tbuckley/cabot-search huggingface dataset:
Primary Bronchial Epithelial Cells Are Protected From Rhinovirus Infection By Activators Of The Nrf-2 Pathway
Authors: R Morgan-Walsh, E Goode, N Smithers, T S Hinks, T Havelock, N J Green, A Walker, A J Fisher, R Budd, D Singh, E J Swindle, C Blume, R Djukanovic, D E Davies
Journal: American Journal of Respiratory and Critical Care Medicine (2013)
Menstrual cycle regularity and length across the reproductive lifespan and risk of premature mortality: prospective cohort study
Authors: Yi-Xin Wang, Mariel Arvizu, Janet W Rich-Edwards, Jennifer J Stuart, JoAnn E Manson, Stacey A Missmer, An Pan, Jorge E Chavarro
Journal: BMJ (2020)

To evaluate whether irregular or long menstrual cycles throughout the life course are associated with all cause and cause specific premature mortality (age <70 years).Prospective cohort study.Nurses' Health Study II (1993-2017).79 505 premenopausal women without a history of cardiovascular disease, cancer, or diabetes and who reported the usual length and regularity of their menstrual cycles at ages 14-17 years, 18-22 years, and 29-46 years.Hazard ratios and 95% confidence intervals for all cause and cause specific premature mortality (death before age 70 years) were estimated from multivariable Cox proportional hazards models.During 24 years of follow-up, 1975 premature deaths were documented, including 894 from cancer and 172 from cardiovascular disease. Women who reported always having irregular menstrual cycles experienced higher mortality rates during follow-up than women who reported very regular cycles in the same age ranges. The crude mortality rate per 1000 person years of follow-up for women reporting very regular cycles and women reporting always irregular cycles were 1.05 and 1.23 for cycle characteristics at ages 14-17 years, 1.00 and 1.37 for cycle characteristics at ages 18-22 years, and 1.00 and 1.68 for cycle characteristics at ages 29-46 years. The corresponding multivariable adjusted hazard ratios for premature death during follow-up were 1.18 (95% confidence interval 1.02 to 1.37), 1.37 (1.09 to 1.73), and 1.39 (1.14 to 1.70), respectively. Similarly, women who reported that their usual cycle length was 40 days or more at ages 18-22 years and 29-46 years were more likely to die prematurely than women who reported a usual cycle length of 26-31 days in the same age ranges (1.34, 1.06 to 1.69; and 1.40, 1.17 to 1.68, respectively). These relations were strongest for deaths related to cardiovascular disease. The higher mortality associated with long and irregular menstrual cycles was slightly stronger among current smokers.Irregular and long menstrual cycles in adolescence and adulthood are associated with a greater risk of premature mortality (age <70 years). This relation is slightly stronger among women who smoke.
Abstract B08: Identification and characterization of Rho family GTPases as drivers of drug resistance in <i>BRAFV600</i> mutant melanoma
Authors: Jacob L. Schillo, Charlotte R. Feddersen, Afshin Varzavand, Hayley R. Vaughn, Lexy S. Wadsworth, Andrew P. Voigt, Eliot Y. Zhu, Jesse D. Riordan, Christopher S. Stipp, Adam J. Dupuy
Journal: Cancer Research (2020)

Abstract The serine/threonine protein kinase BRAF is mutated in approximately 50% of cutaneous melanomas, leading to hyperactivation of the MAPK/ERK pathway. The most common mutations, BRAFV600, can be targeted by selective kinase inhibitors, such as vemurafenib. Although initial clinical response to BRAF inhibition (BRAFi) is encouraging, 90% of patients develop drug resistance within a few months. Drug resistance can be delayed, but not prevented, by combining BRAFi with an MEK inhibitor (MEKi), such as cobimetinib. While some resistance mechanisms are known, disease progression on drug cannot be explained in all patients. We performed a gain-of-function mutagenesis screen utilizing the Sleeping Beauty transposon system to identify novel drivers of resistance in BRAFV600E mutant melanoma cells sensitive to current therapies. We chose four of the top candidates from our screen and validated the ability to drive resistance to both vemurafenib and vemurafenib-cobimetinib combination treatment in multiple melanoma cell lines. In an effort to determine the broader role of candidate vemurafenib-resistance drivers, we conducted an additional in vivo mutagenesis screen, of which genetic analysis is ongoing. Our initial cell-based screen identified two members of the Dbl family of guanine nucleotide exchange factors (GEFs), VAV1 and MCF2, as candidate drivers of vemurafenib resistance. A375 melanoma cells overexpressing VAV1 or MCF2 maintain significant growth under vemurafenib treatment, while control cells do not. Functional tests of VAV1 and MCF2 identified that the active form of two Rho family members, RAC1 and CDC42, increases following treatment with vemurafenib, suggesting a PAK-mediated pathway of resistance. In addition, all candidates that were tested elevated ERK signaling in the presence of vemurafenib. Many of the extracellular signaling pathways known to drive increased vemurafenib resistance activate Rho signaling. Our results suggest that Dbl family members may play an important role in this process. Understanding how Rho activation occurs and its consequences for drug resistance in melanoma will provide critical insights into the design and validation of future targeted therapies. Citation Format: Jacob L. Schillo, Charlotte R. Feddersen, Afshin Varzavand, Hayley R. Vaughn, Lexy S. Wadsworth, Andrew P. Voigt, Eliot Y. Zhu, Jesse D. Riordan, Christopher S. Stipp, Adam J. Dupuy. Identification and characterization of Rho family GTPases as drivers of drug resistance in BRAFV600 mutant melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B08.
The mother of invention
Authors: Robert Stirrups
Journal: The Lancet Infectious Diseases (2020)

The COVID-19 pandemic has presented innumerable challenges, but it has also inspired people from all professions and walks of life to share their skills and help solve the myriad problems the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created. The role that designers can play has not been widely considered, but a new exhibition at the Victoria & Albert Museum in Dundee, UK, called Now accepting contactless, makes a strong case that innovative design has a substantial role to play when managing a pandemic.
Short duration antibiotic therapy for native joint arthritis caused by<i>Neisseria</i>infection?
Authors: Maïlys Ducours, Samar El-Hout, Arnaud Desclaux, Hervé Dutronc, Thylbert Deltombe, Thomas Fauthoux, François Vercruysse, Marie Kostine, Charles Cazanave
Journal: Annals of the Rheumatic Diseases (2020)

Short duration antibiotic therapy for native joint arthritis caused by Neisseria infection?We read with great interest the article "Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomised, non-inferiority trial" by Gjika et al. 1 As staff members of a French Regional Referral Centre for complex bone and joint infections, we want to share our experience with short-duration antibiotic treatment for native joint arthritis caused by Neisseria gonorrhoeae (Ng) and Neisseria meningitidis (Nm).We conducted a retrospective study including all patients with arthritis caused by Gram-negative cocci treated in our institution from January 2018 to July 2020.Ten patients were included (seven men, three women; median age 34 years; table 1).Most patients had monarthritis (n=6); knees were the most frequently affected joints (n=7).Fever was inconsistent (n=5).Blood culture analyses were performed for nine patients and were positive for three patients.All but two patients (because absence of joint fluid) underwent joint aspiration.Direct examination and bacterial culture were positive in five and six of eight patients, respectively.Diagnoses were made using PCR of synovial fluid in two patients (#7 and #8) because their bacterial culture were negative without explanation (in particular no prior antibiotic therapy), antibiotic sensitivity could not be assessed for them.Six patients were infected with Ng and four with Nm.Ng was always resistant to ciprofloxacin and exhibited intermediate sensitivity to penicillin G. Nm was always sensitive to amoxicillin with a minimal inhibitory
STING regulates BCR signaling in normal and malignant B cells
Authors: Chih-Hang Anthony Tang, Avery C. Lee, Shiun Chang, Qin Xu, Andong Shao, Yun Lo, Walker T. Spalek, Javier A. Pinilla-Ibarz, Juan R. Del Valle, Chih-Chi Andrew Hu
Journal: Cellular and Molecular Immunology (2020)

Abstract STING is an endoplasmic reticulum (ER)-resident protein critical for sensing cytoplasmic DNA and promoting the production of type I interferons; however, the role of STING in B cell receptor (BCR) signaling remains unclear. We generated STING V154M knock-in mice and showed that B cells carrying constitutively activated STING specifically degraded membrane-bound IgM, Igα, and Igβ via SEL1L/HRD1-mediated ER-associated degradation (ERAD). B cells with activated STING were thus less capable of responding to BCR activation by phosphorylating Igα and Syk than those without activated STING. When immunized with T-independent antigens, STING V154M mice produced significantly fewer antigen-specific plasma cells and antibodies than immunized wild-type (WT) mice. We further generated B cell-specific STING KO mice and showed that STING KO B cells indeed responded to activation by transducing stronger BCR signals than their STING-proficient counterparts. When B cell-specific STING KO mice were T-independently immunized, they produced significantly more antigen-specific plasma cells and antibodies than immunized STING WT mice. Since both human and mouse IGHV-unmutated malignant chronic lymphocytic leukemia (CLL) cells downregulated the expression of STING, we explored whether STING downregulation could contribute to the well-established robust BCR signaling phenotype in malignant CLL cells. We generated a STING-deficient CLL mouse model and showed that STING-deficient CLL cells were indeed more responsive to BCR activation than their STING-proficient counterparts. These results revealed a novel B cell-intrinsic role of STING in negatively regulating BCR signaling in both normal and malignant B cells.
Recent advances in drug delivery systems for targeting cancer stem cells
Authors: Hongxia Duan, Yanhong Liu, Zhonggao Gao, Wei Huang
Journal: Acta Pharmaceutica Sinica B (2020)

Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of self-renewal, unlimited proliferation, and multi-directional differentiation potential. In addition, CSCs have the ability to escape immune surveillance. Thus, they play an important role in the occurrence and development of tumors, and they are closely related to tumor invasion, metastasis, drug resistance, and recurrence after treatment. Therefore, specific targeting of CSCs may improve the efficiency of cancer therapy. A series of corresponding promising therapeutic strategies based on CSC targeting, such as the targeting of CSC niche, CSC signaling pathways, and CSC mitochondria, are currently under development. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for CSC targeting are increasingly being developed. In this review, we summarize the advances in CSC-targeted DDSs. Furthermore, we highlight the latest developmental trends through the main line of CSC occurrence and development process; some considerations about the rationale, advantages, and limitations of different DDSs for CSC-targeted therapies were discussed.
Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients
Authors: Roberto Bolli, Emerson C. Perin, James T. Willerson, Phillip C. Yang, Jay H. Traverse, Timothy D. Henry, Carl J. Pepine, Raul D. Mitrani, Joshua M. Hare, Michael P. Murphy, Keith L. March, Sohail Ikram, David P. Lee, Connor O’Brien, Jean-Bernard Durand, Kathy Miller, Joao A. Lima, Mohammad R. Ostovaneh, Bharath Ambale-Venkatesh, Adrian P. Gee, Sara Richman, Doris A. Taylor, Shelly L. Sayre, Judy Bettencourt, Rachel W. Vojvodic, Michelle L. Cohen, Lara M. Simpson, Dejian Lai, David Aguilar, Catalin Loghin, Lem Moyé, Ray F. Ebert, Barry R. Davis, Robert D. Simari
Journal: JACC CardioOncology (2020)
Differential Markers of Bacterial and Viral Infections in Children for Point-of-Care Testing
Authors: Yu-Ting Tsao, Yao-Hung Tsai, Wan-Ting Liao, Ching-Ju Shen, Ching-Fen Shen, Chao-Min Cheng
Journal: Trends in Molecular Medicine (2020)

Children suffering from infectious diseases, both bacterial and viral, are often treated with empirical antibiotics. Keeping in mind both the menace of microorganisms and antibiotic toxicity, it is imperative to develop point-of-care testing (POCT) to discriminate bacterial from viral infections, and to define indications for antibiotic treatment. This article reviews potential protein biomarkers and host-derived gene expression signatures for differentiating between bacterial and viral infections in children, and focuses on emerging multiplex POCT devices for the simultaneous detection of sets of protein biomarkers or streamlined gene expression signatures that may provide rapid and cost-effective pathogen-discriminating tools.
Prostate-specific Antigen Progression in Enzalutamide-treated Men with Nonmetastatic Castration-resistant Prostate Cancer: Any Rise in Prostate-specific Antigen May Require Closer Monitoring
Authors: Fred Saad, Cora N. Sternberg, Eleni Efstathiou, Karim Fizazi, Katharina Modelska, Xun Lin, Jennifer Sugg, Joyce Steinberg, Bettina Noerby, Neal D. Shore, Maha Hussain
Journal: European Urology (2020)

There is no universally accepted definition for prostate-specific antigen (PSA) progression. However, changes in PSA in patients with castration-resistant prostate cancer (CRPC) are used to inform treatment decisions.To determine whether the Prostate Cancer Working Group 2 (PCWG2) definition of PSA progression is adequate to predict radiographic or clinical progression in enzalutamide-treated men with nonmetastatic CRPC (nmCRPC).A post hoc, retrospective analysis of men with nmCRPC from PROSPER (NCT02003924) was performed.Continued androgen deprivation therapy; patients randomized 2:1 to enzalutamide 160 mg/d or placebo.Metastasis-free survival (MFS) in men with and without PSA progression, defined by PCWG2, and PSA at the time of radiographic progression were assessed.As of June 28, 2017, in enzalutamide-treated patients, the risk of metastasis or death was increased significantly in those with PSA progression versus those without (hazard ratio [HR] 3.99; 95% confidence interval [CI], 2.95-5.41; p < 0.0001). Median MFS was not reached (NR; 95% CI, NR-NR) in patients without PSA progression and was 22.6 mo (95% CI, 21.9-29.0) in those with PSA progression. In placebo-treated patients, PSA progression was not significantly associated with MFS (HR 1.72; 95% CI, 0.86-3.45; p = 0.1). Median MFS was NR (95% CI, 25.6-NR) in patients without PSA progression and 18.3 mo (95% CI, 14.9-19.4) in those with PSA progression. The median PSA increase from nadir at the time of radiographic progression was 1.4 ng/mL in enzalutamide-treated men and 25.6 ng/mL for the placebo arm.In men with nmCRPC and rapidly rising PSA, radiographic progression often occurred without PCWG2-defined PSA progression, suggesting that any increase in PSA may warrant closer monitoring. While PCWG2-defined PSA progression was associated with radiographic progression in enzalutamide-treated men, our findings argue for prospective re-evaluation of this threshold.In this report, we looked at changes in prostate-specific antigen (PSA) in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer who no longer respond to testosterone-lowering treatment. We found that even very small changes in PSA while on treatment could be an early indication of disease progression and should trigger closer monitoring.
Abstract S04-01: Famotidine use and quantitative symptom tracking for COVID-19 in nonhospitalized patients: A case series
Authors: Tobias Janowitz, Eva C. Gablenz, David J. Pattinson, Timothy C. Wang, Joseph Conigliaro, Kevin J. Tracey, David A. Tuveson
Journal: Clinical Cancer Research (2020)

Abstract Objective: Treatment options for nonhospitalized patients with coronavirus disease 2019 (COVID-19) to reduce morbidity, mortality, and spread of the disease are an urgent global need. The over-the-counter histamine-2 receptor antagonist famotidine is a putative therapy for COVID-19. We quantitively assessed longitudinal changes in patient-reported outcome measures in nonhospitalized patients with COVID-19 who self-administered high-dose famotidine orally. Design: Patients were enrolled consecutively after signing written informed consent. Data on demographics, COVID-19 diagnosis, famotidine use, drug related side-effects, temperature measurements, oxygen saturations, and symptom scores were obtained using questionnaires and telephone interviews. Based on an NIH-endorsed Protocol to research Patient Experience of COVID-19, we collected longitudinal severity scores of five symptoms (cough, shortness of breath, fatigue, headaches, and anosmia) and general unwellness on a 4-point ordinal scale modeled on performance status scoring. All data are reported at the patient level. Longitudinal combined normalized symptom scores were statistically compared. Results: Ten consecutive patients with COVID-19 who self-administered high-dose oral famotidine were identified. The most frequently used famotidine regimen was 80mg three times daily (n=6) for a median of 11 days (range: 5 to 21 days). Famotidine was well tolerated. All patients reported marked improvements of disease-related symptoms after starting famotidine. The combined symptom score improved significantly within 24 hours of starting famotidine and peripheral oxygen saturation (n=2), and device recorded activity (n=1) increased. Conclusions: The results of this case series suggest that high-dose oral famotidine is well tolerated and associated with improved patient reported outcomes in nonhospitalized patients with COVID-19. A blinded outpatient trial is planned. The findings may be transferable and relevant to the treatment of patients with cancer and COVID-19. Citation Format: Tobias Janowitz, Eva C. Gablenz, David J. Pattinson, Timothy C. Wang, Joseph Conigliaro, Kevin J. Tracey, David A. Tuveson. Famotidine use and quantitative symptom tracking for COVID-19 in nonhospitalized patients: A case series [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S04-01.
Decreased Incidence of Type 1 Diabetes in Young Finnish Children
Authors: Anna Parviainen, Anna But, Heli Siljander, Mikael Knip, Mikael Knip, Per-Henrik Groop, Jorma Ilonen, Timo Otonkoski, Riitta Veijola, Alar Abram, Henrikka Aito, Ivan Arkhipov, Elina Blanco-Sequeiros, Jonas Bondestam, Markus Granholm, Maarit Haapalehto-Ikonen, Torsten Horn, Hanna Huopio, Joakim Janer, Christian Johansson, Liisa Kalliokoski, Päivi Keskinen, Anne Kinnala, Maarit Korteniemi, Hanne Laakkonen, Jyrki Lähde, Päivi Miettinen, Päivi Nykänen, Erik Popov, Mari Pulkkinen, Maria Salonen, Pia Salonen, Juhani Sankala, Virpi Sidoroff, Anne-Maarit Suomi, Tuula Tiainen, Riitta Veijola
Journal: Diabetes Care (2020)

OBJECTIVE The incidence of type 1 diabetes has been rising for decades, particularly among young children. Between 2006 and 2011, the incidence rate (IR) reached a plateau in Finland. In this observational, register-based cohort study, we assess recent trends in the disease rate in Finnish children. RESEARCH DESIGN AND METHODS Based on data from the Finnish Pediatric Diabetes Register, we studied the incidence of type 1 diabetes among children younger than 15 years of age between 2003 and 2018. We assessed sex-specific IRs per 100,000 person-years (PY) by 4-year time periods in three age-groups (0.50–4.99, 5.00–9.99, and 10.00–14.99 years). RESULTS Among the 7,871 children with newly diagnosed type 1 diabetes, the median age at diagnosis increased from 7.88 to 8.33 years (P = 0.001), while the overall IR decreased from 57.9/100,000 PY in 2003–2006 to 52.2/100,000 PY in 2015–2018, yielding an IR ratio (IRR) of 0.90 (95% CI 0.85–0.96, P = 0.001). This decline was mainly due to the decrease in the youngest age-group (IRR 0.77 [95% CI 0.68–0.87]; P &amp;lt; 0.001), being significant both among boys and girls. In the middle age-group, a significant decrease was observed only among girls. No changes were observed in the oldest children. CONCLUSIONS The incidence of type 1 diabetes decreased among young Finnish children between 2003 and 2018. Current findings imply that environmental factors driving the immune system toward islet autoimmunity are changing in young children.
Abstract B30: The histone demethylase PHF8 epigenetically regulates the TGFbeta pathway to promote melanoma metastasis
Authors: Rana Moubarak, Ana De Pablos-Aragoneses, Vanessa Ortiz-Barahona, Richard Von Itter, Yixiao Gong, Michael Gowen, Sebastian Stefan, Diana Argibay, Eleazar De Miera-Vega, Igor Dolgalev, Elena Sokolova, Farbod Darvishian, Aristotelis Tsirigos, Iman Osman, Eva Hernando
Journal: Cancer Research (2020)

Abstract The specific contribution of epigenetic dysregulation to the metastatic process remains understudied. Through a meta-analysis of gene expression datasets followed by a functional mini-screen, we identified PHF8, a histone demethylase of the Jumonji C proteins family, as a novel prometastatic factor in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro, and increases dissemination but not tumor growth in vivo, thus strengthening its specific contribution to the acquisition of metastatic potential. PHF8 demethylase activity is required for its proinvasive role. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates molecular changes that directly control the TGFβ signaling pathway and, as a direct consequence, melanoma invasion. Citation Format: Rana Moubarak, Ana De Pablos-Aragoneses, Vanessa Ortiz-Barahona, Richard Von Itter, Yixiao Gong, Michael Gowen, Sebastian Stefan, Diana Argibay, Eleazar De Miera-Vega, Igor Dolgalev, Elena Sokolova, Farbod Darvishian, Aristotelis Tsirigos, Iman Osman, Eva Hernando. The histone demethylase PHF8 epigenetically regulates the TGFbeta pathway to promote melanoma metastasis [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B30.