tbuckley/cabot-search huggingface dataset:
Mucins limit the antitumor activity of 5FU against human pancreatic cancer
Authors: Ashish Kalra, Robert Campbell
Journal: Cancer Research (2008)

3218  Introduction: Mucins are heavily O-glycosylated glycoproteins expressed on apical surface of normal epithelial cells. In cancer cells mucins are overexpressed along the entire cell surface. Clinical studies show a correlation between overexpression of MUC1 mucin and poor survival rates of pancreatic cancer patients. Treatment of pancreatic cancer with chemotherapy has shown limited clinical success. The infusion of 5-fluorouracil (5FU) along with radiation has been the mainstay in treatment of pancreatic cancer. In this study we seek to investigate whether the inhibition of mucin O-glycosylation in human pancreatic adenocarcinoma can enhance response to 5FU therapy.   Methods: The human pancreatic cancer cell lines Capan-1, HPAF-II were maintained in their respective growth media. MUC1 expression levels were determined using fluorescence and DIC microscopy. Nontoxic concentration of benzyl-α-GalNAc (inhibitor of O-glycosylation) was determined 72 h following exposure of cells to reagent. The effect of inhibiting O-glycosylation on 5FU cytotoxicity was determined by exposing cells to benzyl-α-GalNAc for 48 h followed by 5FU treatment. MUC1 levels in tumors were determined by immunohistochemistry. Intratumoral injections of benzyl-α-GalNAc were administered to inhibit O-glycosylation in tumors. 5FU was administered intravenously (125 mg/kg). Animal bodyweight and tumor volumes were monitored during the experiment.   Results: Human pancreatic cancer cells revealed high and moderate MUC1 levels for Capan-1 and HPAF-II respectively. The exposure of Capan-1 and HPAF-II cells to benzyl-α-GalNAc for 72 h revealed a maximum non-toxic concentration of 0.4 and 0.8 mg/ml respectively. Normal cell proliferation and morphology were not altered 24, 48 and 72 h post removal of inhibitor. We observed significantly higher association of Capan-1 and HPAF-II cells to anti-MUC1 antibody (CD227) compared to control cells when pretreated with inhibitor (*P≤0.001). Pretreatment also enhanced 5FU activity. Capan-1 viability reduced from 65 to 54% (*P≤0.001) whereas HPAF-II viability lowered from 77 to 56% (*P≤0.001). Immunohistochemical staining revealed high MUC1 levels in Capan-1 compared to HPAF-II tumors. Intratumoral injections of inhibitor reduced MUC1 O-glycosylation in tumor cells. Pretreatment of Capan-1 tumors with inhibitor followed by 5FU resulted in significantly lower tumor volumes (*P≤0.05) as compared 5FU treatment alone.   Conclusions: Our studies show high levels of MUC1 expression on Capan-1 compared to moderate levels on HPAF-II cells. Inhibition of MUC1 O-glycosylation was achieved in vitro and in vivo by exposure to benzyl-α-GalNAc. Inhibition of mucin O-glycosylation enhanced the therapeutic activity of 5FU in both cellular and tumor models of pancreatic cancer. Our experimental findings suggest that overexpression of mucins by human pancreatic tumors may limit the effectiveness of chemotherapy.
The World Cancer Declaration: time to consolidate wins and work towards 2025
Authors: Sonali Johnson, Zuzanna Tittenbrun, Yannick Romero, Julie Torode, Silvina Frech, May Abdel-Wahab, Arsen Juric, Lisa Stevens, Freddie Bray, Marion Piñeros, James Cleary, Elizabeth Mattfeld, André Ilbawi, Bente Mikkelsen
Journal: The Lancet Oncology (2021)
miRNA-22 deletion limits white adipose expansion and activates brown fat to attenuate high-fat diet-induced fat mass accumulation
Authors: Vanessa M. Lima, Jianming Liu, Bruna B. Brandão, Caroline A. Lino, Camila S. Balbino Silva, Márcio A.C. Ribeiro, Tiago E. Oliveira, Caroline C. Real, Daniele de Paula Faria, Carly Cederquist, Zhan-Peng Huang, Xiaoyun Hu, Maria Luiza Barreto-Chaves, Julio C.B. Ferreira, William T. Festuccia, Marcelo A. Mori, C. Ronald Kahn, Da-Zhi Wang, Gabriela P. Diniz
Journal: Metabolism (2021)
Corresponding doses of mometasone furoate (MF) in once-daily inhaled fixed-dose combination (FDC) of indacaterol/mometasone furoate (IND/MF) and indacaterol/glycopyrronium/mometasone furoate (IND/GLY/MF): results from randomized clinical studies
Authors: Roland Buhl, Huib Kerstjens, Ivan Nikolaev, Soniya Vaidya, Christian Bartels, Monish Jain, Juergen Jauernig, Ioannis Kottakis, Chenyu Qian, Hanns-Christian Tillman
Journal: Journal of Allergy and Clinical Immunology (2021)
Biomarkers associated with blinatumomab outcomes in acute lymphoblastic leukemia
Authors: Andrew H. Wei, Josep-Maria Ribera, Richard A. Larson, David Ritchie, Armin Ghobadi, Yuqi Chen, Abraham Anderson, Cedric E. Dos Santos, Janet Franklin, Hagop Kantarjian
Journal: Leukemia (2021)

Abstract This study aimed to identify biomarkers for clinical outcomes in a phase 3 clinical study of blinatumomab or chemotherapy in adults with Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Patients were randomized 2:1 to receive blinatumomab, a BiTE ® therapy, for 4 weeks (9 μg/day cycle 1 week 1, 28 μg/day thereafter) every 6 weeks, or chemotherapy. Baseline blood samples were evaluated to identify biomarkers prognostic (both treatment groups) or predictive (either treatment groups) for overall survival, event-free survival, hematologic remission, minimal residual disease (MRD) response, duration of response, or adverse events. Baseline values were balanced between treatment groups. Prognostic biomarkers were platelets, tumor burden, and percentage of T cells: each 1-log increase in platelets at baseline was prognostic for improved 6-month survival; lower tumor burden was prognostic for hematologic remission; and a higher percentage of CD3 + T-cells was prognostic for MRD response. Consistent with the BiTE mechanism of action, higher percentage of CD45 + CD3 + CD8 + T cells was associated with hematologic remission following blinatumomab. No examined biomarkers were significant for the risk of grade ≥3 adverse events. Incorporating baseline biomarkers into future studies may help to identify subgroups most likely to benefit from blinatumomab.
Ultraviolet Irradiation Units Installed In the Homes of Children With Asthma Reduces Asthma Severity
Authors: Jonathan Bernstein, Mark Glazman, Anand Seth, Marepalli Rao, Janet Katz, Umesh Singh, William Greisner, Michelle Lierl, Benjamin Prince, Kunjana Mavunda, Cheryl Bernstein, Amanda Rudman Spergel
Journal: Journal of Allergy and Clinical Immunology (2021)
Association of NT-ProBNP, Blood Pressure, and Cardiovascular Events
Authors: Aliza Hussain, Wensheng Sun, Anita Deswal, James A. de Lemos, John W. McEvoy, Ron C. Hoogeveen, Kunihiro Matsushita, David Aguilar, Biykem Bozkurt, Salim S. Virani, Amil M. Shah, Elizabeth Selvin, Chiadi Ndumule, Christie M. Ballantyne, Vijay Nambi
Journal: Journal of the American College of Cardiology (2021)
Allergen‐specific immunotherapy induces the suppressive secretoglobin 1A1 in cells of the lower airways
Authors: Ulrich M. Zissler, Constanze A. Jakwerth, Ferdinand Guerth, Larissa Lewitan, Sandra Rothkirch, Miodrag Davidovic, Moritz Ulrich, Madlen Oelsner, Holger Garn, Carsten B. Schmidt‐Weber, Adam M. Chaker
Journal: Allergy (2021)

While several systemic immunomodulatory effects of allergen-specific immunotherapy (AIT) have been discovered, local anti-inflammatory mechanisms in the respiratory tract are largely unknown. We sought to elucidate local and epithelial mechanisms underlying allergen-specific immunotherapy in a genome-wide approach.We induced sputum in hay fever patients and healthy controls during the pollen peak season and stratified patients by effective allergen immunotherapy or as untreated. Sputum was directly processed after induction and subjected to whole transcriptome RNA microarray analysis. Nasal secretions were analyzed for Secretoglobin1A1 (SCGB1A1) and IL-24 protein levels in an additional validation cohort at three defined time points during the 3-year course of AIT. Subsequently, RNA was extracted and subjected to an array-based whole transcriptome analysis.Allergen-specific immunotherapy inhibited pro-inflammatory CXCL8, IL24, and CCL26mRNA expression, while SCGB1A1, IL7, CCL5, CCL23, and WNT5BmRNAs were induced independently of the asthma status and allergen season. In our validation cohort, local increase of SCGB1A1 occurred concomitantly with the reduction of local IL-24 in upper airways during the course of AIT. Additionally, SCGB1A1 was identified as a suppressor of epithelial gene expression.Allergen-specific immunotherapy induces a yet unknown local gene expression footprint in the lower airways that on one hand appears to be a result of multiple regulatory pathways and on the other hand reveals SCGB1A1 as novel anti-inflammatory mediator of long-term allergen-specific therapeutic intervention in the local environment.
COVID-19 and the collapse of global trade: building an effective public health response
Authors: Pepita Barlow, May CI van Schalkwyk, Martin McKee, Ron Labonté, David Stuckler
Journal: The Lancet Planetary Health (2021)

The scale of the COVID-19 pandemic is a consequence of international trade and globalisation, with the virus spreading along established trade and travel routes. However, the pandemic also affects international trade through reductions in both supply and demand. In this Viewpoint we describe the many implications for health and propose ways to mitigate them. Problems include reduced access to medical supplies (in particular, personal protective equipment and tests), budgetary shortfalls as a result of reduced tariffs and taxes, and a general decline in economic activity-leading, in many cases, to recessions, threats to social safety nets, and to increased precariousness of income, employment, and food security. However, in exceptional cases, the pandemic has also brought some transient benefits, including to the environment. Looking ahead, there will be great pressure to further liberalise rules on trade to encourage economic recovery, but it is essential that trade policy be informed by its many consequences for health to ensure that the benefits are maximised and threats are minimised through active identification and mitigation.
The BH3-mimetic GX15-070 induces autophagy-dependent cell death of therapy-sensitive and -resistant aggressive B cell non-Hodgkin’s lymphoma (B-NHL)
Authors: Scott Olejniczak, Myron Czuczman, Paul Hoskin, Elizabeth Gruber, Francisco Hernandez-Ilizaliturri
Journal: Cancer Research (2008)

3356  The Bcl-2 family of proteins represents a rheostat that controls cellular viability. Interactions between members of BH3-domain containing proteins play an important role in the development, progression and prognosis in various subtypes of B-cell lymphomas. We previously reported that targeting Bcl-2 family proteins with GX15-070, a novel pan-inhibitor of anti-apoptotic Bcl-2 family members, induced time- and dose- dependent cell death of lymphoma pre-clinical models. Moreover, GX15-070 improved rituximab and/or chemotherapy activity in vitro. In an attempt to improve our knowledge of the therapeutic effects of BH3-mimetics, we studied the mechanisms that mediate GX15-070 anti-tumor activity in a panel of therapy-sensitive (TSCL) and therapy-resistant cell lines (TRCL) and primary lymphoma cells isolated from patients with treatment-naive or refractory/relapsed diffuse large B-cell lymphomas (DLBCL). NHL cell lines and/or primary malignant B-cell cells isolated from DLBCL patients (n=8) were exposed in vitro to GX15-070 (100nM - 1μM) +/- zVAD-fmk. Viability was determined by trypan blue exclusion and/or CellTitre-Glo® luminescent assay 24 to 72 hours following treatment. PARP cleavage and LC3 conversion were studied by Western blotting. In vitro exposure of TSCL/TRCL to GX15-070 resulted in induction of caspase-independent cell death. The ability of GX15-070 to induce caspase-dependent PARP cleavage varied between patient samples and was not observed in therapy-resistant cell lines (TRCL). Surprisingly, conversion of LC3 was observed in all cell lines and most DLBCL cells tested, suggesting that GX15-070 is a potent inducer of autophagy. To determine if autophagy contributed to GX15-070 activity, autophagy was inhibited by treatment with 3-methyladenine or siRNA-mediated Beclin-1 knock-down. Under conditions where autophagy was inhibited, cell death induced by GX15-070 was significantly reduced. These data suggest that GX15-070-induced cell death is mediated by autophagy in therapy-sensitive and -resistant aggressive B-NHL. In summary, our data suggest that GX15-070 is a novel and potent therapeutic strategy against aggressive B-cell lymphoma. A better understanding in the mechanisms of action of BH3-mimetics, including GX15-070, is necessary for the optimal design of clinical trials for B-cell lymphoma patients. Supported by USPHS grant PO1-CA103985 from the National Cancer Institute.
Depth and Rapidity of Response With Abrocitinib and Dupilumab in Patients With Moderate-to-Severe Atopic Dermatitis (AD) in JADE COMPARE
Authors: Peter Lio, Mark Boguniewicz, Andrew Alexis, Mark Lebwohl, Kristian Reich, Andrew Pink, Kenji Kabashima, Robert Bissonnette, Roman Nowicki, Hernan Valdez, Fan Zhang, Marco DiBonaventura, Claire Clibborn, Michael Cameron
Journal: Journal of Allergy and Clinical Immunology (2021)
Medicare/Medicaid Insurance, Rurality, and Black Race Associated With Provision of Hepatocellular Carcinoma Treatment and Survival
Authors: Andrew M. Moon, Hanna K. Sanoff, YunKyung Chang, Jennifer L. Lund, A. Sidney Barritt, Paul H. Hayashi, Karyn B. Stitzenberg
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: Early treatment of hepatocellular carcinoma (HCC) is associated with improved survival, but many patients with HCC do not receive therapy. We aimed to examine factors associated with HCC treatment and survival among incident patients with HCC in a statewide cancer registry. Materials and Methods: All patients with HCC from 2003 through 2013 were identified in the North Carolina cancer registry. These patients were linked to insurance claims from Medicare, Medicaid, and large private insurers in North Carolina. Associations between prespecified covariates and more advanced HCC stage at diagnosis (ie, multifocal cancer), care at a liver transplant center, and provision of HCC treatment were examined using multivariate logistic regression. A Cox proportional hazards model was developed to assess the association between these factors and survival. Results: Of 1,809 patients with HCC, 53% were seen at a transplant center &lt;90 days from diagnosis, with lower odds among those who were Black (adjusted odds ratio [aOR], 0.54; 95% CI, 0.39–0.74), had Medicare insurance (aOR, 0.35; 95% CI, 0.21–0.59), had Medicaid insurance (aOR, 0.46; 95% CI, 0.28–0.77), and lived in a rural area; odds of transplant center visits were higher among those who had prediagnosis alpha fetoprotein screening (aOR, 1.74; 95% CI, 1.35–2.23) and PCP and gastroenterology care (aOR, 1.66; 95% CI, 1.27–2.18). Treatment was more likely among patients who had prediagnosis gastroenterology care (aOR, 1.68; 95% CI, 0.98–2.86) and transplant center visits (aOR, 2.42; 95% CI, 1.74–3.36). Survival was strongly associated with age, cancer stage, cirrhosis complications, and receipt of HCC treatment. Individuals with Medicare (adjusted hazard ratio [aHR], 1.58; 95% CI, 1.20–2.09) and Medicaid insurance (aHR, 1.55; 95% CI, 1.17–2.05) had shorter survival than those with private insurance. Conclusions: In this population-based cohort of patients with HCC, Medicare/Medicaid insurance, rural residence, and Black race were associated with lower provision of HCC treatment and poorer survival. Efforts should be made to improve access to care for these vulnerable populations.
Physician requirements for adoption of telehealth following the SARS-CoV-2 pandemic
Authors: Michael Hodgkins, Meg Barron, Shireesha Jevaji, Stacy Lloyd
Journal: npj Digital Medicine (2021)

Abstract It took the advent of SARS-CoV-2, a “black swan event”, to widely introduce telehealth, remote care, and virtual house calls. Prior to the epidemic (2019), the American Medical Association (AMA) conducted a routine study to compare physicians’ adoption of emerging technologies to a similar survey in 2016. Most notable was a doubling in the adoption of telehealth/virtual technology to 28% and increases in the use of remote monitoring and management for improved care (13–22%). These results may now seem insignificant when compared to the unprecedented surge in telehealth visits because of SARS-CoV-2. Even as this surge levels off and begins to decline, many observers believe we will continue to see a persistent increase in the use of virtual visits compared to face-to-face care. The requirements for adoption communicated by physicians in both the 2016 and 2019 surveys are now more relevant than ever: Is remote care as effective as in-person care and how best to determine when to use these modalities? How do I safeguard my patients and my practice from liability and privacy concerns? How do I optimize using these technologies in my practice and, especially integration with my EHR and workflows to improve efficiency? And how will a mix of virtual and in-person visits affect practice revenue and sustainability? Consumers have also expressed concerns about payment for virtual visits as well as privacy and quality of care. If telehealth and remote care are here to stay, continuing to track their impact during the current public health emergency is critically important to address so that policymakers and insurers will take necessary steps to ensure that the “new normal” will reflect a health care delivery model that can provide comparable or improved results today and into the future.
Modulating inflammation through the neutralization of Interleukin-6 and tumor necrosis factor-α by biofunctionalized nanoparticles
Authors: Ana Cláudia Lima, Diana Amorim, Inês Laranjeira, Armando Almeida, Rui L. Reis, Helena Ferreira, Filipa Pinto-Ribeiro, Nuno M. Neves
Journal: Journal of Controlled Release (2021)
Recent progresses and remaining challenges for the detection of Zika virus
Authors: Xianlong Zhang, Guoliang Li, Guang Chen, Niu Zhu, Di Wu, Yongning Wu, Tony D. James
Journal: Medicinal Research Reviews (2021)

Abstract Zika virus (ZIKV) has emerged as a particularly notorious mosquito‐borne flavivirus, which can lead to a devastating congenital syndrome in the fetuses of pregnant mothers (e.g., microcephaly, spasticity, craniofacial disproportion, miscarriage, and ocular abnormalities) and cause the autoimmune disorder Guillain‐Barre' syndrome of adults. Due to its severity and rapid dispersal over several continents, ZIKV has been acknowledged to be a global health concern by the World Health Organization. Unfortunately, the ZIKV has recently resurged in India with the potential for devastating effects. Researchers from all around the world have worked tirelessly to develop effective detection strategies and vaccines for the prevention and control of ZIKV infection. In this review, we comprehensively summarize the most recent research into ZIKV, including the structural biology and evolution, historical overview, pathogenesis, symptoms, and transmission. We then focus on the detection strategies for ZIKV, including viral isolation, serological assays, molecular assays, sensing methods, reverse transcription loop mediated isothermal amplification, transcription‐mediated amplification technology, reverse transcription strand invasion based amplification, bioplasmonic paper‐based device, and reverse transcription isothermal recombinase polymerase amplification. To conclude, we examine the limitations of currently available strategies for the detection of ZIKV, and outline future opportunities and research challenges.
Fragmentation of Small-Cell Lung Cancer Regulatory States in Heterotypic Microenvironments
Authors: Dylan L. Schaff, Shambhavi Singh, Kee-Beom Kim, Matthew D. Sutcliffe, Kwon-Sik Park, Kevin A. Janes
Journal: Cancer Research (2021)

Abstract Small-cell lung cancers derive from pulmonary neuroendocrine cells, which have stem-like properties to reprogram into other cell types upon lung injury. It is difficult to uncouple transcriptional plasticity of these transformed cells from genetic changes that evolve in primary tumors or secondary metastases. Profiling of single cells is also problematic if the required sample dissociation activates injury-like signaling and reprogramming. Here we defined cell-state heterogeneities in situ through laser capture microdissection–based 10-cell transcriptomics coupled with stochastic-profiling fluctuation analysis. In labeled cells from a small-cell lung cancer mouse model initiated by neuroendocrine deletion of Rb1-Trp53, variations in transcript abundance revealed cell-to-cell differences in regulatory state in vitro and in vivo. Fluctuating transcripts in spheroid culture were partly shared among Rb1-Trp53–null models, and heterogeneities increased considerably when cells were delivered intravenously to colonize the liver. Colonization of immunocompromised animals drove a fractional appearance of alveolar type II–like markers and poised cells for paracrine stimulation from immune cells and hepatocytes. Immunocompetency further exaggerated the fragmentation of tumor states in the liver, yielding mixed stromal signatures evident in bulk sequencing from autochthonous tumors and metastases. Dozens of transcript heterogeneities recurred irrespective of biological context; their mapped orthologs brought together observations of murine and human small-cell lung cancer. Candidate heterogeneities recurrent in the liver also stratified primary human tumors into discrete groups not readily explained by molecular subtype but with prognostic relevance. These data suggest that heterotypic interactions in the liver and lung are an accelerant for intratumor heterogeneity in small-cell lung cancer. Significance: These findings demonstrate that the single-cell regulatory heterogeneity of small-cell lung cancer becomes increasingly elaborate in the liver, a common metastatic site for the disease. See related articles by Singh and colleagues, p. 1840 and Sutcliffe and colleagues, p. 1868
Effectiveness of a stand-alone, smartphone-based virtual reality exposure app to reduce fear of heights in real-life: a randomized trial
Authors: Dorothée Bentz, Nan Wang, Merle K. Ibach, Nathalie S. Schicktanz, Anja Zimmer, Andreas Papassotiropoulos, Dominique J. F. de Quervain
Journal: npj Digital Medicine (2021)

Abstract Smartphone-based virtual reality (VR) applications (apps) might help to counter low utilization rates of available treatments for fear of heights. Demonstration of effectiveness in real-life situations of such apps is crucial, but lacking so far. Objective of this study was to develop a stand-alone, smartphone-based VR exposure app— Easy Heights —and to test its effectiveness in a real-life situation. We performed a single-blind, parallel group, randomized controlled trial. We recruited 70 participants with fear of heights, aged 18–60 years. Primary outcome was performance in a real-life Behavioral Avoidance Test (BAT) on a lookout tower after a single 1-h app use (phase 1) and after additional repeated (6 × 30 min) app use at home (phase 2). After phase 2, but not phase 1, participants in the Easy Heights condition showed significantly higher BAT scores compared to participants in the control condition (Cohen’s d = 1.3, p = 0.0001). Repeated use of our stand-alone, smartphone-based VR exposure app reduces avoidance behavior and fear, providing a low-threshold treatment for fear of heights.