tbuckley/cabot-search huggingface dataset:
Instrumental variable meta-analysis of aggregated randomized drug trial data for evaluating proposed target mechanisms
Authors: Sarah F Ackley, Fanny Elahi, M Maria Glymour
Journal: BMJ (2021)

Clinical trials provide an opportunity to understand not only drug efficacy but also disease biology. Instrumental variable meta-analysis provides an approach to combining results from multiple trials into a single estimate of the effect of modifying a biological target on an outcome of interest.
Abstract GS1-08: The MYC oncogene suppresses tumor immune infiltration and function which is reversible with combinatorial immunotherapies
Authors: Joyce V Lee, Filomena Housley, Christina Yau, Golzar Hemmati, Yibing Zhang, Susan Samson, Carole Baas, Hope Rugo, Mehrdad Matloubian, Andrei Goga
Journal: Cancer Research (2021)

Abstract Immunotherapy has great potential to improve outcomes for breast cancer patients. Yet, deciding on how to rationally combine therapeutic agents and predict patient populations who would benefit remains challenging. Less than 20% of patients with metastatic breast cancer respond to current immunotherapy regiments, further demonstrating the need for research in this area. We postulate that oncogene activation leads to immune-related vulnerabilities which can be exploited to discover new immunotherapy combinations with improved efficacy. MYC is an oncogene that is frequently overexpressed in the majority of triple negative breast cancers (TNBCs), and is frequently found in disease recurrence, metastasis, and chemotherapy resistance. Despite the association of MYC with poor patient outcome, little is known about how MYC facilitates immune evasion in TNBC. Using TNBC patient datasets from the TCGA, we discovered that the MYC gene signature is anti-correlated with T-cell activation signatures and a subset of genes that regulate antigen processing and presentation with MHC-I. We further examined the effects of MYC using a MYC-driven mammary tumor mouse model (MTB-TOM). MYC activation leads to downregulation of MHC-I expression on tumor cells, poor CD8+ T cell infiltration and consequently poor response to anti-PD-L1 monotherapy. We demonstrate three methods to improve response to immunotherapy—by inactivation of MYC, by inducing an interferon response within the breast tumor, or by inducing MYC tumor synthetic lethality with a small molecule inhibitor of PIM kinases. Using these combination immunotherapy strategies, we observed that a majority of animals eradicated their breast tumors and demonstrated a durable anti-tumor response following subsequent tumor re-challenge. Our data suggest MYC is an indicator of whether a breast cancer patient will respond to immunotherapy. Analysis of the MYC gene signature as a predictor of patient response to pembrolizumab in combination with paclitaxel followed by AC in the neoadjuvant I-SPY 2 trial is on-going and will be presented. Our study is the first to describe oncogenic MYC downregulation of MHC-I in a TNBC model of breast cancer and to demonstrate translatable approaches to overcome MYC orchestrated immune evasion. Citation Format: Joyce V Lee, Filomena Housley, Christina Yau, Golzar Hemmati, Yibing Zhang, Susan Samson, Carole Baas, Hope Rugo, Mehrdad Matloubian, Andrei Goga. The MYC oncogene suppresses tumor immune infiltration and function which is reversible with combinatorial immunotherapies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-08.
Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency
Authors: Malin Fromme, Carolin V Schneider, Vitor Pereira, Karim Hamesch, Monica Pons, Matthias C Reichert, Federica Benini, Paul Ellis, Katrine H Thorhauge, Mattias Mandorfer, Barbara Burbaum, Vivien Woditsch, Joanna Chorostowska-Wynimko, Jef Verbeek, Frederik Nevens, Joan Genesca, Marc Miravitlles, Alexa Nuñez, Benedikt Schaefer, Heinz Zoller, Sabina Janciauskiene, Nélia Abreu, Luís Jasmins, Rui Gaspar, Rodrigo Liberal, Guilherme Macedo, Ravi Mahadeva, Catarina Gomes, Kai Markus Schneider, Michael Trauner, Aleksander Krag, Bibek Gooptu, Douglas Thorburn, Aileen Marshall, John R Hurst, David A Lomas, Frank Lammert, Nadine T Gaisa, Virginia Clark, William Griffiths, Christian Trautwein, Alice M Turner, Noel G McElvaney, Pavel Strnad
Journal: Gut (2021)

Objective Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the ‘Pi*Z’ variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous ‘Pi*Z’ carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common ‘Pi*S’ variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. Design Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. Results Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8–53.7)) and primary liver cancer (aOR=44.5 (10.8–183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2–2.2)) and cholelithiasis (aOR=1.3 (1.2–1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1–8.2)) and primary liver cancer (aOR=6.6 (1.6–26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. Conclusion Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.
Multishell Nanoparticles with “Linkage Mechanism” for Thermal Responsive Photodynamic and Gas Synergistic Therapy
Authors: Jiawei Zhu, Weili Wang, Xiaorui Wang, Liping Zhong, Xuejiao Song, Wenjun Wang, Yongxiang Zhao, Xiaochen Dong
Journal: Advanced Healthcare Materials (2021)

Abstract The strategies of combining photodynamic therapy (PDT) with other therapeutics are considered to be the most suitable methods in improving the antitumor therapeutic efficiency. Herein, a “Linkage Mechanism” strategy based on thermal controllable multishell nanoparticles (CuS@SiO 2 ‐ l ‐Arg ( l ‐arginine)@PCM (phase‐change material)‐Ce6 (chiorin e6)) is proposed for combing PDT and NO‐based gas therapy. Upon 1060 nm laser irradiation, the PCMs will melt under the photothermal effect induced by CuS and the loaded Ce6 and l ‐Arg can accurately release from the nanoparticles. Under further 660 nm laser irradiation, the released Ce6 will produce plenty of singlet oxygen ( 1 O 2 ) for PDT, while the generated 1 O 2 can oxidize l ‐Arg to release NO for the synergy of PDT and gas therapy. The “Linkage Mechanism” can achieve precise release of the payloads under the control of photothermal effect at tumor site, and the chain reaction of PDT and gas therapy overcomes the problem of premature release of gas during transportation. Benefiting from the guidance of fluorescence imaging and second near infrared photoacoustic imaging by Ce6 and CuS, both in vitro and in vivo experiments present effective antitumor efficiencies. The nanoparticles provide new ideas for controllable release of drugs and the synergistic effect of multiple treatments, possessing great application prospects.
A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS–Driven Lung Cancer
Authors: Hongchen Cai, Su Kit Chew, Chuan Li, Min K. Tsai, Laura Andrejka, Christopher W. Murray, Nicholas W. Hughes, Emily G. Shuldiner, Emily L. Ashkin, Rui Tang, King L. Hung, Leo C. Chen, Shi Ya C. Lee, Maryam Yousefi, Wen-Yang Lin, Christian A. Kunder, Le Cong, Christopher D. McFarland, Dmitri A. Petrov, Charles Swanton, Monte M. Winslow
Journal: Cancer Discovery (2021)

Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. SIGNIFICANCE: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS-driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models.This article is highlighted in the In This Issue feature, p. 1601.
Using viral load and epidemic dynamics to optimize pooled testing in resource-constrained settings
Authors: Brian Cleary, James A. Hay, Brendan Blumenstiel, Maegan Harden, Michelle Cipicchio, Jon Bezney, Brooke Simonton, David Hong, Madikay Senghore, Abdul K. Sesay, Stacey Gabriel, Aviv Regev, Michael J. Mina
Journal: Science Translational Medicine (2021)

Virological testing is central to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) containment, but many settings face severe limitations on testing. Group testing offers a way to increase throughput by testing pools of combined samples; however, most proposed designs have not yet addressed key concerns over sensitivity loss and implementation feasibility. Here, we combined a mathematical model of epidemic spread and empirically derived viral kinetics for SARS-CoV-2 infections to identify pooling designs that are robust to changes in prevalence and to ratify sensitivity losses against the time course of individual infections. We show that prevalence can be accurately estimated across a broad range, from 0.02 to 20%, using only a few dozen pooled tests and using up to 400 times fewer tests than would be needed for individual identification. We then exhaustively evaluated the ability of different pooling designs to maximize the number of detected infections under various resource constraints, finding that simple pooling designs can identify up to 20 times as many true positives as individual testing with a given budget. Crucially, we confirmed that our theoretical results can be translated into practice using pooled human nasopharyngeal specimens by accurately estimating a 1% prevalence among 2304 samples using only 48 tests and through pooled sample identification in a panel of 960 samples. Our results show that accounting for variation in sampled viral loads provides a nuanced picture of how pooling affects sensitivity to detect infections. Using simple, practical group testing designs can vastly increase surveillance capabilities in resource-limited settings.
Adenosine A3 agonists reverse neuropathic pain via T cell–mediated production of IL-10
Authors: Mariaconcetta Durante, Silvia Squillace, Filomena Lauro, Luigino Antonio Giancotti, Elisabetta Coppi, Federica Cherchi, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Grant Kolar, Carrie Wahlman, Adeleye Opejin, Cuiying Xiao, Marc L. Reitman, Dilip K. Tosh, Daniel Hawiger, Kenneth A. Jacobson, Daniela Salvemini
Journal: Journal of Clinical Investigation (2021)

The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A3ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing, but unknown. The present study discovered that Rag-KO mice lacking T and B cells, as compared with WT mice, are insensitive to the anti-allodynic effects of A3AR agonists. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T cells from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in Rag-KO mice. CD4+ T cells from Adora3-KO or Il10-KO mice did not. Transfer of CD4+ T cells from WT mice, but not Il10-KO mice, into Il10-KO mice or Adora3-KO mice fully reinstated the anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when cocultured with CD4+ T cells in an IL-10-dependent manner. A3AR action on CD4+ T cells infiltrated in the DRG decreased phosphorylation of GluN2B-containing N-methyl-D-aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of A3AR on CD4+ T cells to release IL-10 is required and sufficient evidence for the use of A3AR agonists as therapeutics.
Vaccines for older adults
Authors: Anthony L Cunningham, Peter McIntyre, Kanta Subbarao, Robert Booy, Myron J Levin
Journal: BMJ (2021)

Abstract The proportion of the global population aged 65 and older is rapidly increasing. Infections in this age group, most recently with SARS-CoV-2, cause substantial morbidity and mortality. Major improvements have been made in vaccines for older people, either through the addition of novel adjuvants—as in the new recombinant zoster vaccine and an adjuvanted influenza vaccine—or by increasing antigen concentration, as in influenza vaccines. In this article we review improvements in immunization for the three most important vaccine preventable diseases of aging. The recombinant zoster vaccine has an efficacy of 90% that is minimally affected by the age of the person being vaccinated and persists for more than four years. Increasing antigen dose or inclusion of adjuvant has improved the immunogenicity of influenza vaccines in older adults, although the relative effectiveness of the enhanced influenza vaccines and the durability of the immune response are the focus of ongoing clinical trials. Conjugate and polysaccharide pneumococcal vaccines have similar efficacy against invasive pneumococcal disease and pneumococcal pneumonia caused by vaccine serotypes in older adults. Their relative value varies by setting, depending on the prevalence of vaccine serotypes, largely related to conjugate vaccine coverage in children. Improved efficacy will increase public confidence and uptake of these vaccines. Co-administration of these vaccines is feasible and important for maximal uptake in older people. Development of new vaccine platforms has accelerated following the arrival of SARS-CoV-2, and will likely result in new vaccines against other pathogens in the future.
Prevalence of Subclinical Myocardial Dysfunction in Hospitalized Patients With Covid-19 and Association With In-hospital Mortality
Authors: A. Minhas, N. A. Gilotra, E. Goerlich, B. T. Garibaldi, T. S. Metkus, G. Sharma, N. Bavaro, S. Phillip, E. D. Michos, A. G. Hays
Journal: Circulation (2020)
A scorecard of progress towards measles elimination in 15 west African countries, 2001–19: a retrospective, multicountry analysis of national immunisation coverage and surveillance data
Authors: Oghenebrume Wariri, Esin Nkereuwem, Ngozi A Erondu, Bassey Edem, Oluwatosin O Nkereuwem, Olubukola T Idoko, Emmanuel Agogo, Joseph E Enegela, Tom Sesay, Iya Saidou Conde, Landry Kaucley, Anthony Afum-Adjei Awuah, Sule Abdullahi, Richard Ray Luce, Richard Banda, Terna Nomhwange, Beate Kampmann
Journal: The Lancet Global Health (2021)

The WHO Regional Office for the Africa Regional Immunization Technical Advisory Group, in 2011, adopted the measles control and elimination goals for all countries of the African region to achieve in 2015 and 2020 respectively. Our aim was to track the current status of progress towards measles control and elimination milestones across 15 west African countries between 2001 and 2019.We did a retrospective multicountry series analysis of national immunisation coverage and case surveillance data from Jan 1, 2001, to Dec 31, 2019. Our analysis focused on the 15 west African countries that constitute the Economic Community of West African States. We tracked progress in the coverage of measles-containing vaccines (MCVs), measles supplementary immunisation activities, and measles incidence rates. We developed a country-level measles summary scorecard using eight indicators to track progress towards measles elimination as of the end of 2019. The summary indicators were tracked against measles control and elimination milestones.The weighted average regional first-dose MCV coverage in 2019 was 66% compared with 45% in 2001. 73% (11 of 15) of the west African countries had introduced second-dose MCV as of December, 2019. An estimated 4 588 040 children (aged 12-23 months) did not receive first-dose MCV in 2019, the majority (71%) of whom lived in Nigeria. Based on the scorecard, 12 (80%) countries are off-track to achieving measles elimination milestones; however, Cape Verde, The Gambia, and Ghana have made substantial progress.Measles will continue to be endemic in west Africa after 2020. The regional measles incidence rate in 2019 was 33 times the 2020 elimination target of less than 1 case per million population. However, some hope exists as countries can look at the efforts made by Cape Verde, The Gambia, and Ghana and learn from them.None.
A not-so proximate account of cleansing behavior
Authors: Jonathan Sigger, Thomas E. Dickins
Journal: Behavioral and Brain Sciences (2021)

Abstract In this commentary we outline perceptual control theory and suggest this as a fruitful way for Lee and Schwarz (L&amp;S) to fully embody their account of cleansing behavior. Moreover, we take issue with the command control approach that L&amp;S have taken seeing this as an unnecessary cognitive commitment within an embodied model of cleansing behavior.
Covid-19: Vaccine success drives England’s lockdown exit
Authors: Gareth Iacobucci, Elisabeth Mahase
Journal: BMJ (2021)

The government has announced plans for a gradual lifting of the current covid-19 lockdown in England from next month, based on its assessment of the current evidence (box 1). Box 1 ### The evidence behind the government's decisions #### Siren study The Pfizer and BioNTech covid-19 vaccine is at least 70% effective against symptomatic and asymptomatic infection 21 days after the first dose and at least 85% seven days after the second dose, shows a UK study of healthcare workers. The Siren study previously investigated the effect of prior infection on protection against reinfection but has now been amended to investigate vaccine effectiveness. The first results following this update have looked at the eight weeks after the first Pfizer-BioNTech vaccine dose. The report from Public Health England has said that there were 977 new infections during 710 587 person days of follow-up in the unvaccinated group, equating to an incidence density of 14 infections per 10 000 person days of follow-up. In comparison, there were 71 new infections 21 days after the first dose … RETURN TO TEXT
Abstract PS9-48: Depression, sexual dysfunction and quality of life among breast cancer patients with ovarian function suppression: A cross sectional study between ovarian ablation verse GnRH agonists
Authors: Junnnan Xu, Tao Sun
Journal: Cancer Research (2021)

Abstract Background: Ovarian function suppression is being widely utilized as endocrine therapy to reduce estrogen release in premenopausal breast cancer patients and was achieved either by medical treatment with the Gonadotropin releasing hormone (GnRH) agonist or bilateral oophorectomy. This study aimed to examine the difference between GnRHa and ovarian ablation on depression, sexual dysfunction and quality of life.Methods: The premenopausal breast cancer patients who received ovarian function suppression were enrolled from seven hospital between June 2019 and February 2020. Our independent variable was the type of ovarian suppression, categorized as Ovarian Ablation (OA cohort, n=62) and medical GnRH agonist (GnRHa cohort, n=260). The self-administered questionnaire (OFS-Q5) developed and used in this study aimed to assess the depression (PHQ-9), sexual dysfunction (FSFI) and quality of life (EORTC QLQ-BR23), as well as the contributing factors.Results: In this cross-sectional study, 322 patients with ovarian function suppression completed surveys were collected. The mean sum score of the PHQ-9 in GnRHa cohort tend to be lower than that in ovarian ablation (OA) cohort (9.6 ±5.2 vs. 11.0 ±5.8, OR=1.495, P=0.080). Patients with major depression (PHQ-9≧15) was indicated significantly fewer in GnRHa cohort. Less patients met the criteria for sexual dysfunction (66.1%, FSFI&amp;lt; 26.55) in OA cohort compared with 81.5% of patients with GnRHa (P = 0.008). The ratio of sexual dysfunction remained lower for ovarian ablation women in long-term ovarian suppression (duration of ovarian suppression &amp;gt; 2 years: OA vs GnRHa, 36.7% vs 78.4%, P=2.4E-05). The differences of most subscales of QLQ-BR23 were insignificant in both cohorts.Conclusions: Our finding demonstrate here for the first time that ovarian ablation resulted in worse depression, favour sexual function than those with medical GnRHa, with similar quality of life. More attention need to paid on adverse effect in patients with diverse ovarian function suppression. Citation Format: Junnnan Xu, Tao Sun. Depression, sexual dysfunction and quality of life among breast cancer patients with ovarian function suppression: A cross sectional study between ovarian ablation verse GnRH agonists [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-48.