tbuckley/cabot-search huggingface dataset:
Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine
Authors: Cheryl Keech, Gary Albert, Iksung Cho, Andreana Robertson, Patricia Reed, Susan Neal, Joyce S Plested, Mingzhu Zhu, Shane Cloney-Clark, Haixia Zhou, Gale Smith, Nita Patel, Matthew B Frieman, Robert E Haupt, James Logue, Marisa McGrath, Stuart Weston, Pedro A Piedra, Chinar Desai, Kathleen Callahan, Maggie Lewis, Patricia Price-Abbott, Neil Formica, Vivek Shinde, Louis Fries, Jason D Lickliter, Paul Griffin, Bethanie Wilkinson, Gregory M Glenn
Journal: New England Journal of Medicine (2020)

NVX-CoV2373 is a recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant.We initiated a randomized, placebo-controlled, phase 1-2 trial to evaluate the safety and immunogenicity of the rSARS-CoV-2 vaccine (in 5-μg and 25-μg doses, with or without Matrix-M1 adjuvant, and with observers unaware of trial-group assignments) in 131 healthy adults. In phase 1, vaccination comprised two intramuscular injections, 21 days apart. The primary outcomes were reactogenicity; laboratory values (serum chemistry and hematology), according to Food and Drug Administration toxicity scoring, to assess safety; and IgG anti-spike protein response (in enzyme-linked immunosorbent assay [ELISA] units). Secondary outcomes included unsolicited adverse events, wild-type virus neutralization (microneutralization assay), and T-cell responses (cytokine staining). IgG and microneutralization assay results were compared with 32 (IgG) and 29 (neutralization) convalescent serum samples from patients with Covid-19, most of whom were symptomatic. We performed a primary analysis at day 35.After randomization, 83 participants were assigned to receive the vaccine with adjuvant and 25 without adjuvant, and 23 participants were assigned to receive placebo. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean, ≤2 days). One participant had mild fever that lasted 1 day. Unsolicited adverse events were mild in most participants; there were no severe adverse events. The addition of adjuvant resulted in enhanced immune responses, was antigen dose-sparing, and induced a T helper 1 (Th1) response. The two-dose 5-μg adjuvanted regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic Covid-19 patients (8344 and 983, respectively).At 35 days, NVX-CoV2373 appeared to be safe, and it elicited immune responses that exceeded levels in Covid-19 convalescent serum. The Matrix-M1 adjuvant induced CD4+ T-cell responses that were biased toward a Th1 phenotype. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04368988).
Abstract 4376: OP-1250, a complete estrogen receptor antagonist (CERAN) that shrinks estrogen receptor positive tumors and exhibits favorable pharmacokinetics
Authors: Leslie Hodges-Gallagher, Cyrus L. Harmon, Richard Sun, David C. Myles, Peter Kushner
Journal: Cancer Research (2020)

Abstract Fulvestrant (FASLODEX), a Complete Estrogen Receptor ANtagonist (CERAN) is recognized as the most effective endocrine therapy for estrogen receptor positive (ER+) metastatic breast cancer. Unfortunately, fulvestrant must be injected i.m. and has poor drug exposure. Thus, an oral compound that shares fulvestrant's drug virtues with improved drug exposure might be both more effective and more convenient than fulvestrant. This realization has sparked intensive efforts to develop such a compound, however most efforts have focused on discovering novel selective estrogen receptor degraders (SERDS) most of which have also displayed agonist activities on gene expression and uterus, and are therefore are also selective estrogen receptor modulators (SERMs). We predict that CERANs that fully block the activities of estrogen receptor alpha (ERalpha) will have a clinical advantage over SERM/SERDs in shrinking breast tumors as well as preventing and treating endocrine resistance. We have developed a small molecule, OP-1250 that, like fulvestrant, is a CERAN that completely turns off both transcriptional activation functions of ERalpha, as can be seen in a uterine cell assay, and also prevents uterine weight gain in ovariectomized mice. In addition, it blocks degrades ERalpha and blocks the proliferation of a large variety of ER+ breast cells. Using RNAseq, we found many estrogen-regulated biomarkers that are also regulated by SERM/SERDs, however CERANS such as OP-1250 and fulvestrant have no, or even an inverse effect on many such genes. Unlike fulvestrant, OP-1250 gives high and stable oral drug exposure in multiple species. Consequentially, OP-1250 effectively shrinks ER+ tumors in multiple human tumor xenografts in mice at very low daily doses of 3 mg/kg, even in models containing activating ERalpha mutant receptors. Importantly, the pharmacokinetics and biodistribution of OP-1250 has a favorable profile that results in unusual potency of OP-1250 in vivo. Citation Format: Leslie Hodges-Gallagher, Cyrus L. Harmon, Richard Sun, David C. Myles, Peter Kushner. OP-1250, a complete estrogen receptor antagonist (CERAN) that shrinks estrogen receptor positive tumors and exhibits favorable pharmacokinetics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4376.
Abstract 4642: Effects of soy protein diet on plasma isoflavones levels in obese DMBA-induced mammary tumor rat model
Authors: Reza Hakkak, Soheila Korourian
Journal: Cancer Research (2020)

Abstract Obesity epidemic in the US and world grows as the number of overweight and obese adults continues to rise. Obese women have higher mortality rates from all cancers including breast cancer. Several studies have reported the protective effects of soy intake on breast cancer development, while other studies report the adverse effects of soy protein diet on breast cancer development. Soybeans contain isoflavones genistein, daidzein and glycitein, known as isoflavonoids, which are structurally similar to mammalian estrogens, have estrogenic properties and are potential anticarcinogens. Gut flora metabolizes daidzein into equol, a non-steroidal estrogen and has cancer chemopreventive property. The objective of this study was to determine the effects of obesity and a high isoflavones soy protein diet on plasma isoflavones; genistein, daidzein, glycitein, equol and O-Desmethylangolensin (O-MDA) levels using 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor model. Five-week-old female Zucker rats (45 obese fa/fa and 54 lean) were used. After one week of acclimation (age 42 days), rats were randomly assigned to the following diet groups; 1) Lean, casein; 2) Obese, casein; 3) Lean, soy and 4) Obese, soy. Rats had ad lib access to water and diet with either casein or soy protein isolate as source of protein. All rats were orally gavaged at age 50 days with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly and sacrificed 21 weeks post-DMBA treatment. Plasma was collected to measure genistein, daidzein, glycitein, equol and O-MDA levels using liquid chromatography−tandem mass spectrometry (LC-MS/MS). At end of the experiment, 69% of the Lean casein rats developed mammary tumors compared to 50% in lean soy group (p= 0.176). In the obese group, 76% of the soy-fed rats developed mammary tumors compared to 15% (P&amp;lt;0.001) of obese casein- fed rats. Plasma daidzein and genistein concentration were not significantly different in lean vs obese soy-fed rats. However, O-MDA and equol concentration were significantly lower (P&amp;lt;0.05) in obese soy-fed rats compared to lean soy rats. These data suggests that obese rats fed soy protein diet containing high isoflavone levels promoted DMBA-induced mammary tumor development compared to a casein-based diet. Also, obese soy-fed rats exhibited significantly lower plasma equol concentrations than those observed in lean soy-fed rats and this reduction may aid in explaining soy's impaired cancer chemopreventative effects in obese breast cancer model. Citation Format: Reza Hakkak, Soheila Korourian. Effects of soy protein diet on plasma isoflavones levels in obese DMBA-induced mammary tumor rat model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4642.
Interference of miR‐107 with Atg12 is inhibited by HULC to promote metastasis of hepatocellular carcinoma
Authors: Haiming Zhang, Shipeng Li, Haixu Xu, Liying Sun, Zhijun Zhu, Zhi Yao
Journal: MedComm (2020)

Highly upregulated in liver cancer (HULC) had a significant predictive effect on tumor growth and metastasis of hepatocellular carcinoma (HCC); however, the mechanisms of HULC on HCC still need to be clarified. We attempted to determine the roles of HULC and miR-107 in autophagy and invasion of HCC. HULC siRNA reduced the level of autophagy. The impact of HULC siRNA on invasion can be reversed by activating autophagy in HCC cell lines. Further studies on HULC and autophagy were conducted. An interacting sequence between HULC and miR-107, as well as miR-107 and Atg12, was predicted by software. The relationship of each pair of molecules was confirmed by luciferase reporter assays. The negative impacts of miR-107 on autophagy and invasion were proved in HCC cell lines. The inhibitor of miR-107-promoted invasion can also be reversed by Atg12 siRNA. The changes of miR-107, Atg12, epithelial-mesenchymal transition, and autophagy in transplanted tumors of mouse models also confirmed the results in HCC cell lines. Finally, we find that HULC acts as an endogenous sponge, which abolishes the binding of miR-107 on the Atg12 3'-UTR and promotes autophagy and metastasis of HCC.
Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR)
Authors: Xinran Cai, Ye Feng, Meishu Xu, Chaohui Yu, Wen Xie
Journal: Acta Pharmaceutica Sinica B (2020)

Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation.
TENOFOVIR TREATMENT FOR UP TO EIGHT YEARS RESULTS IN PRONOUNCED HBSAG DECLINE IN HBEAG-POSITIVE HIV/HBV CO-INFECTED PATIENTS
Authors: R. Zoutendijk, H.L. Zaaijer, T. de Vries-Sluijs, J.W. Mulder, F.P. Kroon, C. Richter, A.A. van der Eijk, M.J. Sonneveld, B.E. Hansen, R.A. de Man, M.E. van der Ende, H.L. Janssen
Journal: Hepatology (2011)
Defining a signature of residual risk following endocrine treatment in the tamoxifen and exemestane adjuvant multinational (TEAM) trial
Authors: J. Bayani, C.Q. Yao, Quintayo, S. Haider, C.L. Brookes, F. Yan, C.J.H. van de Velde, A. Hasenburg, D.G. Kieback, C. Markopoulos, L. Dirix, C. Seynaeve, P.C. Boutros, D.W. Rea, J.M.S. Bartlett
Journal: Cancer Research (2016)
Abstract 4943: The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic pontine glioma
Authors: Huizi Guo, Harpreet Kaur, Charles G. Eberhart, Eric H. Raabe
Journal: Cancer Research (2020)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. With radiation therapy as the primary treatment, the median survival after diagnosis is 6 months. Identifying molecular markers that regulate tumor growth is urgently needed to develop targeted therapies. LIN28B is a stem cell factor expressed during normal neural development and re-expressed in cancer cells. In many cancers, LIN28B acts as an RNA-binding protein and downregulates the tumor-suppressing let-7 microRNAs. We had previously shown that LIN28A, a homolog of LIN28B, regulates invasion and tumorigenicity in adult high-grade gliomas. LIN28B is known to be highly expressed in DIPG. Thus, we hypothesized that LIN28B would be important in DIPG by promoting tumor growth. We observed that LIN28B was expressed in patient-derived DIPG cell lines (JHHDIPG1, JHHDIPG16A, SUDIPGXIII, HSJD-007, SF7761). Knockdown of LIN28B using short hairpin RNAs decreased DIPG cell proliferation (BrdU incorporation) between 50% to 90% (p&amp;lt;0.01). The knockdown of LIN28B also increased DIPG cell apoptosis (cleaved caspase-3 and cleaved PARP expression) by 2- to 3-fold (p&amp;lt;0.01). To determine the molecular mechanism of LIN28B-mediated phenotypes in DIPG, we studied canonical downstream effectors of LIN28B. We found that when LIN28B was suppressed in DIPG cells, there was a decreased expression of the DNA-binding oncoprotein called high mobility group AT-hook 2. These findings suggest that LIN28B could be a potential therapeutic target for this devastating pediatric brain tumor. Future studies will focus on validating the role of LIN28B in DIPG growth in vivo using orthotopic zebrafish and mouse models. Citation Format: Huizi Guo, Harpreet Kaur, Charles G. Eberhart, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4943.
Dihydroartemisinin ameliorates psoriatic skin inflammation and its relapse by diminishing CD8<sup>+</sup> T-cell memory in wild-type and humanized mice
Authors: Yuchao Chen, Yuhong Yan, Huazhen Liu, Feifei Qiu, Chun-Ling Liang, Qunfang Zhang, Run-Yue Huang, Ling Han, Chuanjian Lu, Zhenhua Dai
Journal: Theranostics (2020)

Conventional immunosuppressants cause side effects and do not prevent the recurrence of autoimmune diseases. Moreover, they may not inhibit autoimmunity mediated by pathogenic memory T-cells. Dihydroartemisinin (DHA) has been shown to regulate autoimmunity. However, it remains unknown whether DHA impacts psoriasis and its recurrence. The objective of this study was to determine therapeutic effects of DHA on psoriasis and its relapse as well as its underlying mechanisms. Methods: We established animal models of imiquimod (IMQ)-induced psoriasis-like wild-type mice and humanized NSG mice receiving lesional human skin from patients with psoriasis. Many immunoassays, including immunohistochemistry, flow cytometry, quantitative RT-PCR and Western blotting, were performed. Results: We found that DHA not only ameliorated acute skin lesion of psoriatic mice, but also alleviated its recurrence by diminishing CD8+ central memory T (TCM) and CD8+ resident memory T (TRM) cells. It attenuated epidermal pathology and T-cell infiltration in the skin of IMQ-induced psoriatic mice while suppressing expression of IL-15, IL-17 and other proinflammatory cytokines in the skin. Surprisingly, DHA reduced the frequency and number of CD8+, but not CD4+, subset of CD44highCD62Lhigh TCM in psoriatic mice, whereas methotrexate (MTX) lowered CD4+, but not CD8+, TCM frequency and number. Indeed, DHA, but not MTX, downregulated eomesodermin (EOMES) and BCL-6 expression in CD8+ T-cells. Furthermore, DHA, but not MTX, reduced the presence of CD8+CLA+, CD8+CD69+ or CD8+CD103+ TRM cells in mouse skin. Interestingly, treatment with DHA, but not MTX, during the first onset of psoriasis largely prevented psoriasis relapse induced by low doses of IMQ two weeks later. Administration of recombinant IL-15 or CD8+, but not CD4+, TCM cells resulted in complete recurrence of psoriasis in mice previously treated with DHA. Finally, we demonstrated that DHA alleviated psoriatic human skin lesions in humanized NSG mice grafted with lesional skin from psoriatic patients while reducing human CD8+ TCM and CD103+ TRM cells in humanized mice. Conclusion: We have provided the first evidence that DHA is advantageous over MTX in preventing psoriasis relapse by reducing memory CD8+ T-cells.
Abstract 4609: TP53, PIK3CA, and BRAF somatic mutations in airway epithelial field of injury associated with lung cancer risk
Authors: Daniel J. Craig, Thomas Morrison, Sadik Khuder, Erin L. Crawford, Leihong Wu, Joshua Xu, Thomas M. Blomquist, James C. Willey
Journal: Cancer Research (2020)

Abstract Background: Lung cancer is the leading cause of cancer-related death in men and women, and cigarette smoking is the most significant preventable risk factor. Early detection through annual low dose CT screening reduces mortality but has low positive predictive value and specificity, in part due to low lung cancer incidence (&amp;lt;10%) among those who currently meet screening criteria. Thus, there is a need for biomarkers that reliably detect those at highest lung cancer risk, thereby enabling more effectivescreening. The purpose of this study was to test the hypothesis that high risk for lung cancer is characterized by high prevalence of low variant allele frequency (VAF) somatic mutations among known lung cancer driver genes in normal airway epithelial cells (AEC). Methods: Synthetic DNA internal standards (IS) were prepared for each of 11 lung cancer driver genes and mixed with each AEC genomic (g)DNA specimen prior to competitive multiplex PCR amplicon NGS library preparation. A custom Perl script was developed to separate IS reads and respective specimen gDNA reads from each target into separate files for parallel variant frequency analysis. This approach enabled reliable detection of mutations with VAF as low as 5 x 10-4 (0.05%). This method was then applied in a retrospective case-control study. Specifically, AEC specimens were collected by bronchoscopic brush biopsy from the normal airways of 19 subjects, including eleven lung cancer cases and eight non-cancer controls, and the association of lung cancer risk with AEC driver gene mutations was tested. Results: TP53 mutations with 0.05-1.0% VAF were more prevalent (p&amp;lt;0.005) and significantly more enriched for tobacco smoke and age-associated mutation signatures in AEC from lung cancer cases compared to non-cancer controls matched for smoking and age. Further, PIK3CA and BRAF mutations in this VAF range were identified in AEC from cases but not controls. Conclusions: Measurement of very low frequency mutations in the 0.05-1.0% VAF range enabled identification of an AEC somatic mutation field of injury associated with lung cancer risk. A biomarker comprising TP53, PIK3CA, and BRAF somatic mutations may better stratify individuals for optimal lung cancer screening and prevention outcomes. Citation Format: Daniel J. Craig, Thomas Morrison, Sadik Khuder, Erin L. Crawford, Leihong Wu, Joshua Xu, Thomas M. Blomquist, James C. Willey. TP53, PIK3CA, and BRAF somatic mutations in airway epithelial field of injury associated with lung cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4609.
Assessment of Health Conditions and Health Service Use Among Transgender Patients in Canada
Authors: Alex Abramovich, Claire de Oliveira, Tara Kiran, Tomisin Iwajomo, Lori E. Ross, Paul Kurdyak
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Transgender individuals experience stigma, discrimination, and socioeconomic disadvantages, leading to a myriad of poor health outcomes and high rates of disease burden; however, transgender health continues to be an understudied area. <h3>Objective</h3> To examine sociodemographic characteristics, health conditions, and health service utilization patterns among transgender individuals compared with the general population. <h3>Design, Setting, and Participants</h3> This cross-sectional study of 2085 transgender individuals from 3 large cities in Ontario, Canada, compared characteristics and health service use among transgender individuals with the general population in the province. Transgender individuals were identified through data obtained from 4 outpatient community and hospital clinics, which were linked with health administrative data between January 2012 and December 2016. Data were analyzed between October 2018 and May 2020. Individuals were age-matched 1:5 to a random 5% sample of the general Ontario population (10 425 individuals). <h3>Main Outcomes and Measures</h3> Sociodemographic variables, health service use, and chronic conditions among transgender individuals and the general population were compared. <h3>Results</h3> This study included a sample of 2085 transgender individuals with a mean (SD) age of 30.40 (12.81) years; 771 (37.0%) identified as transgender women. Compared with 10 425 cisgender controls, trangender individuals were more likely to live in lower-income neighborhoods (lowest-income quintile: 625 [30.0%] vs 2197 [21.1%];<i>P</i> &lt; .001) and experience chronic physical and mental health conditions, including higher rates of asthma (489 [23.5%] vs 2034 [19.5%];<i>P</i> &lt; .001), diabetes (115 [5.5%] vs 352 [3.4%];<i>P</i> &lt; .001), chronic obstructive pulmonary disease (51 [2.4%] vs 156 [1.5%];<i>P</i> &lt; .001), and HIV (34 [1.6%] vs 12 [0.1%];<i>P</i> &lt; .001). Comorbid chronic health conditions were higher among the transgender population compared with the cisgender population (702 [33.7%] vs 2941 [28.2%];<i>P</i> &lt; .001). Transgender individuals also had higher health service use compared with the general population, particularly for mental health and self-harm, including mean (SD) number of psychiatrist visits between January 2012 and December 2016 (8.25 [23.13] vs 0.93 [9.57]; standardized difference, 5.84). <h3>Conclusions and Relevance</h3> This study found higher rates of mental and physical comorbidities and higher health service use among transgender individuals compared with cisgender individuals. Further research should explore reasons for these findings. Clinicians caring for transgender individuals should be aware of the high potential for mental health issues and self-harm.
Pandemic preparedness of an academic medical centre in the Republic of Korea
Authors: Julia Ah-Reum An, Kyoung-Ho Song, Eu Suk Kim, Ruby Kwak, Jongtak Jung, Ji Young Park, Jeong Su Park, Hyunju Lee, Myoung Jin Shin, Hee Young Lee, Seungkwan Lim, Kyoung Un Park, June-Ho Kim, Asaf Bitton, Hong Bin Kim
Journal: Clinical Microbiology and Infection (2020)