tbuckley/cabot-search huggingface dataset:
Molecular profiling of allergen-specific antibody responses may enhance success of specific immunotherapy
Authors: Azahara Rodríguez-Domínguez, Margot Berings, Alexander Rohrbach, Huey-Jy Huang, Mirela Curin, Philippe Gevaert, Paolo M. Matricardi, Rudolf Valenta, Susanne Vrtala
Journal: Journal of Allergy and Clinical Immunology (2020)

House dust mites (HDMs) are among the most important allergen sources containing many different allergenic molecules. Analysis of patients from a double-blind, placebo-controlled allergen-specific immunotherapy (AIT) study indicated that patients may benefit from AIT to different extents depending on their molecular sensitization profiles.Our aim was to investigate in a real-life setting whether stratification of patients with HDM allergy according to molecular analysis may enhance AIT success.Serum and nasal secretion samples from patients with HDM allergy (n = 24) (at baseline, 7, 15, 33, and 52 weeks) who had received 1 year of treatment with a well-defined subcutaneous AIT form (Alutard SQ 510) were tested for IgE and IgG reactivity to 15 microarrayed HDM allergen molecules with ImmunoCAP Immuno-solid-phase Allergen Chip technology. IgG subclass levels to allergens and peptides were determined by ELISA, and IgG blocking was assessed by basophil activation. In vitro parameters were related to reduction of symptoms determined by combined symptom medication score and visual analog scale score.Alutard SQ 510 induced protective IgG mainly against Dermatophagoides pteronyssinus (Der p) 1 and Der p 2 and to a lesser extent to Der p 23, but not to the other important allergens such as Der p 5, Der p 7, and Der p 21, showing better clinical efficacy in patients sensitized only to Der p 1 and/or Der p 2 as compared with patients having additional IgE specificities.Stratification of patients with HDM allergy according to molecular sensitization profiles and molecular monitoring of AIT-induced IgG responses may enhance the success of AIT.
Association of Birth by Cesarean Delivery With Obesity and Type 2 Diabetes Among Adult Women
Authors: Jorge E. Chavarro, Nerea Martín-Calvo, Changzheng Yuan, Mariel Arvizu, Janet W. Rich-Edwards, Karin B. Michels, Qi Sun
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Cesarean delivery is associated with an increased risk of childhood obesity in offspring. However, whether this increased risk also includes obesity-associated conditions remains unclear. <h3>Objective</h3> To evaluate the association of birth by cesarean delivery with offspring's risks of obesity and type 2 diabetes in adulthood. <h3>Design, Setting, and Participants</h3> This prospective cohort study compared the incidence of obesity and type 2 diabetes between birth by cesarean delivery and vaginal delivery among 33 226 women participating in the Nurses' Health Study II who were born between 1946 and 1964, with follow-up through the end of the 2013-2015 follow-up cycle. Participants' mothers provided information on mode of delivery and pregnancy characteristics. Participants provided information every 2 years on weight and diagnosis of type 2 diabetes. Relative risks of obesity and type 2 diabetes were estimated using log-binomial and proportional hazards regression accounting for maternal body mass index and other confounding factors. Statistical analysis was performed from June 2017 to December 2019. <h3>Exposure</h3> Birth by cesarean delivery compared with birth by vaginal delivery. <h3>Main Outcomes and Measures</h3> Risk of obesity and incidence of type 2 diabetes. <h3>Results</h3> At baseline, the participants' mean (SD) age was 33.8 (4.6) years (range, 24.0-44.0 years). A total of 1089 of the 33 226 participants (3.3%) were born by cesarean delivery. After 1 913 978 person-years of follow-up, 12 156 (36.6%) women were obese and 2014 (6.1%) had received a diagnosis of type 2 diabetes. Women born by cesarean delivery were more likely to be classified as obese and to have received a diagnosis of type 2 diabetes during follow-up. The multivariable-adjusted relative risk of obesity among women born by cesarean vs vaginal delivery was 1.11 (95% CI, 1.03-1.19). The multivariable-adjusted hazard ratio for type 2 diabetes among women born by cesarean vs vaginal delivery was 1.46 (95% CI, 1.18-1.81); this association remained significant after additional adjustment for participant's own body mass index (relative risk, 1.34 [95% CI, 1.08-1.67]). These associations persisted when analyses were restricted to women at low risk of cesarean delivery based on maternal characteristics. <h3>Conclusions and Relevance</h3> This study suggests that women born by cesarean delivery may have a higher risk than women born by vaginal delivery of being obese and developing type 2 diabetes during adult life.
Racial differences in time to treatment for melanoma
Authors: Raghav Tripathi, Laura K. Archibald, Rishabh S. Mazmudar, Rosalynn R.Z. Conic, Luke D. Rothermel, Jeffrey F. Scott, Jeremy S. Bordeaux
Journal: Journal of the American Academy of Dermatology (2020)

Longer time from diagnosis to definitive surgery (TTDS) is associated with increased melanoma-specific mortality. Although black patients present with later-stage melanoma and have worse survival than non-Hispanic white patients, the association between race and TTDS is unknown.To investigate racial differences in time to melanoma treatment.Retrospective review of the National Cancer Database (2004-2015). Multivariable logistic regression was used to evaluate the association of race with TTDS, controlling for sociodemographic/disease characteristics.Of the 233,982 patients with melanoma identified, 1221 (0.52%) were black. Black patients had longer TTDS for stage I to III melanoma (P < .001) and time to immunotherapy (P = .01), but not for TTDS for stage IV melanoma or time to chemotherapy (P > .05 for both). When sociodemographic characteristics were controlled for, black patients had over twice the odds of having a TTDS between 41 and 60 days, over 3 times the odds of having a TTDS between 61 and 90 days, and over 5 times the odds of having a TTDS over 90 days. Racial differences in TTDS persisted within each insurance type. Patients with Medicaid had the longest TTDS (mean, 60.4 days), and those with private insurance had the shortest TTDS (mean, 44.6 days; P < .001 for both).Targeted approaches to improve TTDS for black patients are integral in reducing racial disparities in melanoma outcomes.
Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention, and Management
Authors: Ferdinando D’Amico, Daniel C. Baumgart, Silvio Danese, Laurent Peyrin-Biroulet
Journal: Clinical Gastroenterology and Hepatology (2020)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19) pandemic is a worldwide emergency. An increasing number of diarrhea cases is reported. Here we investigate the epidemiology, clinical presentation, molecular mechanisms, management, and prevention of SARS-CoV-2 associated diarrhea. We searched on PubMed, EMBASE, and Web of Science up to March 2020 to identify studies documenting diarrhea and mechanism of intestinal inflammation in patients with confirmed diagnosis of SARS-CoV-2 infection. Clinical studies show an incidence rate of diarrhea ranging from 2% to 50% of cases. It may precede or trail respiratory symptoms. A pooled analysis revealed an overall percentage of diarrhea onset of 10.4%. SARS-CoV uses the angiotensin-converting enzyme 2 (ACE2) and the serine protease TMPRSS2 for S protein priming. ACE2 and TMPRSS2 are not only expressed in lung, but also in the small intestinal epithelia. ACE2 is expressed furthermore in the upper esophagus, liver, and colon. SARS-CoV-2 binding affinity to ACE2 is significantly higher (10–20 times) compared with SARS-CoV. Several reports indicate viral RNA shedding in stool detectable longer time period than in nasopharyngeal swabs. Current treatment is supportive, but several options appear promising and are the subject of investigation. Diarrhea is a frequent presenting symptom in patients infected with SARS-CoV-2. Increasing evidence indicates possible fecal oral transmission, indicating the need for a rapid and effective modification of the screening and diagnostic algorithms. The optimal methods to prevent, manage, and treat diarrhea in COVID-19 infected patients are subjects of intensive research.
Actionable biomarkers: the key to resolving disorders of gastrointestinal function
Authors: Michael Camilleri, Victor Chedid
Journal: Gut (2020)

A valid biomarker is defined as ‘a characteristic that is measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention’.1 The advent and validation of biomarkers based on identification of organic mechanisms, pathogenesis or pathophysiology have the potential to introduce individualisation in management of disorders of lower gastrointestinal function. An actionable biomarker is a biomarker that is associated with a directed treatment to prevent or reverse symptoms or disease, and this has resulted in a paradigm shift in oncological treatment from a tumour type-focussed approach to a molecularly-directed agnostic one, exploring the role of biological agents targeted to the driver genomic alteration irrespective of the cancer histology.2 Such actionable biomarkers have been introduced in functional lower gastrointestinal disorders.3 Importantly, this approach also provides opportunity to provide patients with personalised approach to treatment.

This article highlights the diverse methods to identify the organic pathogenesis (figure 1) and to choose treatments based on approved treatments, off-label treatment with approved medications or, in the future, experimental medications. The a priori criteria for inclusion was based on the evidence of pathobiological relevance, extensive data on normal values, performance characteristics of the biomarker, availability of treatment directed to the biomarker, as well as evidence of efficacy of treatment directed at the specific biomarker. For example, the normal value data in adults for cited measurements are based on the following numbers: gastric emptying (319 (214 females, 105 males));4 colonic transit (220 (145 females, 75 males); 5 colonic compliance (n = 40);6 anorectal manometry with normal balloon expulsion (143 (96 females and 47 males));7 gastric accommodation (354 (230 females, 120 males));8 48 hours faecal bile acid excretion (96 (60 females and 36 males))9 and serum 7αC4 for bile acid diarrhoea (184 …
Selective delivery of T22-PE24-H6 to CXCR4<sup>+</sup> diffuse large B-cell lymphoma cells leads to wide therapeutic index in a disseminated mouse model
Authors: Aïda Falgàs, Victor Pallarès, Naroa Serna, Laura Sánchez-García, Jorge Sierra, Alberto Gallardo, Lorena Alba-Castellón, Patricia Álamo, Ugutz Unzueta, Antonio Villaverde, Esther Vázquez, Ramon Mangues, Isolda Casanova
Journal: Theranostics (2020)

Background: Novel therapeutic strategies are urgently needed to reduce relapse rates and enhance survival in Diffuse Large B-Cell Lymphoma (DLBCL) patients. CXCR4-overexpressing cancer cells are good targets for therapy because of their association with dissemination and relapse in R-CHOP treated DLBCL patients. Immunotoxins that incorporate bacterial toxins are potentially effective in treating haematological neoplasias, but show a narrow therapeutic index due to the induction of severe side effects. Therefore, when considering the delivery of these toxins as cancer therapeutics, there is a need not only to increase their uptake in the target cancer cells, and their stability in blood, but also to reduce their systemic toxicity. We have developed a therapeutic nanostructured protein T22-PE24-H6 that incorporates exotoxin A from Pseudomonas aeruginosa, which selectively targets lymphoma cells because of its specific interaction with a highly overexpressed CXCR4 receptor (CXCR4+) in DLBCL. Methods: T22-PE24-H6 cytotoxicity and its dependence on the CXCR4 receptor were evaluated in DLBCL cell lines using cell viability assays. Different in vitro experiments (mitochondrial membrane potential, Western Blot, Annexin V and DAPI staining) were conducted to determine T22-PE24-H6 cell death mechanisms. In vivo imaging and therapeutic effect studies were performed in a disseminated DLBCL mouse model that mimics organ infiltration in DLBCL patients. Finally, immunohistochemistry and histopathology analyses were used to evaluate the antineoplastic effect and systemic toxicity. Results: In vitro, T22-PE24-H6 induced selective cell death of CXCR4+ DLBCL cells by activating the apoptotic pathway. In addition, repeated T22-PE24-H6 intravenous administration in a CXCR4+ DLBCL-disseminated mouse model showed a significant reduction of lymphoma burden in organs clinically affected by DLBCL cells (lymph nodes and bone marrow). Finally, we did not observe systemic toxicity associated to the nanoparticle treatment in non-DLBCL-infiltrated organs. Conclusion: We have demonstrated here a potent T22-PE24-H6 antineoplastic effect, especially in blocking dissemination in a CXCR4+ DLBCL model without associated toxicity. Thereby, T22-PE24-H6 promises to become an effective alternative to treat CXCR4+ disseminated refractory or relapsed DLBCL patients.
Inotuzumab Ozogamicin (InO) Vs Standard of Care (SC) in Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL): Long-Term Results of the Phase 3 INO-VATE Study
Authors: Hagop M. Kantarjian, Daniel J. DeAngelo, Matthias Stelljes, Michaela Liedtke, Wendy Stock, Nicola Goekbuget, Susan M. O'Brien, Elias J. Jabbour, Tao Wang, Jane Liang White, Barbara Sleight, Erik Vandendries, Anjali S. Advani
Journal: Blood (2017)
Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis
Authors: Leiwen Fu, Bingyi Wang, Tanwei Yuan, Xiaoting Chen, Yunlong Ao, Thomas Fitzpatrick, Peiyang Li, Yiguo Zhou, Yi-fan Lin, Qibin Duan, Ganfeng Luo, Song Fan, Yong Lu, Anping Feng, Yuewei Zhan, Bowen Liang, Weiping Cai, Lin Zhang, Xiangjun Du, Linghua Li, Yuelong Shu, Huachun Zou
Journal: Journal of Infection (2020)

To better inform efforts to treat and control the current outbreak with a comprehensive characterization of COVID-19.
Immune Sensing of Synthetic, Bacterial, and Protozoan RNA by Toll-like Receptor 8 Requires Coordinated Processing by RNase T2 and RNase 2
Authors: Thomas Ostendorf, Thomas Zillinger, Katarzyna Andryka, Thais Marina Schlee-Guimaraes, Saskia Schmitz, Samira Marx, Kübra Bayrak, Rebecca Linke, Sarah Salgert, Julia Wegner, Tatjana Grasser, Sonja Bauersachs, Leon Soltesz, Marc P. Hübner, Maximilian Nastaly, Christoph Coch, Matthias Kettwig, Ingo Roehl, Marco Henneke, Achim Hoerauf, Winfried Barchet, Jutta Gärtner, Martin Schlee, Gunther Hartmann, Eva Bartok
Journal: Immunity (2020)
Assessment of the Contribution of the Work Relative Value Unit Scale to Differences in Physician Compensation Across Medical and Surgical Specialties
Authors: Christopher P. Childers, Melinda Maggard-Gibbons
Journal: JAMA Surgery (2020)

The work relative value units (wRVUs) for a physician service can be conceptualized as the amount of time spent by the physician multiplied by a compensation rate (wRVUs/min). Disproportionately high compensation rates assigned to procedures have been blamed for pay differences across specialties, but to our knowledge, a comprehensive assessment is lacking.
SNP-Array Based Karyotyping Complements Routine Cytogenetics in Diagnosis and Risk Stratification Schemes of MDS
Authors: Ramon V. Tiu, Lukasz P Gondek, Jungwon Huh, Christine O’Keefe, Mikkael A. Sekeres, Ghulam J Mufti, Michael A McDevitt, Jaroslaw Maciejewski
Journal: Blood (2008)
The need for a system view to regulate artificial intelligence/machine learning-based software as medical device
Authors: Sara Gerke, Boris Babic, Theodoros Evgeniou, I. Glenn Cohen
Journal: npj Digital Medicine (2020)

Artificial intelligence (AI) and Machine learning (ML) systems in medicine are poised to significantly improve health care, for example, by offering earlier diagnoses of diseases or recommending optimally individualized treatment plans. However, the emergence of AI/ML in medicine also creates challenges, which regulators must pay attention to. Which medical AI/ML-based products should be reviewed by regulators? What evidence should be required to permit marketing for AI/ML-based software as a medical device (SaMD)? How can we ensure the safety and effectiveness of AI/ML-based SaMD that may change over time as they are applied to new data? The U.S. Food and Drug Administration (FDA), for example, has recently proposed a discussion paper to address some of these issues. But it misses an important point: we argue that regulators like the FDA need to widen their scope from evaluating medical AI/ML-based products to assessing systems. This shift in perspective-from a product view to a system view-is central to maximizing the safety and efficacy of AI/ML in health care, but it also poses significant challenges for agencies like the FDA who are used to regulating products, not systems. We offer several suggestions for regulators to make this challenging but important transition.
The Immune Checkpoint Receptors PD-1, PD-L1, TIM-3 and LAG-3 in Lymphoma: Tumor Cell and Tumor Infiltrating Lymphocyte (TIL) Expression, Patient Prognostication, and Identification of Rational Therapeutic Targets
Authors: Ravi Dashnamoorthy, Benjamin Chen, Pallavi Galera, Hong Chang, Afshin Beheshti, Srimoyee Ghosh, Andrew M Evens
Journal: Blood (2017)
Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation
Authors: Andrew S. Mendiola, Jae Kyu Ryu, Sophia Bardehle, Anke Meyer-Franke, Kenny Kean-Hooi Ang, Chris Wilson, Kim M. Baeten, Kristina Hanspers, Mario Merlini, Sean Thomas, Mark A. Petersen, Alexander Williams, Reuben Thomas, Victoria A. Rafalski, Rosa Meza-Acevedo, Reshmi Tognatta, Zhaoqi Yan, Samuel J. Pfaff, Michael R. Machado, Catherine Bedard, Pamela E. Rios Coronado, Xiqian Jiang, Jin Wang, Michael A. Pleiss, Ari J. Green, Scott S. Zamvil, Alexander R. Pico, Benoit G. Bruneau, Michelle R. Arkin, Katerina Akassoglou
Journal: Nature Immunology (2020)
Ki‐67 index, progesterone receptor expression, histologic grade and tumor size in predicting breast cancer recurrence risk: A consecutive cohort study
Authors: Yanna Zhang, Yidong Zhou, Feng Mao, Ru Yao, Qiang Sun
Journal: Cancer Communications (2020)

Abstract Background The 21‐gene recurrence score (RS) assay has been recommended by major guidelines for treatment decision in hormone receptor (HR)‐positive early breast cancer (EBC). However, the genomic assay is not accessible and affordable worldwide. Alternatively, an increasing number of studies have shown that traditional immunohistochemistry (IHC) can partially or even completely replace the role of the 21‐gene genomic assay. Here, we developed and validated a predictive model (IHC3 model) combining the Ki‐67 index, progesterone receptor (PR) expression, histologic grade, and tumor size to predict the recurrence risk of HR‐positive EBC. Methods The data from 389 patients (development set) with HR‐positive, human epidermal growth factor receptor 2‐negative, lymph node non‐metastasized invasive breast cancer were used to construct the IHC3 model based on the Surexam ® 21‐gene RS and the TAILORx clinical trial criteria. An additional 146 patients with the same characteristics constituted the validation set. The predictive accuracy of the IHC3 model was compared with that of Orucevic et al.’s nomogram. Invasive disease‐free survival (IDFS) was analyzed in the IHC3 predictive low‐recurrence risk (pLR) group and the predictive high‐recurrence risk (pHR) group. The Pearson chi‐square test, Fisher exact test, and log‐rank test were used for analysis. Results The pLR and pHR group could be easily stratified using the decision tree model without network dependence. The accuracies of the IHC3 model were 86.1% in the development set and 87.7% in the validation set. The predictive accuracy of the IHC3 model and Orucevic et al.’s nomogram for the whole cohort was 86.5% and 86.9%, respectively. After a 52‐month of median follow‐up, a significant difference was found in IDFS between of the IHC3 pLR and the pHR groups ( P = 0.001) but not in the IDFS between the low‐ and high‐recurrence risk groups according to the Surexam® 21‐gene RS and the TAILORx clinical trial criteria ( P = 0.556) or 21‐gene binary RS group ( P = 0.511). Conclusions The proposed IHC3 model could reliably predict low and high recurrence risks in most HR‐positive EBC patients. This easy‐to‐use predictive model may be a reliable replacement for the 21‐gene genomic assay in patients with EBC who have no access to or cannot afford the 21‐gene genomic assay.
An FDA Review of Drug Development in Nonmetastatic Castration-resistant Prostate Cancer
Authors: Michael Brave, Chana Weinstock, Jamie R. Brewer, Dow-Chung Chi, Daniel L. Suzman, Joyce Cheng, Lijun Zhang, Rajeshwari Sridhara, Amna Ibrahim, Paul G. Kluetz, Richard Pazdur, Julia A. Beaver
Journal: Clinical Cancer Research (2020)

Abstract The FDA has approved three androgen receptor inhibitors—enzalutamide, apalutamide, and darolutamide—for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.
Cognitive dissonance processes serve an action-oriented adaptive function
Authors: Eddie Harmon-Jones, Cindy Harmon-Jones
Journal: Behavioral and Brain Sciences (2020)

Abstract The action-based model of cognitive dissonance proposes an adaptive function for rationalization that differs from the one offered by Cushman. The one proposed by Cushman is concerned more with the cold construction of cognitions, whereas the one proposed by the action-based model is a motivated protection of a strongly held cognition.
Guidelines for Carotid Endarterectomy
Authors: José Biller, William M. Feinberg, John E. Castaldo, Anthony D. Whittemore, Robert E. Harbaugh, Robert J. Dempsey, Louis R. Caplan, Timothy F. Kresowik, David B. Matchar, James F. Toole, J. Donald Easton, Harold P. Adams, Lawrence M. Brass, Robert W. Hobson, Thomas G. Brott, Linda Sternau
Journal: Circulation (1998)

ince the 1950s carotid endarterectomy has been performed in patients with symptomatic carotid artery stenosis, based on suggestive but inconclusive evidence for its effectiveness.Only during the last 5 years have randomized studies clarified the indications for surgery.In preparing this report, panel members used the same rules of evidence used in the previous report 1,2 (Table ). Management of Risk FactorsFew studies have analyzed control of risk factors in a randomized, prospective manner following carotid endarterectomy.However, a wealth of data are available regarding the general relationship between risk factor control and stroke risk.These data provide some guidance for the care of endarterectomy patients.