tbuckley/cabot-search huggingface dataset:
Abstract IA21: Translating immunotherapy from melanoma to other skin cancers
Authors: Suzanne L. Topalian
Journal: Cancer Research (2020)

Abstract The PD-1 pathway, including the immune cell receptor Programmed Cell Death 1 (PD-1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), mediates immunosuppression within the tumor microenvironment. Drugs designed to “release the brakes” on antitumor immunity by blocking PD-1 have demonstrated substantial and durable activity in patients with advanced unresectable melanoma, as well as those with resected melanomas having a high risk for postsurgical relapse. These findings supported FDA approvals for anti-PD-1 drugs in the adjuvant and advanced melanoma settings. Research in melanoma subtypes and other kinds of cancers has identified two tumor markers associated with the likelihood of anti-PD-1 response: PD-L1 protein expression and tumor mutational burden (TMB), reflecting neoantigen load. Cutaneous melanomas are often caused by UV irradiation, harbor high TMBs, and frequently express PD-L1. Other types of skin cancers caused by UV irradiation, such as squamous cell and basal cell carcinomas, harbor high TMBs, express PD-L1, and have shown sensitivity to anti-PD-1. Merkel cell carcinoma has a unique biology, since only ~20% of cases are caused by UV light (high TMB), while the remaining 80% are associated with the oncogenic Merkel cell polyomavirus (very low TMB). Interestingly, both varieties are highly responsive to PD-1 pathway blockade, indicating that a limited number of strong tumor antigens (viral antigens) can compensate for low TMB to elicit antitumor immunity and tumor rejection. Anti-PD-1 has shown promising activity in neoadjuvant (presurgical) trials in melanoma and Merkel cell carcinoma. Neoadjuvant trials afford the opportunity for in-depth tissue analysis, and a variety of tumor markers are under investigation for correlation with treatment outcomes. The continued interrogation of tumor markers potentially predictive of clinical outcomes is expected to further refine the risk:benefit profile for PD-1/PD-L1 antagonists in melanoma and other skin cancers. Future clinical investigations will focus on difficult-to-treat populations such as immunosuppressed patients, including solid organ transplant recipients and those with HIV infection, who are at increased risk to develop aggressive skin cancers. Supported by National Institutes of Health R01 CA142779, Bristol-Myers Squibb, Melanoma Research Alliance, Barney Foundation, Laverna Hahn Charitable Trust, and Moving for Melanoma of Delaware. Citation Format: Suzanne L. Topalian. Translating immunotherapy from melanoma to other skin cancers [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA21.
DETECTION OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODY IN PRIMARY SCLEROSING CHOLANGITIS - COMPARISON OF THE ALKALINE-PHOSPHATASE AND IMMUNOFLUORESCENT TECHNIQUES
Authors: D Bansi, K Boberg, U Broome, R Chapman, K Fleming, R Jorgensen, K Lindor, E Schrumpf
Journal: Hepatology (1995)
Epigenetic Control of <i>Cdkn2a.Arf</i> Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion
Authors: Brian Koss, Bradley D. Shields, Erin M. Taylor, Aaron J. Storey, Stephanie D. Byrum, Allen J. Gies, Charity L. Washam, Samrat Roy Choudhury, Jeong Hyun Ahn, Hidetaka Uryu, Jason B. Williams, Kimberly J. Krager, Tung-Chin Chiang, Samuel G. Mackintosh, Rick D. Edmondson, Nukhet Aykin-Burns, Thomas F. Gajewski, Gang Greg Wang, Alan J. Tackett
Journal: Cancer Research (2020)

T-cell exhaustion in cancer is linked to poor clinical outcomes, where evidence suggests T-cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Environmental stress produces epigenome remodeling events within TIL resulting from loss of the histone methyltransferase EZH2. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TIL. A multiomics approach revealed a Cdkn2a.Arf-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth
Small intestinal metabolism is central to whole-body insulin resistance
Authors: Giulia Angelini, Serenella Salinari, Lidia Castagneto-Gissey, Alessandro Bertuzzi, James Casella-Mariolo, Sofie Ahlin, Ivo Boskoski, Melania Gaggini, Marco Raffaelli, Guido Costamagna, Giovanni Casella, Pier Luigi Marini, Amalia Gastaldelli, Stefan Bornstein, Geltrude Mingrone
Journal: Gut (2020)

To assess the role of jejunum in insulin resistance in humans and in experimental animals.Twenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model.We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop.In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling.Whole-body insulin sensitivity (SI∙104: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (Rd) area under the curve (AUC)/insulin AUC∙10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017).Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity.A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans.Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans.Proximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity.NCT03111953.
Keeping exhausted T-cells in check in COVID-19
Authors: P. Van Mol, A. Franken, C. Dooms, J. Yserbyt, D. Testelmans, P. Meersseman, G. Hermans, J. Wauters, J. Gunst, K. Nackaerts, J. Vansteenkiste, A. Garg, D. Lambrechts, E. Wauters
Journal: Annals of Oncology (2020)
The Pandemic of Health Care Inequity
Authors: L. Renata Thronson, Sara L. Jackson, Lisa D. Chew
Journal: JAMA Network Open (2020)

G. Caleb Alexander, MD, MS; Matthew Tajanlangit; James Heyward, MPH; Omar Mansour, MHS; Dima M. Qato, PharmD, MPH, PhD; Randall S. Stafford, MD, PhD
Neuronal defects in a human cellular model of 22q11.2 deletion syndrome
Authors: Themasap A. Khan, Omer Revah, Aaron Gordon, Se-Jin Yoon, Anna K. Krawisz, Carleton Goold, Yishan Sun, Chul Hoon Kim, Yuan Tian, Min-Yin Li, Julia M. Schaepe, Kazuya Ikeda, Neal D. Amin, Noriaki Sakai, Masayuki Yazawa, Leila Kushan, Seiji Nishino, Matthew H. Porteus, Judith L. Rapoport, Jonathan A. Bernstein, Ruth O’Hara, Carrie E. Bearden, Joachim F. Hallmayer, John R. Huguenard, Daniel H. Geschwind, Ricardo E. Dolmetsch, Sergiu P. Paşca
Journal: Nature Medicine (2020)
Partners’ access to scans and birth is a postcode lottery, data show
Authors: Gareth Iacobucci
Journal: BMJ (2020)

Trusts must be more responsive to the needs of pregnant women and their partners, researchers have said, after finding that they have been slow to lift bans imposed on attending scans and births, creating a postcode lottery on access. Most trusts in England banned partners attending antenatal scans during the first peak of covid-19 in March and most still had restrictions in place in August, show findings from freedom of information (FOI) requests from public health academics at the University of Cambridge (box 1). But the extent of these restrictions varied significantly. Box 1 ### Restrictions on access to maternity servicesRETURN TO TEXT
A novel approach to 2D/3D registration of X-ray images using Grangeat’s relation
Authors: Robert Frysch, Tim Pfeiffer, Georg Rose
Journal: Medical Image Analysis (2020)

Fast and accurate 2D/3D registration plays an important role in many applications, ranging from scientific and engineering domains all the way to medical care. Today’s predominant methods are based on computationally expensive approaches, such as virtual forward or back projections, that limit the real-time applicability of the routines. Here, we present a novel concept that makes use of Grangeat’s relation to intertwine information from the 3D volume and the 2D projection space in a way that allows pre-computation of all time-intensive steps. The main effort within actual registration tasks is reduced to simple resampling of the pre-calculated values, which can be executed rapidly on modern GPU hardware. We analyze the applicability of the proposed method on simulated data under various conditions and evaluate the findings on real data from a C-arm CT scanner. Our results show high registration quality in both simulated as well as real data scenarios and demonstrate a reduction in computation time for the crucial computation step by a factor of six to eight when compared to state-of-the-art routines. With minor trade-offs in accuracy, this speed-up can even be increased up to a factor of 100 in particular settings. To our knowledge, this is the first application of Grangeat’s relation to the topic of 2D/3D registration. Due to its high computational efficiency and broad range of potential applications, we believe it constitutes a highly relevant approach for various problems dealing with cone beam transmission images.
Food impaction mimicking dislodgment of a lumen-apposing metal stent in a patient undergoing endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis
Authors: Fabio De Vincentis, Omero Triossi, Mario Brancaccio
Journal: Endoscopy (2020)

A 77-year-old woman who was unsuitable for surgery underwent endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) using a lumen-apposing metal stent (LAMS) for acute cholecystitis. Her clinical history included lung adenocarcinoma and a recent development of pulmonary embolism. Chronic medication included immunotherapy and low molecular weight heparin. She was admitted again with a complaint of pain in the right hypochondrium and hyperpyrexia about 2 weeks after the procedure.
Campylobacteriosis following immunosuppression for immune checkpoint inhibitor-related toxicity
Authors: Karla A Lee, Heather Shaw, Véronique Bataille, Paul Nathan
Journal: Journal for ImmunoTherapy of Cancer (2020)

Five patients receiving checkpoint inhibitor immunotherapy (CPI) under our care across two cancer centers over a 12-month period have subsequently developed campylobacterosis. All had received immune-suppressive treatment for CPI-related colitis in the weeks or months preceding the detection of Campylobacter infection, with negative stool cultures at presentation of CPI-related colitis. The immune-suppression required to treat CPI-related toxicity may lead to an increased risk of enteric infection within the gut. While the underlying immune and biologic mechanisms are not well understood, perturbation of the gut microbiota is an increasingly recognized factor capable of influencing CPI-mediated immune reconstitution and response to therapy. Clinicians should be aware that worsening of colitic symptoms in patients with a history of treatment for CPI-related colitis may be due to enteric infection, and not simply a relapse/deterioration of a previously treated CPI-related colitis. Judicious infectious disease evaluation is necessary for patients receiving CPIs as symptoms can mimic immune-related adverse events (irAEs). Furthermore, the benefits of immune-suppressive therapy for the treatment of presumptive irAEs must be weighed against the possible increased risk for either enteric infection or opportunistic infection. Prospective studies are required to investigate microbiome perturbations, resulting from immune-suppression, and guide future treatment of this patient cohort.
Key Evidence Supporting Prescription Opioids Approved by the U.S. Food and Drug Administration, 1997 to 2018
Authors: James Heyward, Thomas J. Moore, Jennifer Chen, Kristin Meek, Peter Lurie, G. Caleb Alexander
Journal: Annals of Internal Medicine (2020)

Background: Little is known about the evidence required by the U.S. Food and Drug Administration (FDA) for new approvals of opioid analgesics. Objective: To characterize the quality of safety and efficacy data in new drug applications (NDAs) for opioid analgesics approved by the FDA between 1997 and 2018. Design: Cross-sectional analysis. Setting: Data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications. Participants: Patients with pain who participated in phase 3 pivotal trials. Intervention: FDA-approved opioid analgesics. Measurements: Key characteristics of each NDA, including the number, size, and duration of pivotal trials; trial control groups; the use of enriched trial populations; and systematically measured safety outcomes. Results: Most of the 48 NDAs evaluated were for new dosage forms (n = 25 [52.1%]) or new formulations (n = 9 [18.8%]); only 1 (2.1%) was for a new molecular entity. Of 39 NDAs approved for treating chronic pain, only 21 products were supported by at least 1 pivotal trial; these trials (n = 28) had a median duration of 84 days (interquartile range [IQR], 25 to 84 days) and enrolled a median of 299 patients (IQR, 174 to 525 patients). Seventeen (81%) of these products were approved on the basis of designs that excluded patients who could not tolerate the drugs, had early adverse effects, or reported few immediate benefits. Among NDAs for chronic pain, 8 (20.5%) included pooled safety reviews that reported systematic assessment of diversion, 7 (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed development of tolerance. Eight of 9 products for acute pain were supported by at least 1 pivotal trial; the pivotal trials (n = 19) had a median duration of 1 day (IQR, 1 to 2 days) and enrolled a median of 329 patients (IQR, 199 to 456 patients). Although all but 1 of the 48 approved NDAs were for previously approved moieties, analysis of available NDAs for referent products yielded similar findings. Limitations: The analysis was limited to approved opioids. Animal studies and nonpivotal trials were excluded. Evidence for safety in NDAs was presented for chronic pain only. Conclusion: Between 1997 and 2018, the FDA approved opioids on the basis of pivotal trials of short or intermediate duration, often in narrowly defined pain populations of patients who could tolerate the drug. Systematic collation of certain important safety outcomes was rare. Primary Funding Source: None.
Ralph C Williams Jr and the world of rheumatology: a tribute from Sweden
Authors: Frank A Wollheim, Göran Kronvall
Journal: Annals of the Rheumatic Diseases (2020)

Ralph C Williams Jr (Ralph) passed away peacefully on 2 February 2020 in Santa Fe in his 92nd year. In 1963, Ralph was appointed assistant professor in the Department of Medicine at the University of Minnesota and created its first academic rheumatology unit. From the start, he would always have one foreign assistant in his unit for 1 or 2 years. Several of them were Scandinavians. These included Gunnar Husby and Ove Mellbye from Norway and Allan Wiik from Denmark. We were fortunate to spend 2 years each in his unit in 1963–1965 (FAW) and 1968–1969 (GK). This changed our lives and we are grateful to be allowed to communicate some memories and highlights of his contributions to international rheumatology in this journal.

As a schoolboy, Ralph enjoyed drawing and singing in the school’s choir. In high school, he was inclined to become an artist. Ralph’s father was Dr Ralph C Williams, a high-ranking army officer and Assistant Surgeon General (figure 1). He was opposed to the idea that his only child should become an artist. When the art teacher convinced the parents of the boy’s talent, their resistance ended, but by then Ralph had changed his mind in favour of becoming a doctor. Ralph entered Cornell University in Ithaca in 1946 and graduated with honours in 1950 after having been elected to Phi Beta Kappa during his junior year. He entered Cornell University Medical School in 1950 and finished as first in class in 1954. During his years in the college, he was a tenor in its choir. At one concert he was the soloist. In the audience was another student named Mary Elizabeth Adams. She did not know the soloist, but fell in love with his voice. Feelings became mutual and in 1951 they were married and Mary gave up …
Reply to: Correspondence on “Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis”
Authors: Marta Magaz, Alberto Alvarez-Larrán, Dolors Colomer, Mónica López, Fanny Turon, Francisco Cervantes, None Virginia-Hernández-Gea, Juan Carlos García-Pagán
Journal: Journal of Hepatology (2020)
Idelalisib-Rituximab Results in Considerable Toxicity but Induces Durable Clinical Remissions in Patients with TP53 Disrupted B Cell Prolymphocytic Leukemia
Authors: Toby A. Eyre, Christopher P. Fox, Ali Boden, Adrian Bloor, Moez Dungawalla, Paneesha Shankara, Richard Went, Anna Schuh
Journal: Blood (2017)
Association of Use of an Integrated Specialty Pharmacy With Total Medical Expenditures Among Members of an Accountable Care Organization
Authors: Apurv Soni, Brian S. Smith, Thomas Scornavacca, Bill McElnea, Alice Shakman, Eric Dickson, David D. McManus
Journal: JAMA Network Open (2020)

This cohort study examines the association of integrated specialty pharmacy use among members of a university hospital accountable care organization (ACO) with total medical expenditure.
The Major Histocompatibility Complex — Genetics and Biology
Authors: Fritz H. Bach, Jon J. van Rood
Journal: New England Journal of Medicine (1976)

The biologic importance of the chromosomal region, called the major histocompatibility complex (MHC), determining the strong transplantation antigens, lies not only in its pre-eminent role in affecting allograft survival but in the control of a large array of biologic phenomena, including immune responsiveness, development and susceptibility to disease. In fact, one might well think of the MHC as a region important in the determination of cell-surface structures and thereby in cell interactions such as those involved in morphogenesis and the maintenance of individuality. Under the pressure of clinical necessity, most of the available information in man . . .
Recent Increase in COVID-19 Cases Reported Among Adults Aged 18–22 Years — United States, May 31–September 5, 2020
Authors: Phillip P. Salvatore, Erisa Sula, Jayme P. Coyle, None PhD, Elise Caruso, Amanda R. Smith, Rebecca S. Levine, PhD, Brittney N. Baack, Roger Mir, Edward R. Lockhart, Tejpratap S.P. Tiwari,, Deborah L. Dee, Tegan K. Boehmer, Brendan R. Jackson, Achuyt Bhattarai
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Although children and young adults are reportedly at lower risk for severe disease and death from infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), than are persons in other age groups (1), younger persons can experience infection and subsequently transmit infection to those at higher risk for severe illness (2-4). Although at lower risk for severe disease, some young adults experience serious illness, and asymptomatic or mild cases can result in sequelae such as myocardial inflammation (5). In the United States, approximately 45% of persons aged 18-22 years were enrolled in colleges and universities in 2019 (6). As these institutions reopen, opportunities for infection increase; therefore, mitigation efforts and monitoring reports of COVID-19 cases among young adults are important. During August 2-September 5, weekly incidence of COVID-19 among persons aged 18-22 years rose by 55.1% nationally; across U.S. Census regions,* increases were greatest in the Northeast, where incidence increased 144.0%, and Midwest, where incidence increased 123.4%. During the same period, changes in testing volume for SARS-CoV-2 in this age group ranged from a 6.2% decline in the West to a 170.6% increase in the Northeast. In addition, the proportion of cases in this age group among non-Hispanic White (White) persons increased from 33.8% to 77.3% during May 31-September 5. Mitigation and preventive measures targeted to young adults can likely reduce SARS-CoV-2 transmission among their contacts and communities. As colleges and universities resume operations, taking steps to prevent the spread of COVID-19 among young adults is critical (7).
Can N-3 polyunsaturated fatty acids be considered a potential adjuvant therapy for COVID-19-associated cardiovascular complications?
Authors: Ahmed M. Darwesh, Wesam Bassiouni, Deanna K. Sosnowski, John M. Seubert
Journal: Pharmacology & Therapeutics (2020)

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has currently led to a global pandemic with millions of confirmed and increasing cases around the world. The novel SARS-CoV-2 not only affects the lungs causing severe acute respiratory dysfunction but also leads to significant dysfunction in multiple organs and physiological systems including the cardiovascular system. A plethora of studies have shown the viral infection triggers an exaggerated immune response, hypercoagulation and oxidative stress, which contribute significantly to poor cardiovascular outcomes observed in COVID-19 patients. To date, there are no approved vaccines or therapies for COVID-19. Accordingly, cardiovascular protective and supportive therapies are urgent and necessary to the overall prognosis of COVID-19 patients. Accumulating literature has demonstrated the beneficial effects of n-3 polyunsaturated fatty acids (n-3 PUFA) toward the cardiovascular system, which include ameliorating uncontrolled inflammatory reactions, reduced oxidative stress and mitigating coagulopathy. Moreover, it has been demonstrated the n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors to a group of potent bioactive lipid mediators, generated endogenously, which mediate many of the beneficial effects attributed to their parent compounds. Considering the favorable safety profile for n-3 PUFAs and their metabolites, it is reasonable to consider n-3 PUFAs as potential adjuvant therapies for the clinical management of COVID-19 patients. In this article, we provide an overview of the pathogenesis of cardiovascular complications secondary to COVID-19 and focus on the mechanisms that may contribute to the likely benefits of n-3 PUFAs and their metabolites.