tbuckley/cabot-search huggingface dataset:
High seroconversion rate but low antibody titers after two injections of BNT162b2 (Pfizer-BioNTech) vaccine in patients treated with chemotherapy for solid cancers
Authors: R. Palich, M. Veyri, A. Vozy, S. Marot, J. Gligorov, M.-A. Benderra, P. Maingon, L. Morand-Joubert, Z. Adjoutah, A.-G. Marcelin, J.-P. Spano, J. Barrière
Journal: Annals of Oncology (2021)
Abstract #LB-131: Biomarker evaluation in the Phase III, placebo (P)-controlled, randomized BeTa trial of bevacizumab (B) and erlotinib (E) for patients (pts) with advanced non-small cell lung cancer (NSCLC) after failure of standard 1st-line chemotherapy: correlation with treatment outcomes
Authors: Roy Herbst, Howard Stern, Lukas Amler, Gregory Otterson, Ming Lin, Paula O'Connor, John Hainsworth
Journal: Cancer Research (2009)

Background Epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) receptor that may be expressed or mutated in NSCLC. E inhibits the activity of the EGFR and has demonstrated improved survival when used as monotherapy to treat patients with recurrent NSCLC. The BETA Lung study assessed the outcomes of pts with advanced stage NSCLC, treated with E+B or E+P in the 2nd-line. Clinical activity for the E+B combination was demonstrated by a doubling of progression free survival (median PFS 3.4 mos [B+E] vs. 1.7 mos [E+P]; hazard ratio [HR]=0.62). However, there was no improvement in overall survival (median OS 9.3 mos [B+E] vs.9.2 mos [E+P]; HR=0.97). EGFR immunohistochemistry (IHC), EGFR fluorescence in situ hybridization (FISH), EGFR and Kras mutation status, and expression of the epithelial mesenchymal transition (EMT) markers were correlated with treatment outcomes in accordance with the study plan. Methods Pts enrolled were randomized (1:1) to E+B or E+P. Edosing was 150 mg daily. B/P dosing was 15mg/kg intravenous every 3 weeks. Responses were assessed every 6 weeks until week 24 and every 12 weeks thereafter. Treatment continued until disease progression or unacceptable toxicity. Archival tumor tissue was collected for biomarker analysis. EGFR FISH and IHC analyses were performed using the PathVysion® and PharmDx kits from Abbott-Vysis and DAKO, respectively. Highly sensitive analyses of EGFR TK mutations in exons 18-21 and Kras mutations in exons 2 and 3 were performed using DHPLC (denaturing high-performance liquid chromatography) and mutations were validated by sequencing. Markers of EMT, including e-cadherin and vimentin expression, were assessed using established IHC protocols.Results  477 of 636 enrolled subjects provided tissue samples. The PFS and OS HRs for pts with an EGFR IHC result were 0.63 (95% CI: 0.49 -0.80) and 1.03 (95% CI: 0.80 -1.34), respectively. They were 0.62 (95% CI: 0.46 -0.84) and 1.24 (95% CI: 0.90 -1.71) for subjects with an EGFR FISH result; and 0.62 (95% CI: 0.49 -0.78) and 1.09 (95% CI: 0.85 -1.40) for those with an EGFR mutation result. The PFS and OS HRs for patients with a K-ras mutation result were 0.63 (95% CI: 0.50 -0.79) and 1.10 (95% CI: 0.86 -1.41). Conclusions Tissue for biomarker analysis was collected from 75% of the pts enrolled in the BETA Lung study. These patients were representative of the overall enrolled patient population. The PFS and OS results for the biomarker defined sub-groups were consistent with the overall results of the trial. A detailed correlation of these biomarkers with outcomes will be presented.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-131.
Digestive Manifestations in Patients Hospitalized with COVID-19.
Authors: B Joseph Elmunzer, Rebecca L Spitzer, Lydia D Foster, Ambreen A Merchant, Eric F Howard, Vaishali A Patel, Mary K West, Emad Qayed, Rosemary Nustas, Ali Zakaria, Marc S Piper, Jason R Taylor, Lujain Jaza, Nauzer Forbes, Millie Chau, Luis F Lara, Georgios I Papachristou, Michael L Volk, Liam G Hilson, Selena Zhou, Vladimir M Kushnir, Alexandria M Lenyo, Caroline G McLeod, Sunil Amin, Gabriela N Kuftinec, Dhiraj Yadav, Charlie Fox, Jennifer M Kolb, Swati Pawa, Rishi Pawa, Andrew Canakis, Christopher Huang, Laith H Jamil, Andrew M Aneese, Benita K Glamour, Zachary L Smith, Katherine A Hanley, Jordan Wood, Harsh K Patel, Janak N Shah, Emil Agarunov, Amrita Sethi, Evan L Fogel, Gail McNulty, Abdul Haseeb, Judy A Trieu, Rebekah E Dixon, Jeong Yun Yang, Robin B Mendelsohn, Delia Calo
Journal: Clinical Gastroenterology and Hepatology (2020)
An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions
Authors: Alex J. Clark, Umaiyal Kugathasan, Georgios Baskozos, David A. Priestman, Nadine Fugger, Museer A. Lone, Alaa Othman, Ka Hing Chu, Iulia Blesneac, Emma R. Wilson, Matilde Laurà, Bernadett Kalmar, Linda Greensmith, Thorsten Hornemann, Frances M. Platt, Mary M. Reilly, David L. Bennett
Journal: Cell Reports Medicine (2021)
Does Hearing Impairment Affect Physical Function?
Authors: Willa D. Brenowitz, Margaret I. Wallhagen
Journal: JAMA Network Open (2021)

Pablo Martinez-Amezcua, MD, PhD, MHS; Danielle Powell, AuD, PhD; Pei-Lun Kuo, MD, PhD, MPH; Nicholas S. Reed, AuD; Kevin J. Sullivan, PhD, MPH; Priya Palta, PhD, MHS; Moyses Szklo, MD, DrPH; Richey Sharrett, MD, DrPH; Jennifer A. Schrack, PhD; Frank R. Lin, MD, PhD; Jennifer A. Deal, PhD
Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation
Authors: Niklas Rutsch, Chester E. Chamberlain, Wesley Dixon, Lauren Spector, Lisa R. Letourneau-Freiberg, Wint W. Lwin, Louis H. Philipson, Alexander Zarbock, Karline Saintus, Juehu Wang, Michael S. German, Mark S. Anderson, Clifford A. Lowell
Journal: Diabetes Care (2021)

OBJECTIVE Multiple genome-wide association studies have identified a strong genetic linkage between the SKAP2 locus and type 1 diabetes (T1D), but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel SKAP2 coding mutation in a patient with T1D to gain further insight into how this impacts immune tolerance. RESEARCH DESIGN AND METHODS We identified a 24-year-old individual with T1D and other autoimmune and inflammatory conditions. The proband and first-degree relatives were recruited for whole-exome sequencing. Functional studies of the protein variant were performed using a cell line and primary myeloid immune cells collected from family members. RESULTS Sequencing identified a de novo SKAP2 variant (c.457G&amp;gt;A, p.Gly153Arg) in the proband. Assays using monocyte-derived macrophages from the individual revealed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, likely resulting in a break in immune tolerance and T1D. CONCLUSIONS SKAP2 plays a key role in myeloid cell activation and migration. This particular mutation in a patient with T1D and multiple autoimmune conditions implicates a role for activating SKAP2 variants in autoimmune T1D.
Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR/CRISPR‐associated protein 9–Mediated Gene Editing
Authors: Martijn G.S. Rutten, Terry G.J. Derks, Nicolette C.A. Huijkman, Trijnie Bos, Niels J. Kloosterhuis, Kees C.W.A. van de Kolk, Justina C. Wolters, Mirjam H. Koster, Laura Bongiovanni, Rachel E. Thomas, Alain de Bruin, Bart van de Sluis, Maaike H. Oosterveer
Journal: Hepatology (2021)

Background and Aims Patients with glycogen storage disease type 1a (GSD‐1a) primarily present with life‐threatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long‐term complications still occur, such as liver tumor development. Variations in residual glucose‐6‐phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal health care and quality of life for GSD‐1a patients. Currently available GSD‐1a animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity or the contribution of gene‐gene interactions (GGIs) in the liver. Approach and Results To meet these needs, we generated and characterized a hepatocyte‐specific GSD‐1a mouse model using somatic CRISPR/CRISPR‐associated protein 9 (Cas9)–mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis (HS), and increased liver tumor incidence. This approach was furthermore successful in simultaneously modulating hepatic G6PC and carbohydrate response element‐binding protein, a transcription factor that is activated in GSD‐1a and protects against HS under these conditions. Importantly, it also allowed for the modeling of a spectrum of GSD‐1a phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and HS. Conclusions In conclusion, we show that somatic CRISPR/Cas9‐mediated gene editing allows for the modeling of a spectrum of hepatocyte‐borne GSD‐1a disease symptoms in mice and to efficiently study GGIs in the liver. This approach opens perspectives for translational research and will likely contribute to personalized treatments for GSD‐1a and other genetic liver diseases.
Effect of Vaccination on Household Transmission of SARS-CoV-2 in England
Authors: Ross J Harris, Jennifer A Hall, Asad Zaidi, Nick J Andrews, J Kevin Dunbar, Gavin Dabrera
Journal: New England Journal of Medicine (2021)

Effect of Vaccination on Household Transmission of SARS-CoV-2 in EnglandTo the Editor: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevents infection and reduces the severity of coronavirus disease 2019 (Covid-19) in vaccinated persons. 1,2We investigated whether vaccination would reduce transmission in the household setting in the context of postvaccination infection.We analyzed data from the Household Transmission Evaluation Dataset (HOSTED), which has information on all laboratory-confirmed cases of Covid-19 in England and in which data on all persons sharing the same address are linked. 3 We then linked to individual-level data on all Covid-19 vaccinations in England (see the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org).We compared the risk of secondary infection (defined as a positive SARS-CoV-2 test 2 to 14 days after the positive test for the index case) among unvaccinated household contacts of persons with SARS-CoV-2 infection who had received at least one dose of the ChAdOx1 nCoV-19 or BNT162b2 vaccine 21 days or more before testing positive with the risk among unvaccinated household contacts of unvaccinated persons with infection.We fitted logistic-regression models with adjustment for the age and sex of the person with the index case of Covid-19 (index patient) and the household contact, geographic region, calendar week of the index case, deprivation (a composite score of socioeconomic and other factors), and household type and size.We also considered the timing of effects among index patients who had been vaccinated at any time up to the date of the positive test.* Odds ratios were adjusted for the age and sex of the index patient and their household contact, geographic region, calendar week of the index case, and an index of multiple deprivation and household type and size.CI denotes confidence interval, and Covid-19 coronavirus disease 2019.
Urine APOL1 Isoforms Reflect Plasma-Derived Liver-Synthesized Proteins
Authors: Magnus Althage, Timothy M. Heinrich, Tasso Miliotis, Anna Bogstedt, Lijun Ma, Michael D. Gautreaux, Pamela J. Hicks, Nicholette D. Palmer, Iain MacPhee, Judith Hartleib-Geschwindner, Peter J. Greasley, Barry I. Freedman
Journal: Journal of the American Society of Nephrology (2021)

APOL1 kidney risk variants (KRVs) cause approximately 30% of ESKD in Blacks.[1][1],[2][2] Studies support kidney-synthesized APOL1 KRV isoforms, not liver-synthesized circulating isoforms, as causing nephropathy.[3][3],[4][4] Small molecule inhibitors and APOL1 antisense oligonucleotides are novel
Tocilizumab in VEXAS relapsing polychondritis: a single-center pilot study in Japan
Authors: Yohei Kirino, Kaoru Takase-Minegishi, Naomi Tsuchida, Lisa Hirahara, Yosuke Kunishita, Ryusuke Yoshimi, Hideaki Nakajima
Journal: Annals of the Rheumatic Diseases (2021)

Recently, a rare severe autoinflammatory disease vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome caused by somatic variants in the UBA1 gene was discovered.1 We reported the clinical features of eight relapsing polychondritis (RP) patients with UBA1 variants, six of which were accompanied by myelodysplastic syndrome (MDS).2

The clinical features of VEXAS syndrome are heterogeneous, including high-grade fever, polychondritis, large vessel vasculitis, skin eruptions, arthritis, thrombosis, scleritis and serositis, which require intensive immunosuppressive agents. Most of our patients before this study had received high doses of prednisolone (PSL) and cytotoxic immunosuppressants including methotrexate, cyclophosphamide and azathioprine.1 2 However, even with concomitant immunosuppressant treatment, PSL tapering often led to a relapse of high-grade fever and skin rash in these patients; therefore, ≥20 mg oral PSL was required in most cases, resulting in frequent hospitalisation and death due to opportunistic infections. In addition, many cases of VEXAS syndrome already have MDS at the time of diagnosis, and cytotoxic immunosuppressive agents should be avoided or reduced in dose because they might cause further cytopenia.

Tocilizumab (TCZ), an anti-interleukin (IL)-6 receptor antagonist approved for the treatment of inflammatory diseases, such as rheumatoid arthritis and giant cell arteritis, may be useful in managing severe inflammation in VEXAS–RP and preserving the cumulative dose of PSL, which …
Opioids: first jury trial opens in US as Johnson &amp; Johnson pays $230m to settle out of court
Authors: Owen Dyer
Journal: BMJ (2021)

The State of New York’s lawsuit against US opioid makers and distributors1 opened on 29 June without several expected defendants, as five companies including Johnson & Johnson removed themselves at the last minute by agreeing to pay out-of-court settlements.

The big four US pharmacy chains— CVS, Rite Aid, Walgreens, and Walmart—also agreed to settle out of court in the days leading up to the trial, which is the first major opioid lawsuit to be heard before a jury in the US. Walgreens settled only minutes before opening arguments began.

The case is too large for a regular courtroom, so is being heard in a law school auditorium on Long Island. The jurors, wearing masks …
A phase 2 multiple ascending dose study of the inhaled pan-JAK inhibitor nezulcitinib (TD-0903) in severe COVID-19
Authors: Dave Singh, Maxim Bogus, Valentyn Moskalenko, Robert Lord, Edmund J. Moran, Glenn D. Crater, David L. Bourdet, Nathan D. Pfeifer, Jacky Woo, Elad Kaufman, David A. Lombardi, Emily Y. Weng, Tuan Nguyen, Ashley Woodcock, Brett Haumann, Rajeev Saggar
Journal: European Respiratory Journal (2021)

<b>The inhaled lung-selective pan-JAK inhibitor nezulcitinib appears generally well tolerated in hospitalised patients with severe #COVID-19, with trends for improved oxygenation and clinical status, shortened hospitalisation, and fewer deaths <i>versus</i> placebo</b>https://bit.ly/35Xs1Rf
Abstract 15724: WT1 as a Regulator of Adipocyte Derived Stem Cell Mediated Cardiac Revascularization and Regeneration
Authors: Jihad Aljabban, Imad Aljabban, Roman Camarda, Hussam Salhi, Osama El-Sayed, Dexter Hadley, Ramin E Beygui
Journal: Circulation (2019)

Introduction: Cardiovascular disease (CVD) is significant cause of morbidity and mortality in the world. Cardiac regeneration technology can serve to mitigate this healthcare burden, but clinical a...
Abstract 15597: Temporal Differences in the Cardioprotective Effects of Cardiomyocyte Specific Genetic Ablation of the Mitochondrial Fission Factor Dynamic Related Protein 1
Authors: Lin Piao, Yong-Hu Fang, Robert Hamanaka, Gokhan Mutlu, Stephen L Archer, Willard W Sharp
Journal: Circulation (2019)

Introduction: Increased mitochondrial fission occurs following myocardial ischemia/reperfusion (IR) injury. Acute, in vitro, genetic inhibition of the mitochondrial fission factor, Dynamin related ...
<i>TET2</i> and <i>DNMT3A</i> Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors
Authors: Silvia Maifrede, Bac Viet Le, Margaret Nieborowska-Skorska, Konstantin Golovine, Katherine Sullivan-Reed, Wangisa M.B. Dunuwille, Joseph Nacson, Michael Hulse, Kelsey Keith, Jozef Madzo, Lisa Beatrice Caruso, Zachary Gazze, Zhaorui Lian, Antonella Padella, Kumaraswamy N. Chitrala, Boris A. Bartholdy, Ksenia Matlawska-Wasowska, Daniela Di Marcantonio, Giorgia Simonetti, Georg Greiner, Stephen M. Sykes, Peter Valent, Elisabeth M. Paietta, Martin S. Tallman, Hugo F. Fernandez, Mark R. Litzow, Mark D. Minden, Jian Huang, Giovanni Martinelli, George S. Vassiliou, Italo Tempera, Katarzyna Piwocka, Neil Johnson, Grant A. Challen, Tomasz Skorski
Journal: Cancer Research (2021)

Abstract Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms' tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically. Significance: TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase–positive malignant hematopoietic cells to PARP inhibitors.
Abstract 270: mTORC1 is Essential for Cardiomyocyte Homeostasis and Female Sex Related Cardioprotection
Authors: Dennis B Guergen, Nelli Beiner, Rusan Catar, Thorsten Mielke, Hauke Busch, Melanie Boerries, Joern Dengjel, Marijke Brink, Florian Grahammer, Tobias B Huber, Angelika Kusch, Duska Dragun
Journal: Circulation Research (2016)

Mechanistic target of rapamycin (mTOR) kinase operates in two functionally and structurally distinct protein complexes mTORC1 and mTORC2. Raptor is a defining mTORC1 protein critical for cardiac growth in response to stress. Our previous studies showed sexual dimorphism in LV remodeling of normotensive DOCA-salt mice, where females retain normal LV architecture and males developed maladaptive LV hypertrophy. We hypothesized involvement of mTORC1 in regulation of this sexual dimorphism and induced cardiomyocyte (CM) specific raptor deletion (ra-cKO) in our model of normotensive mineralocorticoid challenge. Deletion of raptor in CM lead to decreased mTORC1 downstream target activation of 4E-BP1 and strong compensatory hyperactivation of mTORC2 target AKT in both sexes. In contrast to healthy wild type females, female DOCA-salt ra-cKO mice developed severe dilative phenotype with tremendous interstitial fibrosis (15fold increase vs. WT) of similar extent as males. Functionally, ra-cKO females had stronger decrease in EF (51 vs. 26%) than ra-cKO males (50 vs. 32%). Greater loss of sarcomeric ultrastructure and mitochondrial morphology in transmission electron microscopy was observed in male ra-cKOs. Analysis of label-free proteomics and transcriptomics approaches revealed genotype and sex-specific clustering and identified significantly regulated single proteins or gene sets. Concordant to observed ultrastructural changes, down-regulation of genes for Z-disc, t-tubule and sarcomere organization was prominent in male hearts, whereas females displayed up-regulation of gene sets for inflammation, angiogenesis and mitochondrial function. Intact mTORC1 is indispensible for CM homeostasis of both sexes as reflected by development of severe phenotype even by a mild stressor in our model. More specific, female sex-specific cardioprotection is completely lost in absence of mTORC1. Despite similar phenotypic changes in both sexes, sex-specific differences in regulation of gene expression points toward sex-specific functional selectivity of mTORC1 in regulation of CM homeostasis. Given the broad indications for mTOR inhibitors and especially used high concentration in oncology, one could anticipate adverse cardiac side effects.
Breaking New Ground with Incretin Therapy in Diabetes
Authors: Katherine R. Tuttle
Journal: New England Journal of Medicine (2021)

The number of persons with diabetes is projected to grow from 463 million to 700 million worldwide between 2019 and 2045, with the greatest effect occurring in low- and middle-income countries.1 Given the growing number of cases of diabetes (90% of which are type 2), an increased incidence of complications of diabetes, particularly cardiovascular disease and chronic kidney disease, is anticipated.2,3 The need is urgent to develop and deploy effective therapies for diabetes — especially those that reduce the risks of serious complications — across populations. The novel concept of combining a glucose-dependent insulinotropic polypeptide with a glucagon-like peptide-1 (GLP-1) . . .