tbuckley/cabot-search huggingface dataset:
Incidence, prevalence and mortality of bullous pemphigoid in England 1998–2017: a population‐based cohort study*
Authors: M.S.M. Persson, K.E. Harman, Y. Vinogradova, S.M. Langan, J. Hippisley‐Cox, K.S. Thomas, S. Gran
Journal: British Journal of Dermatology (2020)

A rising incidence and high mortality were found for bullous pemphigoid (BP) over a decade ago in the UK. Updated estimates of its epidemiology are required to understand the healthcare needs of an ageing population.To determine the incidence, prevalence and mortality rates of BP in England from 1998 to 2017.We conducted a cohort study of longitudinal electronic health records using the Clinical Practice Research Datalink and linked Hospital Episode Statistics. Incidence was calculated per 100 000 person-years and annual point prevalence per 100 000 people. Multivariate analysis was used to determine incidence rate ratios by sociodemographic factors. Mortality was examined in an age-, sex- and practice-matched cohort, using linked Office of National Statistics death records. Hazard ratios (HRs) were stratified by matched set.The incidence was 7·63 [95% confidence interval (CI) 7·35-7·93] per 100 000 person-years and rose with increasing age, particularly for elderly men. The annual increase in incidence was 0·9% (95% CI 0·2-1·7). The prevalence almost doubled over the observation period, reaching 47·99 (95% CI 43·09-53·46) per 100 000 people and 141·24 (95% CI 125·55-158·87) per 100 000 people over the age of 60 years. The risk of all-cause mortality was highest in the 2 years after diagnosis (HR 2·96; 95% CI 2·68-3·26) and remained raised thereafter (HR 1·54; 95% CI 1·36-1·74).We report a modest increase in the incidence rate of BP, but show that the burden of disease in the elderly population is considerable. Mortality is high, particularly in the first 2 years after diagnosis.
The association between the treatment-induced hypertension (Htn) and response to neoadjuvant sunitinib in renal cell carcinoma (RCC).
Authors: Baidehi Maiti, Laura S. Wood, Paul Elson, Jorge A. Garcia, Robert Dreicer, Steven C. Campbell, Brian I. Rini
Journal: Journal of Clinical Oncology (2012)

e15095 Background: Prior studies have shown that development of htn, which is an on-target side effect of VEGF inhibition, is a potential biomarker for response to sunitinib in patients with metastatic RCC. The association of htn with response to neoadjuvant sunitinib was evaluated from a completed phase II trial. Methods: Patients with initially unresectable RCC were treated with sunitinib 50 mg daily until surgical eligibility or disease progression / toxicity. Htn was defined as SBP &gt;=140mm and/or DBP &gt;= 90mm while on sunitinib. Fisher’s exact test was used to assess associations between htn and clinical outcome. Results: Twenty-nine patients with unresectable RCC (72% male; 76% clear cell histology; median age 61 years (range 37-80)) were enrolled. One patient withdrew consent and was excluded from subsequent analysis. Overall, 78% of patients had primary tumor shrinkage, 57% became eligible for surgery based on primary tumor change in the opinion of the treating urologic surgeon, 50% underwent surgery and 57% developed htn. Patients who had primary tumor shrinkage had a non-significantly higher incidence of htn compared to patients who did not have primary tumor shrinkage (77% vs. 50%; p=0.31). Patients who became surgically resectable after sunitinib, however, had significantly more htn than patients who did not attain eligibility for surgery (88% vs. 45% p=0.03). Similar results were seen when the analysis was restricted to patients with clear cell histology tumors (n=20, p=1.0 and 0.06 respectively). Conclusions: There is a significant positive association between the incidence of htn and the ability of neoadjuvant sunitinib to affect surgical eligibility in patients with unresectable RCC.
Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia
Authors: Alexey V. Danilov, Charles Herbaux, Harriet S. Walter, Peter Hillmen, Simon A. Rule, Ebenezer A. Kio, Lionel Karlin, Martin J.S. Dyer, Siddhartha S. Mitra, Ping Cheng Yi, Rita Humeniuk, Xi Huang, Ziqian Zhou, Pankaj Bhargava, Juliane M. Jürgensmeier, Christopher D. Fegan
Journal: Clinical Cancer Research (2020)

Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL.Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day).Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study.Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).
Neural Regeneration: A Novel Strategy for Treating Inflammatory Bowel Disease by Targeting Delivery of Methotrexate through Glucan Particles (Adv. Healthcare Mater. 6/2020)
Authors: Ying Sun, Bingchao Duan, Huanhuan Chen, Xiaojuan Xu
Journal: Advanced Healthcare Materials (2020)

In article number 1901805 by Xiaojuan Xu and co-workers, a targeted oral delivery system is constructed by loading methotrexate (MTX) into yeast glucan particles (YGPs) for inflammatory bowel disease therapy, which can be internalized into macrophages efficiently. Furthermore, YGPs accumulate in the inflammation site of colitis mice, enabling YGPs/MTX to target the inflammatory site, significantly improve the efficacy of MTX, and reduce the cytotoxicity of MTX.
The proline metabolic cycle modulates the hypoxic response
Authors: Steven P. Donald, Gregory L. Borchert, Yongmin Liu, James M. Phang
Journal: Cancer Research (2005)

1135  The proline/pyrroline-5-carboxylate (Pro/P5C) cycle, a cellular redox shuttle, transfers redox potential between the cytosolic and mitochondrial cellular compartments and activates redox-sensitive genes. The hypoxia-inducible transcription factor HIF-1 is a key regulator of the hypoxic response, mediating the upregulation of genes sensitive to low oxygen tension through binding of the HIF-1 transcription factor to its hypoxic response element (HRE) in promoters of responsive genes. This study investigates the proximal metabolic events involving the proline metabolic cycle leading to the activation of HIF-1. Protein modification events at proline residues of HIF-1α, one member of the heterodimeric transcription factor complex, are known to contribute to the regulation of the protein. To limit HIF-1α availability, a prolylhydroxylase hydroxylates proline residues in the oxygen-dependent degradation domain of HIF-1α and tags the protein for degradation through the ubiquitin pathway. However, the mechanisms of this regulation are not completely understood. Having shown previously that the Pro/P5C metabolic cycle generates reactive oxygen species and promotes apoptosis when over expressed in colon carcinoma and normal colon cells, we tested the effect of these metabolites on the activation of the HIF-1 complex. We found that P5C added to an in vitro prolylhydroxylase assay inhibits activity in a dose-dependent manner. Also, in cells stably transfected with inducible proline oxidase, enzyme activity and the production of P5C promotes the binding of HIF-1 to its DNA target in a gel-shift assay. Furthermore, exogenous treatment of cells with P5C synergizes with hypoxia in increasing the production of inducible nitric oxide synthase (iNOS) mRNA, presumably through its HRE. This effect of P5C on hypoxic expression of iNOS has been demonstrated in a variety of cell types including murine macrophage, embryonic fibroblasts and cells derived from the colonic epithelium of mice. Although modification of target proteins at proline residues has been shown to affect gene expression, this is the first example, that we know of, where proline metabolic products directly modulate gene expression.
SALAD-BAAR: A NUMERICAL RISK SCORE FOR ADMISSION OR ER PRESENTATION IN AMBULATORY CARDIOLOGY PATIENTS
Authors: Emeka Anyanwu, Rhys F.M. Chua, Stephanie A. Besser, Marynia Kolak, Elizabeth L. Tung, James Liao, Corey Tabit
Journal: Journal of the American College of Cardiology (2020)
68Ga–Prostate-Specific Membrane Antigen Uptake in a Pancreatic Neuroendocrine Tumor
Authors: Thien Vinh Luong, Peter Iversen, Kirsten Bouchelouche, Anne Kirstine Arveschoug
Journal: Clinical Nuclear Medicine (2020)

We present a 60-year-old man with known prostate cancer treated with robot-assisted radical prostatectomy. Prostate-specific antigen levels did not decline accordingly, and a second Ga-PSMA PET/CT demonstrated a new focus with high Ga-PSMA uptake in the pancreatic tail. A subsequent CT scan did not display the lesion as a typical pancreatic tumor, and a spleen scintigraphy was also negative excluding an ectopic intrapancreatic accessory spleen. Ga-DOTATOC PET/CT showed uptake in the same area of the pancreatic tail consistent with a neuroendocrine tumor. This case illustrates that neuroendocrine tumors can be important pitfalls in Ga-PSMA PET/CT performed in prostate cancer patients.
David Oliver: Why force GP streaming on NHS emergency departments?
Authors: David Oliver
Journal: BMJ (2020)

The government recently announced plans to expand GP streaming in emergency departments, after claims that it had reduced pressure on them. GP streaming was rolled out in 2017 when Simon Stevens, NHS chief executive, announced a plan to have it in place at all NHS hospitals with emergency departments.1 This would, he claimed, free up capacity in hospitals and cut overcrowding. Some £100m (€112m; $125m) of capital expenditure was set aside to upgrade facilities, and the initiative was then incorporated into the NHS 10 year plan.2 But what is GP streaming, and does it work?

Stevens picked out Luton and Dunstable Hospital Trust as an exemplar, after its emergency department showed dramatically improved performance against waiting time targets despite considerable local demand.1 GP streaming had been a key part of this very local improvement drive. So, what had Luton done?

The model …
LEFT VENTRICULAR FUNCTION IMPROVES AFTER OFF-PUMP OR PUMP-ASSISTED CABG WITHOUT HYPOTHERMIC CIRCULATORY ARREST
Authors: George V. Letsou, Andrew D. Lee, Abhijit Salaskar, Qianzi Zhang, Namrata Shrestha, Michelle Suh, Fadi Musfee
Journal: Journal of the American College of Cardiology (2020)
CLINICAL CHARACTERISTICS OF “FAILING” ADULT FONTAN PATIENTS ACROSS 14 CENTERS: A REPORT FROM THE FOSTER STUDY
Authors: Matthew J. Lewis, Christiane Haeffele, Sharon Chen, Leigh Reardon, Jamil A. Aboulhosn, Natalia Nugaeva, Heather Joan Ross, Yuli Kim, Richard A. Krasuski, Anne Marie Valente, Matthew Carazo, Eric Krieger, Jilian Angiulo, Wendy Book, Fred Rodriguez, Alexander Egbe, Roni Jacobson, Michael Earing, Jonathan W. Cramer, Ari M. Cedars, Jong Ko, Chris Broda, Peter Ermis, Marlon Rosenbaum
Journal: Journal of the American College of Cardiology (2020)
LIPID.CARE WEB APPS: DIGITAL TECHNOLOGY TO FACILITATE COLLABORATIVE LEARNING AND PATIENT-CENTERED PRACTICES AMONG CARDIOLOGY AND LIPID CARE TEAMS AND PATIENTS WITH HYPERCHOLESTEROLEMIA
Authors: Chris Guerin, Erin O’Connell Peiffer, Paula J. Eichenbrenner, Cherilyn Heggen, Jeffrey Carter, Tamar Sapir, Kathleen Moreo
Journal: Journal of the American College of Cardiology (2020)
In vitro degradation of pure magnesium―the synergetic influences of glucose and albumin
Authors: Wei Yan, Yi-Jie Lian, Zhi-Yuan Zhang, Mei-Qi Zeng, Zhao-Qi Zhang, Zheng-Zheng Yin, Lan-Yue Cui, Rong-Chang Zeng
Journal: Bioactive Materials (2020)

The biocorrosion of magnesium in the external physiological environment is still difficult to accurately evaluate the degradation behavior in vivo, particularly, in the microenvironment of the patients with hyperglycemia or diabetes. Thus, we explored the synergistic effects of glucose and protein on the biodegradation of pure magnesium, so as to have a deeper understanding the mechanism of the degradation in vivo. The surface morphology and corrosion product composition of pure magnesium were investigated using SEM, EDS, FTIR, XRD and XPS. The effect of glucose and albumin on the degradation rate of pure magnesium was investigated via electrochemical and immersion tests. The adsorption of glucose and albumin on the sample surface was observed using fluorescence microscopy. The results showed that the presence of 2 g/L glucose changed the micromorphology of corrosion products on the magnesium surface by reacting with metal cations, thus inhibiting the corrosion of pure magnesium. Protein formed a barrier layer to protect the magnesium at early stage of immersion. The chelation reaction between protein and magnesium surface might accelerate the degradation at later stage. There may be a critical glucose (albumin) content. Biodegradation of pure magnesium was inhibited at low concentrations and promoted at high concentrations. The synergistic effect of glucose and protein restrained the adsorption of aggressive chloride ions to a certain extent, and thus inhibited the degradation of pure magnesium considerably. Moreover, XPS results indicated that glucose promoted the adsorption of protein on the sample surface.
68Ga-FAPI PET/CT Improves Therapeutic Strategy by Detecting a Second Primary Malignancy in a Patient With Rectal Cancer
Authors: Haojun Chen, Liang Zhao, Dan Ruan, Long Sun, Qin Lin
Journal: Clinical Nuclear Medicine (2020)

Abstract A 71-year-old man with pathologically confirmed rectal cancer underwent 18 F-FDG PET/CT before radical operation, which showed multiple nodules with low uptake in bilateral pleura and 1 solitary pulmonary nodule with slight uptake in left lung. The subpleural nodule was diagnosed as benign lesion through the biopsy. 68 Ga-labeled fibroblast-activation-protein inhibitor PET/CT was performed for further evaluation, which showed low uptake in bilateral subpleural nodules but focally increased uptake in the nodule of left lung. This nodule was found to be a primary lung adenocarcinoma by the CT-guided biopsy. A diagnosis of rectum and lung double primary malignancies was finally made.
Abstract 15018: Idiopathic, Isolated, Fibrotic Atrial Cardiomyopathy: An Overlooked Type of Cardiomyopathy
Authors: Minglong Chen, Weizhu Ju, Daowu Wang, Mingfang Li, Rundi Qi, Lijun Tang, Bing Yang, Hongwu Chen, Fengxiang Zhang, Jiaxian Wang, Hailei Liu, Chang Cui
Journal: Circulation (2015)

Introduction Myocardium fibrosis is a hallmark of cardiomyopathy and a proposed substrate for cardiac arrhythmias. Nevertheless, fibrosis of atrial myocardium and fibrotic atrial cardiomyopathy has not been systemically addressed. Hypothesis We hypothesized that idiopathic, isolated, fibrotic atrial cardiomyopathy (IIF-ACM) is a specific cardiomyopathy, which is characterized by atrial fibrosis and related arrhythmias. Methods In the past 8 years, 34 patients (male 13, mean age 46.5±13.3 yrs) were diagnosed with IIF-ACM based on: 1) clinical evaluation; 2) cardiac image examination; and 3) electro-anatomic mapping detected atrial scarring. Serum biomarkers of collagen metabolism and cardiomyopathy-related genetic screening were performed. Tissue pathology and virus detections were done for two patients. Results During clinical evaluation, electric silent areas were detected in all patients by intra-cardiac electro-anatomical mapping. Among 34 patients, 26 presented with atrial tachycardia (AT), 5 with sick sinus syndrome (SSS) and 3 with atrial standstill. 5 AT patients further developed SSS during the correction of AT by radiofrequency ablation. Late gadolinium-enhancement cardiovascular magnet resonance showed mild to severely dilated atria, without bilateral ventricular scarring or functional impairment. Serum biomarkers of collagen screening demonstrated significant increased collagen synthesis than collagen degradation in IIF-ACM patients. Cardiomyopathy-related genetic screening depicted no clinically relevant mutation. Histological studies showed global fibrosis of atria (Fig. 1). Conclusions We systemically reported 34 patients with IIF-ACM, which is characterized by atrial scarring and relevant arrhythmias. Ventricular functions of note were preserved in all patients. However, the underlying etiology of IIF-ACM remains to be investigated.
LATE THROMBOEMBOLIC OUTCOMES FOLLOWING PERCUTANEOUS LEFT ATRIAL APPENDAGE OCCLUSION
Authors: Demilade Adedinsewo, Najiyah Salwa, Susie Sennhauser, Jeffrey Winder, Salman Farhat, Kalpathi Venkatachalam, Peter Pollak, Pragnesh Parikh
Journal: Journal of the American College of Cardiology (2020)
ATRIAL FIBRILLATION AND OBESITY: LONG-TERM INCIDENCE AND OUTCOMES AFTER BARIATRIC SURGERY
Authors: Maddalena Ardissino, Osama Moussa, Christian Eichhorn, Rohin Reddy, Omar Khan, Paul Ziprin, Ara Darzi, Peter Collins, Sanjay Purkayastha
Journal: Journal of the American College of Cardiology (2020)
Co-targeting PI3K and ras pathways in trastuzumab resistance.
Authors: Mike J Gray, Gloria Wangrong YangKolodji, Debu Tripathy
Journal: Journal of Clinical Oncology (2013)

e13515 Background: HER2+ breast cancers (BC) account for 20–25% of invasive BC and are associated with an aggressive phenotype and poor patient outcome. The development of trastuzumab and other HER2-targeted therapy dramatically improved outcomes for HER2-positive BC, but most patients with advanced HER2+ BC will eventually become resistant to treatment, underlying the importance of developing alternative or combination treatments. Alterations in the PI3K/mTOR/Akt pathways are cited as contributors to the development of trastuzumab resistance, however targeting these kinases as single agents has yielded less than expected clinical results. This suggests that combinational treatment with other kinase pathway inhibitors may be required, including those targeting the Ras/MAPK pathway, which is typically not mutationally activated in breast cancer. Methods: Trastuzumab resistant HER2+ BC cell lines were subjected to dose responses with the mTOR inhibitor everolimus or the AKT inhibitor MK-2206 alone or in combination with the MEK 1/2 inhibitor GSK212 and changes in EC50s determined by MTT assay. Western blot analysis was performed to assess changes in the mTOR/AKT/ MAPK pathways or apoptotic regulators accompanying single or combination treatments. Results: In 4 of 5 trastuzumab-resistant HER2+ BC cell lines, each lacking activating mutations in the Ras/Raf pathway, combination treatment with everolimus or MK-2206 with GSK212 had significantly greater efficacy than by either inhibitor alone. Furthermore, combinational treatment targeting the mTOR and AKT pathways showed only an additive effect, and was much less effective than targeting both the MEK and PI3K pathways. Western analysis showed that AKT and mTOR inhibition caused a transient increase in ERK 1/2 activity in sensitive cell lines, suggesting that treatment by mTOR or AKT inhibitors activated critical survival pathways in the MAPK signaling that were blocked by GSK212. Conclusions: Treatment with mTOR or AKT inhibitors in combination with MEK inhibitors can act in a synergistic manner with greater efficacy than each inhibitor alone. Moreover, ERK 1/2 activity may serve as a predictive biomarker in trastuzumab-refractory patients treated with mTOR/MEK or AKT/MEK doublet therapy.
Gene expression identifies heterogeneity of soft tissue sarcomas
Authors: K. M. Skubitz, S. Pambuccian, A. P. Skubitz
Journal: Journal of Clinical Oncology (2006)

9574 Background: Soft tissue sarcomas (STS) exhibit heterogeneity in their clinical behavior, even within histological subtypes. Histological appearance is determined by gene expression. However, metastatic propensity, tumor growth, and response to chemotherapy may be determined by gene expression patterns that do not correlate well with morphology. One approach to identify heterogeneity is to search for markers that correlate with differences in tumor behavior. Alternatively, subsets may be identified based on gene expression patterns independent of knowledge of clinical outcome. We have reported gene expression patterns that distinguish two broad classes of clear cell renal carcinoma (ccRCC) independent of histological appearance, and other patterns that can distinguish heterogeneity of serous ovarian carcinoma (OVCA). Methods: In this study, gene expression in 41 samples of STS (including malignant fibrous histiocytoma (MFH), leiomyosarcoma, liposarcoma, and synovial sarcoma), 12 samples of fibromatosis, and 17 normal tissues was determined at Gene Logic Inc. (Gaithersburg, MD) using Affymetrix GeneChip U_133 arrays containing approximately 40,000 genes/ESTs. Gene expression analysis was performed with the Gene Logic Genesis Enterprise System Software. Results: Hierarchical clustering using two gene sets, one that distinguished two subsets of ccRCC, and a second set that distinguished two subsets of OVCA, both generated subgroups within the STS that for some, but not all, subtypes correlated with histology, and also suggested the existence of subsets of MFH. Both gene sets also identified the same two subsets of the fibromatosis samples. In addition, genes expressed uniquely in MFH, leiomyosarcomas, and liposarcomas among these and 512 samples from 17 other normal tissue types were identified. Conclusions: The ability to sub-classify histological subtypes of STS, including identifying possible subsets of MFH, using gene sets derived from studies of two different carcinomas suggests that these subgroups may have biological significance. Some of the genes identified as over-expressed in particular subsets of STS compared with a variety of normal tissues may reflect possible targets to which anti-tumor therapy could be directed, and may also be useful for sub-classification of STS. No significant financial relationships to disclose.