tbuckley/cabot-search huggingface dataset:
Endoscopic ultrasound and fine-needle aspiration for the detection of residual nodal disease after neoadjuvant chemoradiotherapy for esophageal cancer
Authors: Ruben D. van der Bogt, Berend J. van der Wilk, Jan-Werner Poley, Kausilia K. Krishnadath, Erik J. Schoon, Liekele E. Oostenbrug, Peter D. Siersema, Frank P. Vleggaar, Marco J. Bruno, Katharina Biermann, J. Jan B. van Lanschot, Manon C. W. Spaander
Journal: Endoscopy (2019)

Endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) are potential tools for the detection of residual disease after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. This study investigated yield of EUS and FNA for detection of malignant lymph nodes (LNs) after nCRT.This was a post hoc analysis of the preSANO trial. EUS was performed 10 - 12 weeks after nCRT. 18F-fluorodeoxyglucose positron emission tomography - computed tomography (18F-FDG PET-CT) was used to guide targeting of suspicious LNs. Consecutive FNA sampling was performed for suspicious LNs identified on EUS and/or PET-CT. EUS nodal staging was compared with histopathological examination of the resection specimen. The primary outcome was the proportion of correctly identified patients with malignant LNs by radial EUS.101 consecutive patients were included: 79 patients had no malignant LNs, of whom 62 were classified correctly by EUS (specificity 78 %); 22 patients had malignant LNs, of whom 11 were identified (sensitivity 50 %). Six of these patients had ≥ 1 suspicious LN not fulfilling EUS criteria (round, hypoechogenic, > 5 mm). Malignant LNs in falsely negative patients were predominantly located at distal LN stations. Specificity and sensitivity of conclusive FNA outcomes were 100 % (7/7) and 75 % (3/4), respectively. FNA outcome was uncertain in eight patients, half of whom appeared to have malignant LNs.EUS only detected 50 % of patients with malignant LNs 10 - 12 weeks after nCRT. To optimize sensitivity and minimize the risk of missing residual disease, FNA of LNs should be performed even in cases of low endosonographic suspicion.
Use of whole genome sequencing of commensal Escherichia coli in pigs for antimicrobial resistance surveillance, United Kingdom, 2018
Authors: Emma Stubberfield, Manal AbuOun, Ellie Sayers, Heather M O’Connor, Roderick M Card, Muna F Anjum
Journal: Eurosurveillance (2019)

Background Surveillance of commensal Escherichia coli , a possible reservoir of antimicrobial resistance (AMR) genes, is important as they pose a risk to human and animal health. Most surveillance activities rely on phenotypic characterisation, but whole genome sequencing (WGS) presents an alternative. Aim In this retrospective study, we tested 515 E. coli isolated from pigs to evaluate the use of WGS to predict resistance phenotype. Methods Minimum inhibitory concentration (MIC) was determined for nine antimicrobials of clinical and veterinary importance. Deviation from wild-type, fully-susceptible MIC was assessed using European Committee on Antimicrobial Susceptibility Testing (EUCAST) epidemiological cut-off (ECOFF) values. Presence of AMR genes and mutations were determined using APHA SeqFinder. Statistical two-by-two table analysis and Cohen’s kappa (k) test were applied to assess genotype and phenotype concordance. Results Overall, correlation of WGS with susceptibility to the nine antimicrobials was 98.9% for test specificity, and 97.5% for the positive predictive value of a test. The overall kappa score (k = 0.914) indicated AMR gene presence was highly predictive of reduced susceptibility and showed excellent correlation with MIC. However, there was variation for each antimicrobial; five showed excellent correlation; four very good and one moderate. Suggested ECOFF adjustments increased concordance between genotypic data and kappa values for four antimicrobials. Conclusion WGS is a powerful tool for accurately predicting AMR that can be used for national surveillance purposes. Additionally, it can detect resistance genes from a wider panel of antimicrobials whose phenotypes are currently not monitored but may be of importance in the future.
Downregulation of miR-223 Expression Is an Early Event during Mammary Transformation and Confers Resistance to CDK4/6 Inhibitors in Luminal Breast Cancer
Authors: Francesca Citron, Ilenia Segatto, Gian Luca Rampioni Vinciguerra, Lorena Musco, Francesca Russo, Giorgia Mungo, Sara D'Andrea, Maria Chiara Mattevi, Tiziana Perin, Monica Schiappacassi, Samuele Massarut, Cristina Marchini, Augusto Amici, Andrea Vecchione, Gustavo Baldassarre, Barbara Belletti
Journal: Cancer Research (2019)

miR-223 is an anti-inflammatory miRNA that in cancer acts either as an oncosuppressor or oncopromoter, in a context-dependent manner. In breast cancer, we demonstrated that it dampens the activation of the EGF pathway. However, little is known on the role of miR-223 during breast cancer onset and progression. miR-223 expression was decreased in breast cancer of luminal and HER2 subtypes and inversely correlated with patients' prognosis. In normal luminal mammary epithelial cells, miR-223 acted cell autonomously in the control of their growth and morphology in three-dimensional context. In the MMTV-Δ16HER2 transgenic mouse model, oncogene transformation resulted in a timely abrogation of miR-223 expression, likely due to activation of E2F1, a known repressor of miR-223 transcription. Accordingly, treatment with CDK4/6 inhibitors, which eventually results in restraining E2F1 activity, restored miR-223 expression and miR-223 ablation induced luminal breast cancer resistance to CDK4/6 inhibition, both in vitro and in vivo. Notably, miR-223 expression was lost in microdissected ductal carcinoma in situ (DCIS) from patients with luminal and HER2-positive breast cancer. Altogether, these results identify downmodulation of miR-223 as an early step in luminal breast cancer onset and suggest that it could be used to identify aggressive DCIS and predict the response to targeted therapy. SIGNIFICANCE: miR-223 may represent a predictive biomarker of response to CDK4/6 inhibitors and its loss could identify DCIS lesions that are likely to progress into invasive breast cancer.
PD-1 Is Expressed at Low Levels on All Peripheral Blood Natural Killer Cells but Is a Significant Suppressor of NK Function Against PD-1 Ligand Expressing Tumor Targets
Authors: Zachary Davis, Martin Felices, Todd R Lenvik, Sujan Badal, Peter Hinderlie, Bruce R. Blazar, Daniel A. Vallera, Jeffrey S. Miller
Journal: Blood (2019)
Global Epidemiologic Characteristics of Sexually Transmitted Infections Among Individuals Using Preexposure Prophylaxis for the Prevention of HIV Infection
Authors: Jason J. Ong, Rachel C. Baggaley, Teodora E. Wi, Joseph D. Tucker, Hongyun Fu, M. Kumi Smith, Sabrina Rafael, Vanessa Anglade, Jane Falconer, Richard Ofori-Asenso, Fern Terris-Prestholt, Ioannis Hodges-Mameletzis, Philippe Mayaud
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Despite a global increase in sexually transmitted infections (STIs), there is limited focus and investment in STI management within HIV programs, in which risks for STIs are likely to be elevated. <h3>Objective</h3> To estimate the prevalence of STIs at initiation of HIV preexposure prophylaxis (PrEP; emtricitabine and tenofovir disoproxil fumarate) and the incidence of STIs during PrEP use. <h3>Data Sources</h3> Nine databases were searched up to November 20, 2018, without language restrictions. The implementers of PrEP were also approached for additional unpublished data. <h3>Study Selection</h3> Studies reporting STI prevalence and/or incidence among PrEP users were included. <h3>Data Extraction and Synthesis</h3> Data were extracted independently by at least 2 reviewers. The methodological quality of studies was assessed using the Joanna Briggs Institute critical assessment tool for prevalence and incidence studies. Random-effects meta-analysis was performed. <h3>Main Outcomes and Measures</h3> Pooled STI prevalence (ie, within 3 months of PrEP initiation) and STI incidence (ie, during PrEP use, after 3 months). <h3>Results</h3> Of the 3325 articles identified, 88 were included (71 published and 17 unpublished). Data came from 26 countries; 62 studies (70%) were from high-income countries, and 58 studies (66%) were from programs only for men who have sex with men. In studies reporting a composite outcome of chlamydia, gonorrhea, and early syphilis, the pooled prevalence was 23.9% (95% CI, 18.6%-29.6%) before starting PrEP. The prevalence of the STI pathogen by anatomical site showed that prevalence was highest in the anorectum (chlamydia, 8.5% [95% CI, 6.3%-11.0%]; gonorrhea, 9.3% [95% CI, 4.7%-15.2%]) compared with genital sites (chlamydia, 4.0% [95% CI, 2.0%-6.6%]; gonorrhea, 2.1% [95% CI, 0.9%-3.7%]) and oropharyngeal sites (chlamydia, 2.4% [95% CI, 0.9%-4.5%]; gonorrhea, 4.9% [95% CI, 1.9%-9.1%]). The pooled incidence of studies reporting the composite outcome of chlamydia, gonorrhea, and early syphilis was 72.2 per 100 person-years (95% CI, 60.5-86.2 per 100 person-years). <h3>Conclusions and Relevance</h3> Given the high burden of STIs among individuals initiating PrEP as well as persistent users of PrEP, this study highlights the need for active integration of HIV and STI services for an at-risk and underserved population.
Convergent Evolution of Cysteine-Rich Keratins in Hard Skin Appendages of Terrestrial Vertebrates
Authors: Florian Ehrlich, Julia Lachner, Marcela Hermann, Erwin Tschachler, Leopold Eckhart
Journal: Molecular Biology and Evolution (2019)

Terrestrial vertebrates have evolved hard skin appendages, such as scales, claws, feathers, and hair that play crucial roles in defense, predation, locomotion, and thermal insulation. The mechanical properties of these skin appendages are largely determined by cornified epithelial components. So-called "hair keratins," cysteine-rich intermediate filament proteins that undergo covalent cross-linking via disulfide bonds, are the crucial structural proteins of hair and claws in mammals and hair keratin orthologs are also present in lizard claws, indicating an evolutionary origin in a hairless common ancestor of amniotes. Here, we show that reptiles and birds have also other cysteine-rich keratins which lack cysteine-rich orthologs in mammals. In addition to hard acidic (type I) sauropsid-specific (HAS) keratins, we identified hard basic (type II) sauropsid-specific (HBS) keratins which are conserved in lepidosaurs, turtles, crocodilians, and birds. Immunohistochemical analysis with a newly made antibody revealed expression of chicken HBS1 keratin in the cornifying epithelial cells of feathers. Molecular phylogenetics suggested that the high cysteine contents of HAS and HBS keratins evolved independently from the cysteine-rich sequences of hair keratin orthologs, thus representing products of convergent evolution. In conclusion, we propose an evolutionary model in which HAS and HBS keratins evolved as structural proteins in epithelial cornification of reptiles and at least one HBS keratin was co-opted as a component of feathers after the evolutionary divergence of birds from reptiles. Thus, cytoskeletal proteins of hair and feathers are products of convergent evolution and evolutionary co-option to similar biomechanical functions in clade-specific hard skin appendages.
Modulating Macrophage Phenotype by Sustained MicroRNA Delivery Improves Host‐Implant Integration
Authors: Junquan Lin, Ibrahim Mohamed, Po Hen Lin, Hitomi Shirahama, Ulla Milbreta, Je Lin Sieow, Yanfen Peng, Marianna Bugiani, Siew Cheng Wong, Howard Levinson, Sing Yian Chew
Journal: Advanced Healthcare Materials (2019)

Abstract Biomedical implant failure due to the host's response remains a challenging problem. In particular, the formation of the fibrous capsule is a common barrier for the normal function of implants. Currently, there is mounting evidence indicating that the polarization state of macrophages plays an important role in effecting the foreign body reaction (FBR). This opens up a potential avenue for improving host‐implant integration. Here, electrospun poly(caprolactone‐ co ‐ethyl ethylene phosphate) nanofiber scaffolds are utilized to deliver microRNAs (miRs) to induce macrophage polarization and modulate FBR. Specifically, C57BL/6 mice that are treated with M2‐inducing miRs, Let‐7c and miR‐124, display relatively thinner fibrous capsule formation around the scaffolds at both Week 2 and 4, as compared to treatment with M1‐inducing miR, Anti‐Let‐7c. Histological analysis shows that the density of blood vessels in the scaffolds are the highest in miR‐124 treatment group, followed by Anti‐Let‐7c and Let‐7c treatment groups. Based on immunohistochemical quantifications, these miR‐encapsulated nanofiber scaffolds are useful for localized and sustained delivery of functional miRs and are able to modulate macrophage polarization during the first 2 weeks of implantation to result in significant alteration in host‐implant integration at longer time points.
ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation
Authors: Zechuan Zhang, Xiaoliang Xu, Wenfang Tian, Runqiu Jiang, Yijun Lu, Qikai Sun, Rao Fu, Qifeng He, Jincheng Wang, Yang Liu, Hailong Yu, Beicheng Sun
Journal: Journal of Hepatology (2019)
Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Authors: Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, Maureen R. Hanson
Journal: Journal of Clinical Investigation (2019)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and postexertional malaise. There is little known about the metabolism of specific immune cells in patients with ME/CFS. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 patients with ME/CFS and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism and plasma cytokines. We found that ME/CFS CD8+ T cells had reduced mitochondrial membrane potential compared with those from healthy controls. Both CD4+ and CD8+ T cells from patients with ME/CFS had reduced glycolysis at rest, whereas CD8+ T cells also had reduced glycolysis following activation. Patients with ME/CFS had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from correlations seen in healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.
Safety and Antitumor Activity of Sitravatinib in Combination with Tislelizumab in Patients With Advanced Solid Tumors: Ovarian Cancer Cohort Data
Authors: B. Gao, J. Goh, B. Markman, M. Voskoboynik, H.K. Gan, J. Coward, D. Palmieri, J. So, T. Meniawy, C. Chen, X. Xiang, J. Qiu, Y. Xu, L. Yang, M. Millward
Journal: Annals of Oncology (2019)
Abstract A03: All the roads bring to Rome: How acetyl-CoA metabolism supports multistep pancreatic carcinogenesis
Authors: Alessandro Carrer, Sophie Trefely, Steven Zhao, Sydney Campbell, Yogev Sela, Simone Sidoli, Benjamin A. Garcia, Nathaniel W. Snyder, Ben Z. Stanger, Kathryn E. Wellen
Journal: Cancer Research (2019)

Abstract Mutant KRAS is thought to initiate pancreatic tumorigenesis, orchestrating a program that leads to cell de-differentiation, proliferation, and symbiotic cooperation with neighboring cells, enabling the cancer cells to thrive in a particularly harsh microenvironment. Recent studies have highlighted the role of metabolites in regulating the epigenome. Although oncogenic KRAS is known to reprogram cellular metabolism, the role of metabolic control of the epigenome in pancreatic tumorigenesis is poorly understood. We showed that expression of KRASG12D in mouse pancreas promotes elevated histone acetylation levels in pancreatic acinar cells, and that this precedes tumor development. We hypothesized that augmented acetyl-CoA metabolism may play a role in facilitating pancreatic tumorigenesis. To test this, we generated mice deficient for Acly (acetyl-CoA producing enzyme) in pancreas (Pdx1-Cre; Aclyf/f mice). In the context of KRASG12D expression, ACLY deficiency reduces histone acetylation levels in pancreatic acinar cells and impairs formation of neoplastic lesions. ACLY deficiency also impairs pancreatitis-induced tumor development. In testing roles for acetyl-CoA-dependent processes in ADM, we found that targeting either histone acetylation by BET inhibition or cholesterol synthesis with statins suppressed tumor onset. In vivo, response to BET and cholesterol synthesis blockade is associated with recruitment of CD8+ T-cells. The findings indicate that ACLY-dependent metabolic and epigenetic remodeling promote tumor development and point to the potential to target acetyl-CoA metabolism for pancreatic cancer. Potential role of tumor-infiltrating leukocytic cells in modulating acetyl-CoA metabolism in vivo, cancer cell-autonomous mechanisms for acetyl-CoA levels regulation, as well as consequences for therapeutic targeting and dietary interventions, will be discussed. Citation Format: Alessandro Carrer, Sophie Trefely, Steven Zhao, Sydney Campbell, Yogev Sela, Simone Sidoli, Benjamin A. Garcia, Nathaniel W. Snyder, Ben Z. Stanger, Kathryn E. Wellen. All the roads bring to Rome: How acetyl-CoA metabolism supports multistep pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A03.
Higher Vertebrate Specific Gene Ribonuclease Inhibitor (RNH1) Is Essential for Adult Hematopoietic Stem Cell Function and Cell Cycle Regulation
Authors: Nicola Daniele Andina, Mayuresh Sarangdhar, Aubry Tardivel, Giuseppe Bombaci, Mahmoud Hallal, Irene Keller, Ramanjaneyulu Allam
Journal: Blood (2019)
Skin cancer multiplicity in lung transplant recipients: a prospective population‐based study
Authors: M. Way, L. Marquart, D.C. Chambers, P. Hopkins, K. Miura, Z. Jiyad, E.I. Plasmeijer, L.E. Ferguson, M. Davis, D.C. Whiteman, H.P. Soyer, P. O'Rourke, A.C. Green
Journal: British Journal of Dermatology (2019)

Lung transplant recipients are at high risk of skin cancer, but precise annual incidence rates of treated skin cancers per patient are unknown.To perform a prospective assessment of the total burden of histologically confirmed squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) and associated factors in lung transplant recipients.A population-based cohort of 125 Queensland lung transplant recipients aged 18 years and over, recruited between 2013 and 2015, were followed to the end of 2016. All underwent dermatological skin examinations at baseline and annually thereafter and patients self-reported all interim treated skin cancers, which were verified against pathology databases. Standard skin cancer risk factors were obtained via questionnaire, and details of medications were acquired from hospital records.During a median follow-up time of 1·7 years, 29 (23%) and 30 (24%) lung transplant recipients with a median duration of immunosuppression of 3·3 years developed SCC and BCC, respectively. The general population age-standardized incidence rates of SCC and BCC were 201 and 171 per 1000 person-years, respectively (based on first primary SCC or BCC during follow-up); however, on accounting for multiple primary tumours, corresponding incidence rates were 447 and 281 per 1000 person-years. Risk of multiple SCCs increased around sixfold in those aged ≥ 60 years and in those with previous skin cancer, and increased around threefold in those treated with the antifungal medication voriconazole. Multiple BCC risk rose threefold from age 60 years and tenfold for patients with previous skin cancer.Lung transplant recipients have very high incidence of multiple primary skin cancers. Close surveillance and assiduous prevention measures are essential. Linked Comment: Proby and Harwood. Br J Dermatol 2020; 183:416-417.
Large Renal Cysts on Bone Scintigraphy in a Patient With Lower Back Pain
Authors: Yahua Zhu, Jun Geng, Haili Wang, Fuqiang Shao
Journal: Clinical Nuclear Medicine (2019)

Abstract Bone scintigraphy is often utilized to detect the osseous etiology of lower back pain. Here we report a 70-year-old man with lower back pain who was referred a 99m Tc-MDP bone scan to identify possible vertebral compression fracture. The images did not detect any osseous lesion. However, the images revealed photopenic regions in the both kidneys, which were confirmed as renal cysts on the CT images. The patient received laparoscopic unroofing of renal cysts, and his symptoms improved. Our case illustrated that back pain is not always due to osseous etiology, it might be caused by urinary disorder.
Primary Care Screening for Abdominal Aortic Aneurysm
Authors: Janelle M. Guirguis-Blake, Tracy L. Beil, Caitlyn A. Senger, Erin L. Coppola
Journal: JAMA (2019)

<h3>Importance</h3> Ruptured abdominal aortic aneurysms (AAAs) have mortality estimated at 81%. <h3>Objective</h3> To systematically review the evidence on benefits and harms of AAA screening and small aneurysm treatment to inform the US Preventive Services Task Force. <h3>Data Sources</h3> MEDLINE, PubMed (publisher supplied only), Database of Abstracts of Reviews of Effects, and Cochrane Central Register of Controlled Trials for relevant English-language studies published through September 2018. Surveillance continued through July 2019. <h3>Study Selection</h3> Trials of AAA screening benefits and harms; trials and cohort studies of small (3.0-5.4 cm) AAA treatment benefits and harms. <h3>Data Extraction and Synthesis</h3> Two investigators independently reviewed abstracts and full-text articles and extracted data. The Peto method was used to pool odds ratios (ORs) for AAA-related mortality, rupture, and operations; the DerSimonian and Laird random-effects model was used to pool calculated risk ratios for all-cause mortality. <h3>Main Outcomes and Measures</h3> AAA and all-cause mortality; AAA rupture; treatment complications. <h3>Results</h3> Fifty studies (N = 323 279) met inclusion criteria. Meta-analysis of population-based randomized clinical trials (RCTs) estimated that a screening invitation to men 65 years or older was associated with a reduction in AAA-related mortality over 12 to 15 years (OR, 0.65 [95% CI, 0.57-0.74]; 4 RCTs [n = 124 926]), AAA-related ruptures over 12 to 15 years (OR, 0.62 [95% CI, 0.55-0.70]; 4 RCTs [n = 124 929]), and emergency surgical procedures over 4 to 15 years (OR, 0.57 [95% CI, 0.48-0.68]; 5 RCTS [n = 175 085]). In contrast, no significant association with all-cause mortality benefit was seen at 12- to 15-year follow-up (relative risk, 0.99 [95% CI 0.98-1.00]; 4 RCTs [n = 124 929]). One-time screening was associated with significantly more procedures over 4 to 15 years in the invited group compared with the control group (OR, 1.44 [95% CI, 1.34-1.55]; 5 RCTs [n = 175 085]). Four trials (n = 3314) of small aneurysm surgical treatment demonstrated no significant difference in AAA-related mortality or all-cause mortality compared with surveillance over 1.7 to 12 years. These 4 early surgery trials showed a substantial increase in procedures in the early surgery group. For small aneurysm treatment, registry data (3 studies [n = 14 424]) showed that women had higher surgical complications and postoperative mortality compared with men. <h3>Conclusions and Relevance</h3> One-time AAA screening in men 65 years or older was associated with decreased AAA-related mortality and rupture rates but was not associated with all-cause mortality benefit. Higher rates of elective surgery but no long-term differences in quality of life resulted from screening.