tbuckley/cabot-search huggingface dataset:
Drinking Water Disinfection by-Products and Congenital Malformations: A Nationwide Register-Based Prospective Study
Authors: Melle Säve-Söderbergh, Jonas Toljander, Carolina Donat-Vargas, Agneta Åkesson
Journal: Environmental Health Perspectives (2021)

Drinking water chlorination by-products have been associated with adverse reproductive outcomes, although the findings for congenital malformations are still inconclusive.We conducted a nationwide register-based prospective study to assess whether first trimester maternal exposure to the four most common trihalomethanes [total trihalomethanes (TTHM)] via municipal drinking water was associated with risk of congenital malformation among newborns.We included all births during 2005-2015 (live and stillbirths) of mothers residing in Swedish localities having >10,000 inhabitants, two or fewer operating water works, and sufficient municipal TTHM monitoring data. Individual maternal first trimester exposure was obtained by linking TTHM measurements to residential information, categorized into no chlorination and <5, 5-15, and >15μg TTHM/L. We also made chlorination treatment-specific analyses (exclusive use of chloramine or hypochlorite). Outcomes and covariates were obtained via linkage to health care and administrative registers. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression.Based on 623,468 births and a prevalence of congenital malformation of ∼2 cases/100 births, we observed associations between TTHM exposure in areas using chloramine and malformations of the nervous system (OR=1.82; 95% CI: 1.07, 3.12), urinary system (OR=2.06; 95% CI: 1.53, 2.78), genitals (OR=1.77; 95% CI: 1.38, 2.26), and limbs (OR=1.34; 95% CI: 1.10, 1.64), comparing the highest exposed category with the unexposed. No associations were observed in areas using exclusively hypochlorite as the primary water treatment method. By contrast, for malformations of the heart, a significant inverse association was observed only in areas using hypochlorite.TTHM exposure was associated with the increased risk of malformations of the nervous system, urinary system, genitals, and limbs in areas exclusively using chloramine. An association between chloramine-related chlorination by-products and congenital malformations has not previously been highlighted and needs further attention. https://doi.org/10.1289/EHP9122.
Integrative RNA-omics Discovers <i>GNAS</i> Alternative Splicing as a Phenotypic Driver of Splicing Factor–Mutant Neoplasms
Authors: Emily C. Wheeler, Shailee Vora, Daniel Mayer, Andriana G. Kotini, Malgorzata Olszewska, Samuel S. Park, Ernesto Guccione, Julie Teruya-Feldstein, Lewis Silverman, Roger K. Sunahara, Gene W. Yeo, Eirini P. Papapetrou
Journal: Cancer Discovery (2021)

Mutations in splicing factors (SF) are the predominant class of mutations in myelodysplastic syndrome (MDS), but convergent downstream disease drivers remain elusive. To identify common direct targets of missplicing by mutant U2AF1 and SRSF2, we performed RNA sequencing and enhanced version of the cross-linking and immunoprecipitation assay in human hematopoietic stem/progenitor cells derived from isogenic induced pluripotent stem cell (iPSC) models. Integrative analyses of alternative splicing and differential binding converged on a long isoform of GNAS (GNAS-L), promoted by both mutant factors. MDS population genetics, functional and biochemical analyses support that GNAS-L is a driver of MDS and encodes a hyperactive long form of the stimulatory G protein alpha subunit, Gαs-L, that activates ERK/MAPK signaling. SF-mutant MDS cells have activated ERK signaling and consequently are sensitive to MEK inhibitors. Our findings highlight an unexpected and unifying mechanism by which SRSF2 and U2AF1 mutations drive oncogenesis with potential therapeutic implications for MDS and other SF-mutant neoplasms. SF mutations are disease-defining in MDS, but their critical effectors remain unknown. We discover the first direct target of convergent missplicing by mutant U2AF1 and SRSF2, a long GNAS isoform, which activates G protein and ERK/MAPK signaling, thereby driving MDS and rendering mutant cells sensitive to MEK inhibition. This article is highlighted in the In This Issue feature, p. 587.
309P Antineoplastic (ANP) therapies (Tx) after alpelisib (ALP) or placebo (PBO) + fulvestrant (FUL) in patients (Pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–), PIK3CA-mutated (Mut) advanced breast cancer (ABC): An analysis from SOLAR-1
Authors: F. André, H.S. Rugo, D. Juric, G. Rubovsky, T. Yamashita, S.M. Stemmer, Y-S. Lu, M.K. Miller, I. Lorenzo, H. Hu, E.M. Ciruelos
Journal: Annals of Oncology (2021)
1685P COLAR: Results from an intervention study investigating IL-6 blockade with tocilizumab for treatment of immune checkpoint inhibitor induced colitis and arthritis
Authors: R.B. Holmstrøm, O.H. Nielsen, S. Jacobsen, L.B. Riis, S. Theile, J.T. Bjerrum, P. Vilmann, J.S. Johansen, M.K. Boisen, R.L. Eefsen, I.M. Svane, D. Nielsen, I.M. Chen
Journal: Annals of Oncology (2021)
Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia
Authors: Christina Rautenberg, Friedrich Stölzel, Christoph Röllig, Matthias Stelljes, Verena Ingeborg Gaidzik, Michael Lauseker, Oliver Kriege, Mareike Verbeek, Julia Marie Unglaub, Felicitas Thol, Stefan W. Krause, Mathias Hänel, Charlotte Neuerburg, Vladan Vucinic, Christian-Friedrich Jehn, Julia Severmann, Maxi Wass, Lars Fransecky, Jens Chemnitz, Udo Holtick, Kerstin Schäfer-Eckart, Josephine Schröder, Sabrina Kraus, William Krüger, Ulrich Kaiser, Sebastian Scholl, Kathrin Koch, Lea Henning, Guido Kobbe, Rainer Haas, Nael Alakel, Maximilian-Alexander Röhnert, Katja Sockel, Maher Hanoun, Uwe Platzbecker, Tobias A. W. Holderried, Anke Morgner, Michael Heuser, Tim Sauer, Katharina S. Götze, Eva Wagner-Drouet, Konstanze Döhner, Hartmut Döhner, Christoph Schliemann, Johannes Schetelig, Martin Bornhäuser, Ulrich Germing, Thomas Schroeder, Jan Moritz Middeke
Journal: Blood Cancer Journal (2021)

To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26-80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10-3) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response (p = 0.0001), while pretreatment with hypomethylating agents (p = 0.02) and adverse European LeukemiaNet 2017 genetic risk (p < 0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients (p = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation.
Considerations for the delivery of STING ligands in cancer immunotherapy
Authors: M. Petrovic, G. Borchard, O. Jordan
Journal: Journal of Controlled Release (2021)

Several studies have shown the importance of the cGAS-STING pathway in antigen-presenting cells for anti-cancer immunity. Cyclic GMP-AMP (cGAMP) – STING ligand is a negatively charged dinucleotide prone to degradation by hydrolases. Once administered in its soluble form, high doses are needed which in turn may cause side effects such as T cell apoptosis. Moreover, due to its negative charge, transfection of cGAMP into negatively-charged membrane cells is hampered. In order to achieve successful transfection and protection from enzymatic degradation there is a need for a suitable carrier for cGAMP. In this review, we therefore describe currently reported carriers for cGAMP, and correlate their characteristics to the effect they cause. To achieve targeted delivery to the tumor microenvironment, the route of administration and physicochemical parameters of the particles (containing a carrier and cGAMP) such as size and charge need to be determined. Therefore, the choice of the particle formulation and its impact on the preclinical outcome will be discussed.
SARS‐CoV‐2 spike protein harnesses SNX27‐mediated endocytic recycling pathway
Authors: Lin Zhao, Kunhong Zhong, Jia Zhao, Xin Yong, Aiping Tong, Da Jia
Journal: MedComm (2021)

Abstract SARS‐CoV‐2 is an enveloped positive‐sense RNA virus that depends on host factors for all stages of its life. Membrane receptor ACE2 is a well‐established factor for SARS‐CoV‐2 docking. In addition to ACE2, whole‐genome genetic screens have identified additional proteins, such as endosomal trafficking regulators SNX27 and retromer, as key host factors required for SARS‐CoV‐2 infection. However, it is poorly understood how SARS‐CoV‐2 utilize host endocytic transport pathways to produce productive infection. Here, we report that SNX27 interacts with the SARS‐CoV‐2 spike (S) protein to facilitate S protein surface expression. Interestingly, S protein binds to the PDZ domain of SNX27, although it does not contain a PDZ‐binding motif (PDZbm). Either abrogation of the SNX27 PDZ domain or S protein “MTSC” motif, which is critical for SNX27 binding, decreases surface expression of S protein and viral production. Collectively, our study highlights a novel approach utilized by SARS‐CoV‐2 to facilitate virion trafficking to establish virus infection.
1848P Feasible 3D printed models of renal cell cancer with venous thrombus extension for surgical planning and simulation: Phase I NCT03738488
Authors: I. Rivero Belenchon, C.B. Congregado Ruiz, G. Gomez Ciriza, V. Gómez Dos Santos, C. Galvez Garcia, I. Osman Garcia, J.M. Conde Sanchez, F.J. Burgos Revilla, R.A. Medina Lopez
Journal: Annals of Oncology (2021)
Abstract 38: Variations in ORAI1 gene associated with Kawasaki disease
Authors: Yoshihiro Onouchi, Ryuji Fukazawa, Kenichiro Yamamura, Hiroyuki Suzuki, Tomohiro Suenaga, Takashi Takeuchi, Norishige Yoshikawa, Hiromichi Hamada, Takafumi Honda, Kumi Yasukawa, Masaru Terai, Ryota Ebata, Kouji Higashi, Tsutomu Saji, Yasushi Kemmotsu, Shinichi Takatsuki, Kazunobu Ouchi, Fumio Kishi, Tetsushi Yoshikawa, Toshiro Nagai, Kunihiro Hamamoto, Yoshitake Sato, Akihito Honda, Hironobu Kobayashi, Junichi Sato, Shoichi Shibuta, Masakazu Miyawaki, Ko Oishi, Hironobu Yamaga, Noriyuki Aoyagi, Seiji Iwahashi, Yuji Murata, Akihiro Fujino, Kouichi Ozaki, Tomisaku Kawasaki, Jun Abe, Mitsuru Seki, Tohru Kobayashi, Kouichi Arakawa, Shunichi Ogawa, Toshiro Hara, Akira Hata, Toshihiro Tanaka
Journal: Circulation (2015)

Kawasaki disease (KD; MIM611775) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD have suggested up-regulation of Ca2+/NFAT pathway as one of the main pathophysiological processes in KD. In this study, we focused on ORAI1, a gene for a channel involved in store operated Ca2+ entry located on 12q24 where positive linkage signal was seen in our previous sib pair study of KD, and conducted a genetic association study. By re-sequencing 17.4kb of ORAI1 region for 94 subjects, we identified 37 variants with minor allele frequencies larger than 0.05. After selecting 9 tagging SNPs which represent 37 variants we performed an association study using 730 KD cases and 1315 controls. As a result, one tagging SNP located within exon2 showed nominal association (rs3741596; OR = 1.19, 95%CI 1.02~1.40, P = 0.028). The same trend of association was observed in an independent case control panel (1813 KD cases and 1097 controls, OR=1.22, 95% CI 1.06-1.40, P = 0.0056) and a significant P value was observed in a meta-analysis (OR = 1.21, 95%CI 1.09~1.34, P = 0.00041). Furthermore, we also found a rare 6 base-pair insertion polymorphism which cause elongation of proline repeat within N-terminal cytoplasmic domain of the ORAI1 protein was overrepresented in KD cases (rs78448924; OR = 3.91, 95%CI 1.30~11.80, P=0.010). These data indicate altered ORAI1 function confers susceptibility of KD and further highlight importance of the Ca2+/NFAT pathway in the disease pathogenesis.
489P MEN1611 in combination with cetuximab: Targeting PIK3CA mutations in RAS-wild-type patient-derived colorectal cancer xenografts
Authors: S. Capano, G. Merlino, M. Bigioni, P. Tunici, F. Cottino, E. Zanella, V. Vurchio, A. Bertotti, L. Trusolino, D.O. Laurent, A. Pellacani, M. Binaschi
Journal: Annals of Oncology (2021)
1165P Modelling long-term survival outcomes in patients with stage (stg) IB–IIIA EGFR-mutated NSCLC from the ADAURA trial
Authors: P.K. Cheema, B. Heeg, M. Dyer, Y-L. Wu, T. John, F.A. Shepherd, F. de Marinis, B. Melosky, B. Samson, D. Moldaver, S. Shaw, M. Miranda, A. Verhoek
Journal: Annals of Oncology (2021)
1842P Molecular testing in older patients treated for an advanced or metastatic non-squamous non-small cell lung cancer
Authors: T. Lamy, B. Cabarrou, D. Planchard, X. Quantin, S. Schneider, M. Bringuier, B. Besse, M. Pérol, N. Girard, R. Schott, C. Chouaid, C. Ricordel, R. Gervais, D. Debieuvre, C. Audigier-Valette, M. Carton, T. Filleron, G. Simon, M. Robain, C. Baldini
Journal: Annals of Oncology (2021)
571P Real-life monocentric, retrospective study on efficacy and tolerability of lenvatinib (Len) in patients (pts) with advanced radioactive iodine–refractory differentiated thyroid cancer (rDTC)
Authors: S. Zovato, S. Watutantrige, A.M. Ferrara, E. Mioranza, M.G. Ghi, S. Tognazzo, F. Schiavi, E. taschin, G. Doria, A. Rastelli, A. Di Marco, G. Magni, G. Crivellari
Journal: Annals of Oncology (2021)
What to Expect at a Pediatric Telemedicine Visit
Authors: Melissa J. Fitzgerald, Lindsay A. Thompson, Nicole M. Paradise-Black
Journal: JAMA Pediatrics (2021)

What to Expect at a Pediatric Telemedicine VisitWhen parents call child's physician, they may be offered a telemedicine or an in-person visit.Telemedicine or virtual visits use technology that links patients with medical professionals when they are in different locations.Pediatricians have used telemedicine for years, and many are now using this more since the COVID-19 pandemic began.
LBA65 First-line nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) in patients (pts) with unresectable malignant pleural mesothelioma (MPM): 3-year update from CheckMate 743
Authors: S. Peters, A. Scherpereel, R. Cornelissen, Y. Oulkhouir, L. Greillier, M.A. Kaplan, T. Talbot, I. Monnet, S. Hiret, P. Baas, A.K. Nowak, N. Fujimoto, A.S. Tsao, A.S. Mansfield, S. Popat, X. Zhang, N. Hu, D. Balli, J. Sanzari, G. Zalcman
Journal: Annals of Oncology (2021)
Intrahepatic cholangiocyte regeneration from an Fgf‐dependent extrahepatic progenitor niche in a zebrafish model of Alagille Syndrome
Authors: Chengjian Zhao, Joseph J. Lancman, Yi Yang, Keith P. Gates, Dan Cao, Lindsey Barske, Jonathan Matalonga, Xiangyu Pan, Jiaye He, Alyssa Graves, Jan Huisken, Chong Chen, P. Duc Si Dong
Journal: Hepatology (2021)

Abstract Background and Aims Alagille Syndrome (ALGS) is a congenital disorder caused by mutations in the Notch ligand gene JAGGED1 , leading to neonatal loss of intrahepatic duct (IHD) cells and cholestasis. Cholestasis can resolve in certain patients with ALGS, suggesting regeneration of IHD cells. However, the mechanisms driving IHD cell regeneration following Jagged loss remains unclear. Here, we show that cholestasis due to developmental loss of IHD cells can be consistently phenocopied in zebrafish with compound jagged1b and jagged2b mutations or knockdown. Approach and Results Leveraging the transience of jagged knockdown in juvenile zebrafish, we find that resumption of Jagged expression leads to robust regeneration of IHD cells through a Notch‐dependent mechanism. Combining multiple lineage tracing strategies with whole‐liver three‐dimensional imaging, we demonstrate that the extrahepatic duct (EHD) is the primary source of multipotent progenitors that contribute to the regeneration, but not to the development, of IHD cells. Hepatocyte‐to‐IHD cell transdifferentiation is possible but rarely detected. Progenitors in the EHD proliferate and migrate into the liver with Notch signaling loss and differentiate into IHD cells if Notch signaling increases. Tissue‐specific mosaic analysis with an inducible dominant‐negative Fgf receptor suggests that Fgf signaling from the surrounding mesenchymal cells maintains this extrahepatic niche by directly preventing premature differentiation and allocation of EHD progenitors to the liver. Indeed, transcriptional profiling and functional analysis of adult mouse EHD organoids uncover their distinct differentiation and proliferative potential relative to IHD organoids. Conclusions Our data show that IHD cells regenerate upon resumption of Jagged/Notch signaling, from multipotent progenitors originating from an Fgf‐dependent extrahepatic stem cell niche. We posit that if Jagged/Notch signaling is augmented, through normal stochastic variation, gene therapy, or a Notch agonist, regeneration of IHD cells in patients with ALGS may be enhanced.
Effect of Prophylactic Subcutaneous Scopolamine Butylbromide on Death Rattle in Patients at the End of Life
Authors: Harriëtte J. van Esch, Lia van Zuylen, Eric C. T. Geijteman, Esther Oomen-de Hoop, Bregje A. A. Huisman, Heike S. Noordzij-Nooteboom, Renske Boogaard, Agnes van der Heide, Carin C. D. van der Rijt
Journal: JAMA (2021)

<h3>Importance</h3> <i>Death rattle</i>, defined as noisy breathing caused by the presence of mucus in the respiratory tract, is relatively common among dying patients. Although clinical guidelines recommend anticholinergic drugs to reduce the death rattle after nonpharmacological measures fail, evidence regarding their efficacy is lacking. Given that anticholinergics only decrease mucus production, it is unknown whether prophylactic application may be more appropriate. <h3>Objective</h3> To determine whether administration of prophylactic scopolamine butylbromide reduces the death rattle. <h3>Design, Setting, and Participants</h3> A multicenter, randomized, double-blind, placebo-controlled trial was performed in 6 hospices in the Netherlands. Patients with a life expectancy of 3 or more days who were admitted to the participating hospices were asked to give advance informed consent from April 10, 2017, through December 31, 2019. When the dying phase was recognized, patients fulfilling the eligibility criteria were randomized. Of the 229 patients who provided advance informed consent, 162 were ultimately randomized. The date of final follow-up was January 31, 2020. <h3>Interventions</h3> Administration of subcutaneous scopolamine butylbromide, 20 mg four times a day (n = 79), or placebo (n = 78). <h3>Main Outcomes and Measures</h3> The primary outcome was the occurrence of a grade 2 or higher death rattle as defined by Back (range, 0-3; 0, no rattle; 3, rattle audible standing in the door opening) measured at 2 consecutive time points with a 4-hour interval. Secondary outcomes included the time between recognizing the dying phase and the onset of a death rattle and anticholinergic adverse events. <h3>Results</h3> Among 162 patients who were randomized, 157 patients (97%; median age, 76 years [IQR, 66-84 years]; 56% women) were included in the primary analyses. A death rattle occurred in 10 patients (13%) in the scopolamine group compared with 21 patients (27%) in the placebo group (difference, 14%; 95% CI, 2%-27%,<i>P</i> = .02). Regarding secondary outcomes, an analysis of the time to death rattle yielded a subdistribution hazard ratio (HR) of 0.44 (95% CI, 0.20-0.92;<i>P</i> = .03; cumulative incidence at 48 hours: 8% in the scopolamine group vs 17% in the placebo group). In the scopolamine vs placebo groups, restlessness occurred in 22 of 79 patients (28%) vs 18 of 78 (23%), dry mouth in 8 of 79 (10%) vs 12 of 78 (15%), and urinary retention in 6 of 26 (23%) vs 3 of 18 (17%), respectively. <h3>Conclusions and Relevance</h3> Among patients near the end of life, prophylactic subcutaneous scopolamine butylbromide, compared with placebo, significantly reduced the occurrence of the death rattle. <h3>Trial Registration</h3> trialregister.nl Identifier:NTR6264
1030TiP An open-label multicenter phase Ib study of AN0025, a selective inhibitor of the prostaglandin E2 receptor-type-4 receptor, in combination with pembrolizumab in patients with advanced solid tumors
Authors: W. Akerley, M. Reilley, A. Marabelle, C. Baldini, P.A. Cassier, M. Chisamore, T. Tang, N. Lautermilch, D. Hong
Journal: Annals of Oncology (2021)
1452P Use of the Pallia 10 score in patients enrolled in phase I trials at Gustave Roussy Cancer Center
Authors: K. Ouali, C. Mateus, A. Laparra, E. Pavliuc, P. Martin Romano, A. Sampetrean, A. Varga, S. Champiat, L. Verlingue, A. Geraud, A. Marabelle, A. Hollebecque, A. Gazzah, R. Bahleda, S. Postel-Vinay, V. Ribrag, J-C. Soria, F. Scotté, C. Massard, C. Baldini
Journal: Annals of Oncology (2021)
Abstract 14944: Characterization of an apoE-/- Mouse Model Expressing HLA-A*0201
Authors: Jianchang Zhou, Xiaoning Zhao, Kuang-yuh Chyu, Paul C Dimayuga, Wai Man Lio, Fernando Chernomordik, Juliana Yano, Bojan Cercek, Prediman K Shah
Journal: Circulation (2019)

Introduction: Adaptive immune responses are important in atherogenesis. Immunization with an apoB-100 peptide reduced murine atherosclerosis mediated in part by CD8+ T cell response, suggesting an ...
1800O Multi-omic characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation
Authors: Á. Quintanal-Villalonga, H. Taniguchi, Y.A. Zhan, M.M. Hasan, S.S. Chavan, F. Uddin, V. Allaj, P. Manoj, N.S. Shah, J.M. Chan, M. Ciampricotti, A. Chow, U. Bhanot, J. Egger, J. Qiu, E. De Stanchina, N. Rekhtman, H.A. Yu, T. Sen, C.M. Rudin
Journal: Annals of Oncology (2021)