tbuckley/cabot-search huggingface dataset:
Profiles of Emerging and Legacy Per-/Polyfluoroalkyl Substances in Matched Serum and Semen Samples: New Implications for Human Semen Quality
Authors: Yitao Pan, Qianqian Cui, Jinghua Wang, Nan Sheng, Jun Jing, Bing Yao, Jiayin Dai
Journal: Environmental Health Perspectives (2019)

Background: Epidemiological evidence remains equivocal on the associations between environmentally relevant levels of per-/polyfluoroalkyl substances (PFASs) and human semen quality. Objectives: We aimed to test whether the potential effects on semen quality could be better observed when seminal PFAS levels were used as an exposure marker compared with serum PFAS levels. Methods: Matched semen and serum samples from 664 adult men were collected from a cross-sectional population in China from 2015 to 2016. Multiple semen parameters were assessed, along with measurement of 16 target PFASs in semen and serum. Partitioning between semen and serum was evaluated by the ratio of matrix-specific PFAS concentrations. Regression model results were expressed as the difference in each semen parameter associated with the per unit increase in the ln-transformed PFAS level after adjusting for confounders. Results: Perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and emerging chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) were detected at their highest concentrations in both semen and serum, with median concentrations of 0.23, 0.10, and 0.06 ng/mL in semen, respectively, and a semen-to-serum ratio of 1.3:3.1. The between-matrix correlations of these PFAS concentrations were high (R=0.70–0.83). Seminal PFOA, PFOS, and 6:2 Cl-PFESA levels were significantly associated with a lower percentage of progressive sperm and higher percentage of DNA fragmentation (false discovery rate-adjusted p-values of<0.05). Associations between serum PFAS levels and semen parameters were generally statistically weaker, except for DNA stainability, which was more strongly associated with serum-based PFASs than with semen-based PFASs. Conclusions: Our results suggest the potential for deleterious effects following exposure to 6:2 Cl-PFESA and other PFASs. Compared with serum PFAS levels, the much clearer association of seminal PFAS levels with semen parameters suggests its advantage in hazard assessment on semen quality, although the potential for confounding might be higher. Exposure measurements in target tissue may be critical in clarifying effects related to PFAS exposure. https://doi.org/10.1289/EHP4431
4-1BB Agonism Averts TIL Exhaustion and Licenses PD-1 Blockade in Glioblastoma and Other Intracranial Cancers
Authors: Karolina I. Woroniecka, Kristen E. Rhodin, Cosette Dechant, Xiuyu Cui, Pakawat Chongsathidkiet, Daniel Wilkinson, Jessica Waibl-Polania, Luis Sanchez-Perez, Peter E. Fecci
Journal: Clinical Cancer Research (2019)

The success of checkpoint blockade against glioblastoma (GBM) has been disappointing. Anti-PD-1 strategies may be hampered by severe T-cell exhaustion. We sought to develop a strategy that might license new efficacy for checkpoint blockade in GBM.We characterized 4-1BB expression in tumor-infiltrating lymphocytes (TIL) from human GBM. We implanted murine tumor models including glioma (CT2A), melanoma (B16), breast (E0771), and lung carcinomas intracranially and subcutaneously, characterized 4-1BB expression, and tested checkpoint blockade strategies in vivo.Our data reveal that 4-1BB is frequently present on nonexhausted CD8+ TILs in human and murine GBM. In murine gliomas, 4-1BB agonism and PD-1 blockade demonstrate a synergistic survival benefit in a CD8+ T-cell-dependent manner. The combination decreases TIL exhaustion and improves TIL functionality. This strategy proves most successful against intracranial CT2A gliomas. Efficacy in all instances correlates with the levels of 4-1BB expression on CD8+ TILs, rather than with histology or with intracranial versus subcutaneous tumor location. Proffering 4-1BB expression to T cells licenses combination 4-1BB agonism and PD-1 blockade in models where TIL 4-1BB levels had previously been low and the treatment ineffective.Although poor T-cell activation and severe T-cell exhaustion appear to be limiting factors for checkpoint blockade in GBM, 4-1BB agonism obviates these limitations and produces long-term survival when combined with anti-PD-1 therapy. Furthermore, this combination therapy is limited by TIL 4-1BB expression, but not by the intracranial compartment, and therefore may be particularly well-suited to GBM.
Abstract PR07: Phase I/II study of mesothelin-targeted immunotoxin LMB-100 with nab-paclitaxel for patients with advanced pancreatic adenocarcinoma
Authors: Christine C. Alewine, Mehwish Ahmad, Cody J. Peer, Zishuo Hu, Min-jung Lee, Akiro Yuno, Jessica Kindrick, Anish Thomas, Seth Steinberg, Jane B. Trepel, William D. Figg, Raffit Hassan, Ira Pastan
Journal: Cancer Research (2019)

Abstract Purpose: LMB-100 recombinant immunotoxin (iTox) consists of a mesothelin-binding Fab for targeting and a modified Pseudomonas exotoxin A payload. Preclinical studies showed that combining taxanes with iTox results in synergistic antitumor activity. The primary objectives of this phase I/II study were to determine the maximum tolerated dose (MTD) of LMB-100 when given with nanoalbumin bound (nab)-paclitaxel to participants with previously treated advanced pancreatic adenocarcinoma and to assess the objective response rate. Patients and Methods: Patients (n = 20) received fixed-dose nab-paclitaxel (125 mg/m2 on Days 1 and 8) with LMB-100 (65 or 100 mcg/kg on Days 1, 3, and 5) in 21-day cycles. Treatment was limited to 2-3 cycles by protocol. Safety and tolerability, pharmacokinetics, immunogenicity, and relationship of activity to tumor mesothelin expression were assessed. Results: Dose-limiting toxicity (DLT) of Grade 3 myalgia was observed in 2 of 5 patients treated with 100 mcg/kg. DLT of Grade 3 edema from capillary leak syndrome (CLS) was observed in 1 of 6 patients at MTD of 65 mcg/kg. Severe toxicities of Grade 4 left ventricular dysfunction and hypotension from CLS were observed in 1 patient in the phase II expansion, resulting in study closure. LMB-100 anti-drug antibody formation limited LMB-100 exposure in 5 of 13 patients during cycle 2. Seven of 17 patients with evaluable CA19-9 experienced &amp;gt;50% decrease of this tumor marker, and one patient developed a partial response. Response was associated with higher tumor mesothelin expression and Cycle 2 LMB-100 exposure. Conclusions: The combination caused serious toxicity. Despite some observed clinical activity, further testing of this combination will not be pursued. This abstract is also being presented as Poster B01. Citation Format: Christine C. Alewine, Mehwish Ahmad, Cody J. Peer, Zishuo Hu, Min-jung Lee, Akiro Yuno, Jessica Kindrick, Anish Thomas, Seth Steinberg, Jane B. Trepel, William D. Figg, Raffit Hassan, Ira Pastan. Phase I/II study of mesothelin-targeted immunotoxin LMB-100 with nab-paclitaxel for patients with advanced pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR07.
Detection and prevalence of monoclonal gammopathy of undetermined significance: a study utilizing mass spectrometry-based monoclonal immunoglobulin rapid accurate mass measurement
Authors: David Murray, Shaji K. Kumar, Robert A. Kyle, Angela Dispenzieri, Surendra Dasari, Dirk R. Larson, Celine Vachon, James R. Cerhan, S. Vincent Rajkumar
Journal: Blood Cancer Journal (2019)

Abstract High-sensitivity mass spectrometry assays are available to detect monoclonal immunoglobulins. To better assess the prevalence of monoclonal gammopathy of undetermined significance (MGUS), we identified 300 patients diagnosed with MGUS or related gammopathy who had a prior negative work-up for monoclonal proteins as part of the Olmsted County MGUS screening study. Two mass spectrometry-based detection methods (matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) and monoclonal immunoglobulin rapid accurate mass measurements (miRAMM) along with traditional immunofixation were performed on the Olmsted baseline and MGUS diagnostics serum samples. Among the 226 patients considered negative for MGUS based on protein electrophoresis and serum-free light-chain assay, a monoclonal protein could be detected at baseline in 24 patients (10.6%) by immunofixation, 113 patients (50%) by MADLI-TOF mass spectrometry, and 149 patients (65.9%) by miRAMM mass spectrometry. In addition, using miRAMM, some patients demonstrated an oligoclonal to monoclonal transition giving insight into the origin of MGUS. Using the sensitive miRAMM, MGUS is present in 887 of 17,367 persons from the Olmsted County cohort, translating into a prevalence of 5.1% among persons 50 years of age and older. This represents the most accurate prevalence estimate of MGUS thus far.
Regulatory interacting network between the immunomodulatory non-coding RNAs: miR-17-5p, MALAT1 and H19 lncRNAs in modulating the tumour microenvironment in TNBC
Authors: R. Soliman, R.A. Youness, M. El-Shazly, H. Handoussa, M. Gad
Journal: Annals of Oncology (2019)
Connexin-43 is a promising target for pulmonary hypertension due to hypoxaemic lung disease
Authors: Claire Bouvard, Nafiisha Genet, Carole Phan, Baptiste Rode, Raphaël Thuillet, Ly Tu, Paul Robillard, Marilyne Campagnac, Raffaella Soleti, Eric Dumas De La Roque, Frédéric Delcambre, Laurent Cronier, Thibaud Parpaite, Elise Maurat, Patrick Berger, Jean-Pierre Savineau, Roger Marthan, Christophe Guignabert, Véronique Freund-Michel, Christelle Guibert
Journal: European Respiratory Journal (2019)

The mechanisms underlying pulmonary hypertension (PH) are complex and multifactorial, and involve different cell types that are interconnected through gap junctional channels. Although connexin (Cx)-43 is the most abundant gap junction protein in the heart and lungs, and critically governs intercellular signalling communication, its contribution to PH remains unknown. The focus of the present study is thus to evaluate Cx43 as a potential new target in PH. Expressions of Cx37, Cx40 and Cx43 were studied in lung specimens from patients with idiopathic pulmonary arterial hypertension (IPAH) or PH associated with chronic hypoxaemic lung diseases (chronic hypoxia-induced pulmonary hypertension (CH-PH)). Heterozygous Cx43 knockdown CD1 (Cx43 +/− ) and wild-type littermate (Cx43 +/+ ) mice at 12 weeks of age were randomly divided into two groups, one of which was maintained in room air and the other exposed to hypoxia (10% oxygen) for 3 weeks. We evaluated pulmonary haemodynamics, remodelling processes in cardiac tissues and pulmonary arteries (PAs), lung inflammation and PA vasoreactivity. Cx43 levels were increased in PAs from CH-PH patients and decreased in PAs from IPAH patients; however, no difference in Cx37 or Cx40 levels was noted. Upon hypoxia treatment, the Cx43 +/− mice were partially protected against CH-PH when compared to Cx43 +/+ mice, with reduced pulmonary arterial muscularisation and inflammatory infiltration. Interestingly, the adaptive changes in cardiac remodelling in Cx43 +/− mice were not affected. PA contraction due to endothelin-1 (ET-1) was increased in Cx43 +/− mice under normoxic and hypoxic conditions. Taken together, these results indicate that targeting Cx43 may have beneficial therapeutic effects in PH without affecting compensatory cardiac hypertrophy.
Efficacy of soluble fibre, antispasmodic drugs, and gut–brain neuromodulators in irritable bowel syndrome: a systematic review and network meta-analysis
Authors: Christopher J Black, Yuhong Yuan, Christian P Selinger, Michael Camilleri, Eamonn M M Quigley, Paul Moayyedi, Alexander C Ford
Journal: The Lancet. Gastroenterology & hepatology (2019)
Prevention of cisplatin-induced ototoxicity in children and adolescents with cancer: a clinical practice guideline
Authors: David R Freyer, Penelope R Brock, Kay W Chang, L Lee Dupuis, Sidnei Epelman, Kristin Knight, Denise Mills, Robert Phillips, Emma Potter, Demie Risby, Philippa Simpkin, Michael Sullivan, Sandra Cabral, Paula D Robinson, Lillian Sung
Journal: The Lancet Child & Adolescent Health (2019)
Response Assessed by Ultrasonography as Target of Biological Treatment for Crohn’s Disease
Authors: Francesca Zorzi, Subrata Ghosh, Carlo Chiaramonte, Elisabetta Lolli, Martina Ventura, Sara Onali, Elena De Cristofaro, Massimo C. Fantini, Livia Biancone, Giovanni Monteleone, Emma Calabrese
Journal: Clinical Gastroenterology and Hepatology (2019)
Surgical association withdraws support for stent advice after controversy over study
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The European Association for Cardiothoracic Surgery (EACTS) has withdrawn support for guidance on stents that it coauthored, following controversy over the research paper it was based on.

Concerns about the 2016 study, published in the New England Journal of Medicine 1 and funded by stent maker Abbott, were raised by the BBC’s Newsnight ,2 which obtained unpublished data from the trial.

The data reportedly showed that, when using the universal definition of heart attack, patients with left main coronary artery disease treated with stents are 35% more likely to die than those treated with conventional open heart surgery.

In the paper, the researchers only published the findings using an alternative definition of heart attack. Using this definition, the paper claimed that stents and heart surgery are equally effective for people with left main coronary artery disease.

After reviewing the unpublished data (using the universal definition), EACTS has now withdrawn its …
Human Genomic Diversity Where the Mediterranean Joins the Atlantic
Authors: Candela L Hernández, Guillermo Pita, Bruno Cavadas, Saioa López, Luis J Sánchez-Martínez, Jean-Michel Dugoujon, Andrea Novelletto, Pedro Cuesta, Luisa Pereira, Rosario Calderón
Journal: Molecular Biology and Evolution (2019)

Abstract Throughout the past few years, a lively debate emerged about the timing and magnitude of the human migrations between the Iberian Peninsula and the Maghreb. Several pieces of evidence, including archaeological, anthropological, historical, and genetic data, have pointed to a complex and intermingled evolutionary history in the western Mediterranean area. To study to what extent connections across the Strait of Gibraltar and surrounding areas have shaped the present-day genomic diversity of its populations, we have performed a screening of 2.5 million single-nucleotide polymorphisms in 142 samples from southern Spain, southern Portugal, and Morocco. We built comprehensive data sets of the studied area and we implemented multistep bioinformatic approaches to assess population structure, demographic histories, and admixture dynamics. Both local and global ancestry inference showed an internal substructure in the Iberian Peninsula, mainly linked to a differential African ancestry. Western Iberia, from southern Portugal to Galicia, constituted an independent cluster within Iberia characterized by an enriched African genomic input. Migration time modeling showed recent historic dates for the admixture events occurring both in Iberia and in the North of Africa. However, an integrative vision of both paleogenomic and modern DNA data allowed us to detect chronological transitions and population turnovers that could be the result of transcontinental migrations dating back from Neolithic times. The present contribution aimed to fill the gaps in the modern human genomic record of a key geographic area, where the Mediterranean and the Atlantic come together.
Low-Dose Anti-Angiogenic Therapy Sensitizes Breast Cancer to PD-1 Blockade
Authors: Qian Li, Yifan Wang, Weijuan Jia, Heran Deng, Guangdi Li, Weiye Deng, Jiewen Chen, Betty Y.S. Kim, Wen Jiang, Qiang Liu, Jieqiong Liu
Journal: Clinical Cancer Research (2019)

Despite its enormous successes, the overall response rate of cancer immunotherapy remains suboptimal, especially in breast cancer. There is an increased interest in combining immune checkpoint inhibitor with targeted agents to enhance antitumor effect. Anti-angiogenic drugs have been shown to synergize with immune checkpoint blockades, but the optimal setting for combining these two modalities and the underlying mechanisms of synergistic responses are not fully understood.We tested the combination of anti-PD-1 and different doses of VEGFR2-targeting agents in syngeneic breast cancer mouse models. Tumor-infiltrated immune cell subsets were profiled by flow cytometry. A cytokine array was carried out to identify inflammatory changes in different treatment conditions. The efficacy of combined anti-angiogenic and anti-PD-1 therapy was further evaluated in patients with advanced triple-negative breast cancer (TNBC).Blockade of VEGFR2 sensitizes breast tumors to PD-1 blockade in a dose-dependent manner. Although both conventional and low-dose anti-VEGFR2 antibody treatments normalize tumor vessels, low-dose VEGFR2 blockade results in more robust immune cell infiltration and activation and promotes the secretion of osteopontin (OPN) by CD8+ T cells. OPN subsequently induces tumor cell production of TGF-β, which in turn upregulates PD-1 expression on immune cells. In patients with advanced TNBC, combined treatment with low-dose anti-VEGFR2 inhibitor and anti-PD-1 demonstrated excellent tolerability and efficacy. Higher OPN and TGF-β expressions correlated with improved treatment responses.Together, these results demonstrate a dose-dependent synergism between anti-angiogenic therapy and immune checkpoint blockade, thus providing important insights into the optimal strategies for combining immunotherapy with molecular-targeted agents.
Review of the Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia
Authors: Douglas W. Jones, Alik Farber
Journal: JAMA Surgery (2019)

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Abstract 11422: Juul and Previous Generation E-cigarette Exposure Comparably Impair Vascular Endothelial Function
Authors: Poonam Rao, Jiangtao Liu, Matthew L Springer
Journal: Circulation (2019)

Introduction: JUUL and other electronic cigarettes (e-cigs) have been marketed with claims of being less hazardous than cigarettes. While JUUL Labs, in particular, claims that switching from smokin...
The risk of debilitating falls (DF) in Manitobans living with cancer.
Authors: Joel Roger Gingerich, Pascal Lambert, Malcolm Doupe, Marshall W. Pitz, Paul Joseph Daeninck
Journal: Journal of Clinical Oncology (2013)

e17596 Background: Falls and fall-related injuries pose important patient safety challenges. We sought to measure if cancer patients are at increased risk of DF. Methods: This retrospective population-based study was conducted by linking the Manitoba Cancer Registry with health care use records from Manitoba, Canada. All community-dwelling patients who were diagnosed with cancer from 2005-08 were matched with up to three cancer-free controls. DF were defined as falls requiring hospitalization and were identified using ICD-9 and -10 billing codes. A competing risk model was used to compare DF between cancer and cancer-free cohorts and expressed as sub-hazard ratios (SHR). Comparisons across groups were adjusted for age, sex, medication use, region of residence, and the presence of co-morbidities. Results: 22,327 cancer patients were matched to 67,927 controls. The median age was 66.5 years, and the median length of follow-up was 1.98 years. The cumulative 1 and 3-year incidence of DF are shown in the Table. (The adjusted risk of DF was significantly decreased in cancer patients versus matched controls ≥ 80 years old; SHR = 0.82 (95% CI: 0.57 – 0.97, p = 0.03). The adjusted SHR for stages I, II, III and IV in those ≥ 80 were 0.83 (95% CI: 0.64 - 1.09, p 0.18), 0.69 (95% CI: 0.51 - 0.93, p = 0.02), 0.56 (95% CI: 0.38 - 0.83, p &lt; 0.01), and 0.45 (95% CI: 0.31 - 0.66, p &lt; 0.01), respectively. Conclusions: The risk of DF in cancer and non-cancer patients increases with age. When compared to matched controls, only cancer patients ≥ 80 with advanced stage cancers were at decreased risk of DF. This finding is likely due to the higher competing risk of death in cancer patients (i.e., of those ≥ 80, 40.2% with cancer versus 4.0% without cancer die within one year). [Table: see text]
Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization
Authors: Ioanna Panagi, Elliott Jennings, Jingkun Zeng, Regina A. Günster, Cullum D. Stones, Hazel Mak, Enkai Jin, Daphne A.C. Stapels, Nur.Z. Subari, Trung H.M. Pham, Susan M. Brewer, Samantha Y.Q. Ong, Denise M. Monack, Sophie Helaine, Teresa L.M. Thurston
Journal: Cell Host & Microbe (2019)

Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Rα (IL-4Rα). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment.
2-weekly vs 3-weekly CHOP with and without Etoposide in Young Patients with Low-Risk Aggressive Non-Hodgkins Lymphoma Results of the Completed NHL-B-1 Trial of the DSHNHL
Authors: M. Pfreundschuh, L. Truemper, R. Schmits, M. Kloess, N. Schmitz, B. Glass, C. Rudolph, A. Engert, D. Mezger, D. Hossfeld, M. Loeffler, German High Grade
Journal: Blood (2002)
Mucosal-associated invariant T cells restrict allergic airway inflammation
Authors: Longyun Ye, Jiexue Pan, Muhammad Asghar Pasha, Xiaofei Shen, Shanti S. D’Souza, Ivan Ting Hin Fung, Yinna Wang, Bingnan Guo, Dale D Tang, Qi Yang
Journal: Journal of Allergy and Clinical Immunology (2019)