of the tumor ex vivo (with high 123 I-MIGB uptake), confirming that the lesion had been satisfactorily excised. This case highlights the use of a portable gamma camera as a useful tool to locate this rare tumor, with a SPECT/CT positive for 123 I-MIGB and a difficult anatomical location suspected.
Gender Disparity in Citations in High-Impact Journal Articles
Authors: Paula Chatterjee, Rachel M. Werner
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Women are less likely to be promoted and hold leadership positions in academic medicine. How often academic articles are cited is a key measure of scholarly impact and frequently assessed for professional advancement; however, it is unknown whether peer-reviewed articles written by men and women are cited differently. <h3>Objective</h3> To evaluate whether academic articles from high-impact medical journals written by men and women are cited differently. <h3>Design, Setting, and Participants</h3> In this cross-sectional study of all original research and commentary articles from 5 high-impact medical journals (<i>Annals of Internal Medicine, British Medical Journal, JAMA, JAMA Internal Medicine,</i>and<i>The New England Journal of Medicine</i>) from 2015 to 2018, the gender of the primary and senior authors of each article were identified using an online database, and the number of times each article has been cited was identified using Web of Science. The number of citations by primary and senior author gender were then compared. Data were analyzed from July 2020 to April 2021. <h3>Exposures</h3> Primary and senior authors' genders. <h3>Main Outcomes and Measures</h3> Number of citations per article. <h3>Results</h3> Among 5554 articles, women wrote 1975 (35.6%) as primary author and 1273 of 4940 (25.8%) as senior author. Original research articles written by women as primary authors had fewer median (interquartile range) citations than articles written by men as primary authors (36 [17-82] citations vs 54 [22-141] citations;<i>P</i> &lt; .001) and senior authors (37 [17-93] citations vs 51 [20-128] citations;<i>P</i> &lt; .001). Articles written by women as both primary and senior authors had approximately half as many median (interquartile range) citations as those authored by men as both primary and senior authors (33 [15-68] citations vs 59 [23-149] citations;<i>P</i> &lt; .001). Differences in citations remained in each year of the study and were less pronounced among commentary articles. <h3>Conclusions and Relevance</h3> In this study, articles written by women in high-impact medical journals had fewer citations than those written by men, particularly when women wrote together as primary and senior authors. These differences may have important consequences for the professional success of women and achieving gender equity in academic medicine.
Gene editing in a Myo6 semi-dominant mouse model rescues auditory function
Authors: Yuanyuan Xue, Xinde Hu, Daqi Wang, Di Li, Yige Li, Fang Wang, Mingqian Huang, Xi Gu, Zhijiao Xu, Jinan Zhou, Jinghan Wang, Renjie Chai, Jun Shen, Zheng-Yi Chen, Geng-Lin Li, Hui Yang, Huawei Li, Erwei Zuo, Yilai Shu
Journal: Molecular Therapy (2021)

Myosin VI(MYO6) is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases. Myosin VI(MYO6) is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases.