tbuckley/cabot-search huggingface dataset:
Association of Mohs Micrographic Surgery vs Wide Local Excision With Overall Survival Outcomes for Patients With Melanoma of the Trunk and Extremities
Authors: Addison M. Demer, Jamie L. Hanson, Ian A. Maher, Walter Liszewski
Journal: JAMA Dermatology (2020)

Although previous database studies suggest that Mohs micrographic surgery (MMS) treatment is associated with improved overall survival (OS) for head and neck melanomas, outcomes for trunk and extremity (T&E) tumors have not been adequately evaluated.To assess survival outcomes for patients with melanomas of the T&E treated with MMS vs wide local excision (WLE).This retrospective cohort study examined deidentified data from the National Cancer Database between 2004 and 2015. Inclusion criteria for the analysis included diagnosis of trunk, upper extremity, or lower extremity melanoma; known Breslow depth; removal by MMS or WLE; and known last date of survival status.Five-year all-cause mortality (ACM) rates.A total of 188 862 in situ and invasive melanomas were included in the analysis (MMS, 2.3%; WLE, 97.7%); the mean (SD) age of patients included was 58.8 (16.0) years, and 52.7% were male. Multivariate analysis demonstrated no OS difference among trunk (WLE hazard ratio [HR], 1.097; 95% CI, 0.950-1.267; P = .21), upper extremity (WLE HR, 1.013; 95% CI, 0.872-1.176; P = .87), lower extremity (WLE HR, 0.934; 95% CI, 0.770-1.134; P = .49), or combined T&E (WLE HR, 1.031; 95% CI, 0.941-1.130; P = .51) tumors. Factors associated with increased risk of ACM on multivariate analysis of all tumors included increasing age (HR, 1.043; 95% CI, 1.042-1.044; P < .001), no insurance or nonprivate insurance (none: HR, 1.921 [95% CI, 1.782-2.071]; Medicaid: HR, 2.410 [95% CI, 2.242-2.591]; Medicare: HR, 1.237 [95% CI, 1.194-1.281]; other government insurance: HR, 1.279 [95% CI, 1.117-1.465]; P < .001 for all), positive surgical margins (HR, 1.609; 95% CI, 1.512-1.712; P < .001), a Charlson-Deyo comorbidity score greater than 0 (Charlson-Deyo score of 1: HR, 1.340; 95% CI, 1.295-1.385; P < .001; Charlson-Deyo score of ≥2: HR, 2.044; 95% CI, 1.934-2.159; P < .001), tumor ulceration (HR, 2.175; 95% CI, 2.114-2.238; P < .001), and increasing Breslow depth (HR, 1.002 [per 0.1 mm]; P < .001). Female sex (HR, 0.698; 95% CI, 0.680-0.716; P < .001) and nonnodular subtype (lentigo maligna/lentigo maligna melanoma: HR, 0.743; 95% CI, 0.686-0.805; P < .001; superficial spreading: HR, 0.739; 95% CI, 0.710-0.769; P < .001; other subtype: HR, 0.817; 95% CI, 0.790-0.845; P < .001; nodular: HR, 1 [reference]) were associated with improved OS.This cohort study of patients surgically treated for melanomas of the trunk and/or extremities found that, compared with WLE, MMS was not associated with significantly different OS for T&E melanomas.
TCT CONNECT-149 Prognostic Value of Body Mass Index for Short-Term Outcome Following Transcatheter Aortic Valve Replacement
Authors: Marouane Boukhris, Jessica Forcillo, Jeannot Potvin, Malek Badreddine, Ali Hillani, Nicolas Noiseux, Louis-Mathieux Stevens, Jean-François Gobeil, Jean-Bernard Masson
Journal: Journal of the American College of Cardiology (2020)
Multisystem Inflammatory Syndrome in Children in the United States
Authors: Leora R Feldstein, Erica B Rose, Adrienne G Randolph
Journal: New England Journal of Medicine (2020)

23 issue) present case series of the multisystem inflammatory syndrome in children (MIS-C; also called the pediatric inflammatory multisystem syndrome); Levin 3 provides commentary.To address the burden of MIS-C in France, a nationwide surveillance program was launched on April 30, 2020, by Santé Publique France (the French national public health agency) and French pediatric scientific societies.Results in the first 108 cases have been published; similar to the cases reported by Feldstein et al. and Dufort et al., these results showed a median patient age of 8 years, a temporospatial distribution that is evocative of a link to the outbreak of coronavirus disease 2019 , and an overlap of macrophage activation syndrome, serositis, Kawasaki's disease-like features, and myocarditis in half the cases.4 As of June 21, 2020, a total of 195 cases (i.e., hospitalizations) had been reported, with 138 classified as being associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), according to our case definition (Fig. 1). 4 A sharp decrease in the incidence of cases occurred 3 to 4 weeks after the decrease in the Covid-19 outbreak in France.These updated surveillance data highlight the transient nature of MIS-C and suggest that in the absence of a second wave of Covid-19, new cases of MIS-C are expected to remain extremely rare and sporadic.This sequence is highly suggestive of a postinfectious disease for which adaptive immunity might be crucial in the pathogenesis.
Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism
Authors: Md Kamrul Hasan, Emanuela M. Ghia, Laura Z. Rassenti, George F. Widhopf, Thomas J. Kipps
Journal: Leukemia (2020)

Abstract Patients with chronic lymphocytic leukemia (CLL) have high plasma-levels of Wnt5a, which can induce phosphorylation of ERK1/2 and enhance CLL-cell proliferation. Such effects could be inhibited by treatment with an ERK1/2 inhibitor, ERK1/2-specific siRNA, or cirmtuzumab, an anti-ROR1 mAb. The CLL-derived line, MEC1, expresses Wnt5a, but not ROR1. MEC1 cells transfected to express ROR1 (MEC1-ROR1) had higher levels of phosphorylated ERK1/2 than parental MEC1, or MEC1 transfected with ROR1ΔPRD, a truncated ROR1 lacking the cytoplasmic proline-rich domain (PRD), or ROR1 P808A a mutant ROR1 with a P→A substitution at 808, which is required for complexing with the Rac-specific-guanine-nucleotide-exchange factor DOCK2 upon stimulation with Wnt5a. We silenced DOCK2 with siRNA and found this repressed the capacity of Wnt5a to induce ERK1/2 phosphorylation in MEC1-ROR1 or CLL cells. CLL cells that expressed ROR1 had higher levels of phosphorylated ERK1/2 or DOCK2 than CLL cells lacking ROR1. Although we found ibrutinib could inhibit the phosphorylation of ERK1/2 and DOCK2 induced by B-cell-receptor ligation, we found that this drug was unable to inhibit Wnt5a-induced, ROR1-dependent phosphorylation of ERK1/2 or DOCK2. This study demonstrates that Wnt5a can induce activation of ERK1/2 and enhance CLL-cell proliferation via a ROR1/DOCK2-dependent pathway independent of BTK.
AB0070 The effect of prolactin on disease activity in sle
Authors: LC Te Boome, PM Welsing, AA Eijsbouts, FH Van den Hoogen
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Prolactin, a hormone with immunomodulatory effects, possible plays a role in the disease activity of Systemic Lupus Erythematosus (SLE). Results of studies are contradictory regarding the correlation between hyperprolactinemia and disease activity. <h3>Objectives</h3> To establish whether determination of prolactin is helpful in assessing disease activity in SLE by reviewing relevant literature. <h3>Methods</h3> Studies were identified through Medline search. Also references from these articles were reviewed. <h3>Results</h3> Ten articles that sought to establish a relationship between prolactin and SLE activity were identified. Number of patients in the studies varied from 29 to 192, aged 16–73 years, and the percentage of elevated serum prolactin levels in SLE patients was between 2.2–40%. The SLEDAI was used as disease activity index in 7/10 studies. The presence of conditions known to be associated with hyperprolactinemia were either reported or excluded. Steroids treatment was accepted in all studies, DMARDs were used in 8/10 studies. In 5/10 studies bloodsamples were collected midmorning and in 4/10 patients had to fast. Single measurement of serum prolactin concentration and disease activity was done in 6 studies. The other 4 studies had 2–4 measurements per patient. Pearson?s correlation coefficient was the used statistical analysis in 7/10 studies. A relation between prolactin and disease activity was reported in one study. The number of included patients in the studies was small and different statistical methods were used. <h3>Conclusion</h3> The correlation between serum prolactin levels and disease activity is still uncertain. A cross-sectional as well as longitudinal study with using the correct statistics, power calculation and proper recording of secondary causes of elevated prolactin and medication need to be done.
T reg cell–intrinsic requirements for ST2 signaling in health and neuroinflammation
Authors: Saskia Hemmers, Michail Schizas, Alexander Y. Rudensky
Journal: The Journal of Experimental Medicine (2020)

ST2, the receptor for the alarmin IL-33, is expressed by a subset of regulatory T (T reg) cells residing in nonlymphoid tissues, and these cells can potently expand upon provision of exogenous IL-33. Whether the accumulation and residence of T reg cells in tissues requires their cell-intrinsic expression of and signaling by ST2, or whether indirect IL-33 signaling acting on other cells suffices, has been a matter of contention. Here, we report that ST2 expression on T reg cells is largely dispensable for their accumulation and residence in nonlymphoid organs, including the visceral adipose tissue (VAT), even though cell-intrinsic sensing of IL-33 promotes type 2 cytokine production by VAT-residing T reg cells. In addition, we uncovered a novel ST2-dependent role for T reg cells in limiting the size of IL-17A–producing γδT cells in the CNS in a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE). Finally, ST2 deficiency limited to T reg cells led to disease exacerbation in EAE.
Translational research on the role of formula stability in Hetter's phenol–croton oil peels: Analysis of chemical studies and clinical outcomes from a randomized, double-blinded, split-face controlled trial
Authors: Ideli Cristhina Neitzke, Daniella de Grande Curi, Erica Miyake Lin, Kachiu Cecilia Lee, Seaver L. Soon, Ana Cecília Lunardelli Bittencourt, Caroline Motta Aguiar, Domingos Jordão Neto, Amanda Roderjan Cray da Costa Filha, Flávio Luís Beltrame, Patrícia Mathias Döll-Boscardin, Carlos Gustavo Wambier
Journal: Journal of the American Academy of Dermatology (2020)
RNA sequencing and Immunohistochemistry Reveal <i>ZFN7</i> as a Stronger Marker of Survival than Molecular Subtypes in G-CIMP–negative Glioblastoma
Authors: Anna Esteve-Codina, Francesc Alameda, Cristina Carrato, Estela Pineda, Oriol Arpí, Maria Martinez-García, Mar Mallo, Marta Gut, Marc Dabad, Avelina Tortosa, Sonia Del Barco, Jaume Capellades, Josep Puig, Oscar Gallego, Teresa Pujol, Laura Oleaga, Miquel Gil-Gil, Cristian de Quintana-Schmidt, Izaskun Valduvieco, Anna Martinez-Cardús, Beatriz Bellosillo, Ana Maria Muñoz-Marmol, Anna Esteve, Marta Domenech, Angels Camins, Jordi Craven-Bartle, Salvador Villa, Jordi Marruecos, Sira Domenech, Nuria de la Iglesia, Carmen Balana
Journal: Clinical Cancer Research (2020)

Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials.From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes.We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype-negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes.TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.
TCT CONNECT-385 Placebo-Controlled Efficacy of Percutaneous Coronary Intervention for Focal and Diffuse Patterns of Stable Coronary Artery Disease: A Secondary Analysis From ORBITA
Authors: Christopher Rajkumar, Matthew Shun-Shin, Henry Seligman, Yousif Ahmad, Takayuki Warisawa, Christopher Cook, James Howard, Laura Amarin, Alexandra Nowbar, Michael Foley, Ravi Assomull, Niall Keenan, Joban Sehmi, Thomas Keeble, John Davies, Kare Tang, Robert Gerber, Graham Cole, Peter O'Kane, Andrew Sharp, Ramzi Khamis, Gajen Kanaganayagam, Ricardo Petraco, Neil Ruparelia, Iqbal Malik, Sukhjinder Nijjer, Sayan Sen, Darrel Francis, Rasha Al-Lamee
Journal: Journal of the American College of Cardiology (2020)
Widespread Recombination Suppression Facilitates Plant Sex Chromosome Evolution
Authors: Joanna L Rifkin, Felix E G Beaudry, Zoë Humphries, Baharul I Choudhury, Spencer C H Barrett, Stephen I Wright
Journal: Molecular Biology and Evolution (2020)

Classical models suggest that recombination rates on sex chromosomes evolve in a stepwise manner to localize sexually antagonistic variants in the sex in which they are beneficial, thereby lowering rates of recombination between X and Y chromosomes. However, it is also possible that sex chromosome formation occurs in regions with preexisting recombination suppression. To evaluate these possibilities, we constructed linkage maps and a chromosome-scale genome assembly for the dioecious plant Rumex hastatulus. This species has a polymorphic karyotype with a young neo-sex chromosome, resulting from a Robertsonian fusion between the X chromosome and an autosome, in part of its geographic range. We identified the shared and neo-sex chromosomes using comparative genetic maps of the two cytotypes. We found that sex-linked regions of both the ancestral and the neo-sex chromosomes are embedded in large regions of low recombination. Furthermore, our comparison of the recombination landscape of the neo-sex chromosome to its autosomal homolog indicates that low recombination rates mainly preceded sex linkage. These patterns are not unique to the sex chromosomes; all chromosomes were characterized by massive regions of suppressed recombination spanning most of each chromosome. This represents an extreme case of the periphery-biased recombination seen in other systems with large chromosomes. Across all chromosomes, gene and repetitive sequence density correlated with recombination rate, with patterns of variation differing by repetitive element type. Our findings suggest that ancestrally low rates of recombination may facilitate the formation and subsequent evolution of heteromorphic sex chromosomes.
In Situ Vaccination Improves Efficacy of PD-1 Blockade in Unresponsive Lymphoma Tumors through Induction of a Highly Efficient Cross-Presenting Dendritic Cell Subset Expressing TLR3
Authors: Linda Hammerich, Maxime Dhainaut, Tibor Keler, Thomas Davis, Andres M Salazar, Brian D Brown, Joshua Brody
Journal: Blood (2017)
Radiographically Progressive Metastatic Pulmonary Calcification in a Three-Time Liver Transplant Recipient Requiring Intraoperative Resuscitation
Authors: Antonios Charokopos, Sakshi Dua, Mary B. Beasley, Michael S. Chung, Adam Bernheim, Maria Padilla, Aditi Mathur
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

"Radiographically Progressive Metastatic Pulmonary Calcification in a Three-Time Liver Transplant Recipient Requiring Intraoperative Resuscitation." American Journal of Respiratory and Critical Care Medicine, 203(4), pp. 502–503
Variants of Focal Adhesion Scaffold Genes Cause Thoracic Aortic Aneurysm
Authors: Yang Li, Shijuan Gao, Yingchun Han, Li Song, Yu Kong, Yao Jiao, Shan Huang, Jie Du, Yulin Li
Journal: Circulation Research (2020)

Rationale: Thoracic aortic aneurysm (TAA) leads to substantial mortality worldwide. Familial and syndromic TAAs are highly correlated with genetics. However, the incidence of sporadic isolated TAA (iTAA) is much higher, and the genetic contribution is not yet clear. Objective: Here, we examined the genetic characteristics of sporadic iTAA. Methods and Results: We performed a genetic screen of 551 sporadic iTAA cases and 1071 controls via whole-exome sequencing. The prevalence of pathogenic mutations in known causal genes was 5.08% in the iTAA cohort. We selected 100 novel candidate genes using a strict strategy, and the suspected functional variants of these genes were significantly enriched in cases compared with controls and carried by 60.43% of patients. We found more severe phenotypes and a lower proportion of hypertension in cases with pathogenic mutations or suspected functional variants. Among the candidate genes, Testin ( TES ), which encodes a focal adhesion scaffold protein, was identified as a potential TAA causal gene, accounting for 4 patients with 2 missense variants in the LIM1 domain (c.751T&gt;C encoding p.Y251H; c.838T&gt;C encoding p.Y280H) and highly expressed in the aorta. The 2 variants led to a decrease in TES expression. The thoracic aorta was spontaneously dilated in the Tes Y249H knock-in and Tes −/− mice. Mechanistically, the p.Y249H variant or knockdown of TES led to the repression of vascular smooth muscle cell contraction genes and disturbed the vascular smooth muscle cell contractile phenotype. Interestingly, suspected functional variants of other focal adhesion scaffold genes, including TLN1 (Talin-1) and ZYX (zyxin), were also significantly enriched in patients with iTAA; moreover, their knockdown resulted in decreased contractility of vascular smooth muscle cells. Conclusions: For the first time, this study revealed the genetic landscape across iTAA and showed that the focal adhesion scaffold genes are critical in the pathogenesis of iTAA.
TCT CONNECT-401 Stent Underexpansion Is Associated With High Wall Shear Stress: A Biomechanical Analysis of the Shear Stent Study
Authors: Sonali Kumar, David Molony, Kaylyn Crawford, Ryan Dunn, Elizabeth Thompson, Parham Eshtehardi, Olivia Hung, Sameer Khawaja, Imran Shah, Jéssica Navas Simbana, Arnav Kumar, Yi-An Ko, Adrien Lefieux, Joo Myung Lee, Kalina Machado, Ashish Sharma, Sonu Gupta, Shao-Liang Chen, Hiromasa Otake, Takashi Akasaka, Eun-Seok Shin, Bon-Kwon Koo, Goran Stankovic, Chang-Wook Nam, Javier Escaned, Andrejs Erglis, Spencer King, Veneziani Alessandro, Don Giddens, Habib Samady
Journal: Journal of the American College of Cardiology (2020)
Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity
Authors: Jacob A. Turner, Emmanuel Stephen-Victor, Sen Wang, Magali Noval Rivas, Azza Abdel-Gadir, Hani Harb, Ye Cui, Manoussa Fanny, Louis-Marie Charbonnier, Jason Jun Hung Fong, Mehdi Benamar, Leighanne Wang, Oliver T. Burton, Kushagra Bansal, Lynn Bry, Chengsong Zhu, Quan-Zhen Li, Rachel L. Clement, Hans C. Oettgen, Elena Crestani, Rima Rachid, Peter T. Sage, Talal A. Chatila
Journal: Immunity (2020)
Best practices for authors of healthcare-related artificial intelligence manuscripts
Authors: Sujay Kakarmath, Andre Esteva, Rima Arnaout, Hugh Harvey, Santosh Kumar, Evan Muse, Feng Dong, Leia Wedlund, Joseph Kvedar
Journal: npj Digital Medicine (2020)

Since its inception in 2017, npj Digital Medicine has attracted a disproportionate number of manuscripts reporting on uses of artificial intelligence. This field has matured rapidly in the past several years. There was initial fascination with the algorithms themselves (machine learning, deep learning, convoluted neural networks) and the use of these algorithms to make predictions that often surpassed prevailing benchmarks. As the discipline has matured, individuals have called attention to aberrancies in the output of these algorithms. In particular, criticisms have been widely circulated that algorithmically developed models may have limited generalizability due to overfitting to the training data and may systematically perpetuate various forms of biases inherent in the training data, including race, gender, age, and health state or fitness level (Challen et al. BMJ Qual. Saf. 28:231-237, 2019; O'neil. Weapons of Math Destruction: How Big Data Increases Inequality and Threatens Democracy, Broadway Book, 2016). Given our interest in publishing the highest quality papers and the growing volume of submissions using AI algorithms, we offer a list of criteria that authors should consider before submitting papers to npj Digital Medicine.
TCT CONNECT-460 Periprocedural Pericardial Effusion With Tamponade in Patients Undergoing Transcatheter Aortic Valve Replacement: A Single-Center Experience
Authors: Ayush Arora, Yelin Zhao, Jeffrey Hollander, Gisela Salgado, Viacheslav Bobovnikov, Anthony Estrera, Enrique Garcia-Sayan, Prakash Balan
Journal: Journal of the American College of Cardiology (2020)
Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3
Authors: Sarah Nicol Lauder, Kathryn Smart, Veerle Kersemans, Danny Allen, Jake Scott, Ana Pires, Stefan Milutinovic, Michelle Somerville, Sean Smart, Paul Kinchesh, Elena Lopez-Guadamillas, Ellyn Hughes, Emma Jones, Martin Scurr, Andrew Godkin, Lori S Friedman, Bart Vanhaesebroeck, Awen Gallimore
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors. Methods Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later. Results As observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8 + T cells, T cell factor 1 (TCF1) + T cells and CD69 − T cells, compatible with induction of a sustained tumor-specific T cell response. Treg numbers were significantly reduced in both regressor and non-regressor tumors compared with untreated tumors. The remaining Treg in non-regressor tumors were however significantly enriched with cells expressing the coinhibitory receptor LAG3, compared with Treg in regressor and untreated tumors. This striking difference prompted us to sequentially block PI3Kδ and LAG3. This combination enabled successful therapy of all mice, demonstrating the functional importance of LAG3 in non-regression of tumors on PI3Kδ inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3Kδ inhibition is an essential prerequisite to a sequential therapeutic benefit of anti-LAG3 antibodies. Conclusions These data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies.