tbuckley/cabot-search huggingface dataset:
Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation
Authors: Derek K. Smith, Lance Kates, Steffen Durinck, Nisha Patel, Eric W. Stawiski, Noelyn Kljavin, Oded Foreman, Bence Sipos, Mark J. Solloway, Bernard B. Allan, Andrew S. Peterson
Journal: Cell Reports Medicine (2020)

The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Hormone expression suggests that these tumors arise from glucagon-producing alpha cells or insulin-producing β cells, but instability in hormone expression prevents linage determination. We utilize loss of hepatic glucagon receptor (GCGR) signaling to drive alpha cell hyperproliferation and tumor formation to identify a cell of origin and dissect mechanisms that drive progression. Using a combination of genetically engineered Gcgr knockout mice and GCGR-inhibiting antibodies, we show that elevated plasma amino acids drive the appearance of a proliferative population of SLC38A5+ embryonic progenitor-like alpha cells in mice. Further, we characterize tumors from patients with rare bi-allelic germline GCGR loss-of-function variants and find prominent tumor-cell-associated expression of the SLC38A5 paralog SLC7A8 as well as markers of active mTOR signaling. Thus, progenitor cells arise from adult alpha cells in response to metabolic signals and, when inductive signals are chronically present, drive tumor initiation.
THU0001 Tnf-alpha polymorphism at position -308 might protect against radiographic damage in ra irrespective of rheumatoid factor or hla status
Authors: C Orellana, R Sanmartí, JD Cañete, J Yagüe, G Ercilla, A Gómez, G Salvador, J Muñoz-Gómez
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To assess the prevalence of TNF-alpha polymorphisms in patients with early rheumatoid arthritis (RA) in our population and investigate whether there is an association with radiographic severity. <h3>Methods</h3> 68 patients with early RA (49F/19M, mean age 51 ± 15 y, mean disease duration 15 ± 13 mo, RF+ 72%, mean number of tender joints at entry 6.3 ± 5.7, mean number of swollen joints at entry 8.23 ± 7.33). Patients were genotyped for HLA-DRB1 and TNF-alpha alleles. Hands and feet radiographs were taken at entry and then yearly during follow-up. The Larsen method was used to assess radiographic damage. <h3>Results</h3> There were not differences in the distribution of TNF-alpha alleles in the RA patients compared with controls. The TNF-alpha -308GG genotype instead of the ?308GA genotype was found to be more frequent in patients with no erosive disease at entry compared with those presenting erosions (89% vs 62%, p = 0.0023). Patients not showing radiographic erosions during follow-up (36.5 ± 22 mo) also had more frequently the -308GG genotype (96% vs. 74% in erosive disease, p = 0.018). There were no differences in disease duration nor follow-up between patients with erosive and non erosive disease. The TNF-alpha -308GG polymorphism was as frequent in patients with non erosive disease as in controls, and there were not differences either among RF+ve and RF-ve patients nor among patients with or without the shared epitope or who were HLA-DR4 positive. No other associations related to TNF-alpha were found in relation to radiographic damage. <h3>Conclusion</h3> The presence of the ?308GG TNF-alpha genotype appears to be one of the factors related to less severe disease as determined by erosive disease, and may have a protective role compared with the ?308 GA genotype.
Abstract 6409: Targeted degradation of endogenously tagged proteins for phenotypic studies using HaloPROTAC3 and HaloTag technologies
Authors: Elizabeth A. Caine, Sarah Mahan, Kristin Riching, Nancy Murphy, Mark McDougall, Cesear Corona, Chris Heid, Danette L. Daniels, Marjeta Urh
Journal: Cancer Research (2020)

Abstract To understand a protein's function inside the cell, studies are often done to remove it using CRISPR-mediated knockout or RNAi knockdown methods. These approaches have challenges in either obtaining efficient or complete loss, are not possible if the protein target is essential for cell growth, and are genetic methods, not directly protein loss. To overcome these hurdles, we have employed a highly precise and temporally controlled target protein degradation strategy utilizing HaloPROTAC, a HaloTag Proteolysis-targeting chimera small molecule which will specifically degrade HaloTag fusion proteins in live cells. HaloPROTAC3, developed by Prof. Craig Crews at Yale University, recruits HaloTag fusion proteins to VHL E3 ligase complexes, resulting in ubiquitination and degradation of the HaloTag fusion via the ubiquitin-proteasomal pathway. For phenotypic studies, removal of the endogenous proteins is often required, therefore we have developed efficient protocols for the introduction of HaloTag via CRISPR/Cas9 gene editing into either the endogenous N- or C-terminal loci of any target protein. We have additionally appended the 11 amino acid HiBiT to the HaloTag-target protein, allowing for highly quantitative and kinetic monitoring of degradation to be tracked in live cells without the use of antibodies. Shown here are several key therapeutic proteins, BRD4 and B-catenin, which have been endogenously tagged with HiBiT-HaloTag via CRISPR/Cas9 and show rapid and sustained degradation (80-90% loss) after treatment with HaloPROTAC3. For BRD4, this loss was similar to what was observed using a BET-family specific PROTAC. For B-catenin, further phenotypic studies were done to show a muted response to Wnt3a stimulation and TCF/LEF promoter gene activation after degradation of endogenous B-catenin. These examples demonstrate that the technologies can be used readily to elicit robust degradation of target proteins, with control over the protein level and the time frame for which the protein will be lost, in order to more fully understand protein function. Together, these provide new opportunities for phenotypic studies based directly on control of protein levels and loss, with the ability to study the roles of essential proteins not amenable to genetic knockout or knockdown approaches. Citation Format: Elizabeth A. Caine, Sarah Mahan, Kristin Riching, Nancy Murphy, Mark McDougall, Cesear Corona, Chris Heid, Danette L. Daniels, Marjeta Urh. Targeted degradation of endogenously tagged proteins for phenotypic studies using HaloPROTAC3 and HaloTag technologies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6409.
Addressing Postpandemic Clinician Mental Health
Authors: Rachel Schwartz, Jina L. Sinskey, Uma Anand, Rebecca D. Margolis
Journal: Annals of Internal Medicine (2020)

Previous pandemics have seen high psychiatric morbidity among health care workers. Protecting clinician mental health in the aftermath of coronavirus disease 2019 (COVID-19) requires an evidence-based approach to developing and deploying comprehensive clinician mental health support. In a narrative review of 96 articles addressing clinician mental health in COVID-19 and prior pandemics, 7 themes emerged: 1) the need for resilience and stress reduction training; 2) providing for clinicians' basic needs (food, drink, adequate rest, quarantine-appropriate housing, transportation, child care, personal protective equipment); 3) the importance of specialized training for pandemic-induced changes in job roles; 4) recognition and clear communication from leadership; 5) acknowledgment of and strategies for addressing moral injury; 6) the need for peer and social support interventions; and 7) normalization and provision of mental health support programs. In addition to the literature review, in collaboration with the Collaborative for Healing and Renewal in Medicine (CHARM) network, the authors gathered practice guidelines and resources from health care organizations and professional societies worldwide to synthesize a list of resources deemed high-yield by well-being leaders. Studies of previous pandemics demonstrate heightened distress in health care workers years after the event. The COVID-19 pandemic presents unique challenges that surpass those of previous pandemics, suggesting a significant mental health toll on clinicians. Long-term, proactive individual, organizational, and societal infrastructures for clinician mental health support are needed to mitigate the psychological costs of providing care during the COVID-19 pandemic.
Heat shock protein 60 and cardiovascular diseases: An intricate love‐hate story
Authors: Indumathi Krishnan‐Sivadoss, Iván A. Mijares‐Rojas, Ramiro A. Villarreal‐Leal, Guillermo Torre‐Amione, Anne A. Knowlton, C. Enrique Guerrero‐Beltrán
Journal: Medicinal Research Reviews (2020)

Abstract Cardiovascular diseases (CVDs) are the result of complex pathophysiological processes in the tissues comprising the heart and blood vessels. Inflammation is the main culprit for the development of cardiovascular dysfunction, and it may be traced to cellular stress events including apoptosis, oxidative and shear stress, and cellular and humoral immune responses, all of which impair the system's structure and function. An intracellular chaperone, heat shock protein 60 (HSP60) is an intriguing example of a protein that may both be an ally and a foe for cardiovascular homeostasis; on one hand providing protection against cellular injury, and on the other triggering damaging responses through innate and adaptive immunity. In this review we will discuss the functions of HSP60 and its effects on cells and the immune system regulation, only to later address its implications in the development and progression of CVD. Lastly, we summarize the outcome of various studies targeting HSP60 as a potential therapeutic strategy for cardiovascular and other diseases.
Approaching autonomy in medical artificial intelligence
Authors: Danielle S Bitterman, Hugo J W L Aerts, Raymond H Mak
Journal: The Lancet Digital Health (2020)

Artificial intelligence (AI) has the potential to transform the delivery of health care by automating complex tasks that traditionally required substantial training and expertise. Contrary to concerns that fully automated AI will replace health-care providers,1 a more likely scenario is that providers will increasingly interact with task-specific and domain-specific AI systems across a continuum of automation. The level of AI autonomy is broadly accepted to be crucial to the risk-assessment of AI algorithms, yet its definition and classification is poorly defined.
Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study
Authors: Chey Loveday, Amit Sud, Michael E Jones, John Broggio, Stephen Scott, Firza Gronthound, Beth Torr, Alice Garrett, David L Nicol, Shaman Jhanji, Stephen A Boyce, Matthew Williams, Claire Barry, Elio Riboli, Emma Kipps, Ethna McFerran, David C Muller, Georgios Lyratzopoulos, Mark Lawler, Muti Abulafi, Richard S Houlston, Clare Turnbull
Journal: Gut (2020)

To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic.
Intracellular trafficking and functional monitoring of miRNA delivery in glioblastoma using lipopolyplexes and the miRNA-ON RILES reporter system
Authors: Viorel Simion, Elodie Henriet, Viktorija Juric, Ruth Aquino, Claire Loussouarn, Yoan Laurent, Francisco Martin, Patrick Midoux, Emmanuel Garcion, Chantal Pichon, Patrick Baril
Journal: Journal of Controlled Release (2020)
Klebsiella pneumoniae bacteremia revisited: Comparison between 2007 and 2017 prospective cohorts at a medical center in Taiwan
Authors: Yu-Tsung Huang, Chiang-Sang Chen, Hong-An Chen, Hsin-Sui Hsu, Ming-Hui Liang, Man-Hsuan Chang, Chun-Hsing Liao
Journal: Journal of Infection (2020)
Association of Sex or Race With the Effect of Weight Loss on Physical Function
Authors: Kristen M. Beavers, Rebecca H. Neiberg, Stephen B. Kritchevsky, Barbara J. Nicklas, Dalane W. Kitzman, Stephen P. Messier, W. Jack Rejeski, Jamy D. Ard, Daniel P. Beavers
Journal: JAMA Network Open (2020)

Consideration of differential treatment effects among subgroups in clinical trial research is a topic of increasing interest. This is an especially salient issue for weight loss trials.To determine whether stratification by sex and race is associated with meaningful differences in physical function response to weight loss among older adults.This pooled analysis used individual-level data from 8 completed randomized clinical trials of weight loss conducted at Wake Forest University or Wake Forest School of Medicine, Winston-Salem, North Carolina. Data were housed within the Wake Forest Older Americans Independence Center data repository and provided complete exposure, outcome, and covariate information. Data were collected from November 1996 to March 30, 2017, and analyzed from August 15, 2019, to June 10, 2020.Treatment arms within each study were collapsed into caloric restriction (CR [n = 734]) and non-CR (n = 583) categories based on whether caloric restriction was specified in the original study protocol.Objectively measured 6-month change in weight, fast-paced gait speed (meters per second), and Short Physical Performance Battery (SPPB) score.A total of 1317 adults (mean [SD] age, 67.7 [5.4] years; 920 [69.9%] female; 275 [20.9%] Black) with overweight or obesity (mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 33.9 [4.4]) were included at baseline. Six-month weight change achieved among those randomized to CR was -7.7% (95% CI, -8.3% to -7.2%), with no difference noted by sex; however, White individuals lost more weight than Black individuals assigned to CR (-9.0% [95% CI, -9.6% to -8.4%] vs -6.0% [95% CI, -6.9% to 5.2%]; P < .001), and all CR groups lost a significantly greater amount from baseline compared with non-CR groups (Black participants in CR vs non-CR groups, -5.3% [95% CI, -6.4% to -4.1%; P < .001]; White participants in CR vs non-CR groups, -7.2% [95% CI, -7.8% to -6.6%; P < .001]). Women experienced greater weight loss-associated improvement in SPPB score (CR group, 0.35 [95% CI, 0.18-0.52]; non-CR group, 0.08 [95% CI, -0.11 to 0.27]) compared with men (CR group, 0.23 [95% CI, 0.00-0.46]; non-CR group, 0.34 [95% CI, 0.09-0.58]; P = .03). Black participants experienced greater weight loss-associated improvement in gait speed (CR group, 0.08 [95% CI, 0.05-0.10] m/s; non-CR group, 0.02 [95% CI, -0.01 to 0.05] m/s) compared with White participants (CR group, 0.07 [95% CI, 0.06-0.09] m/s; non-CR group, 0.06 [95% CI, 0.04-0.08] m/s; P = .02).The association of weight loss on physical function in older adults appears to differ by sex and race. These findings affirm the need to consider biological variables in clinical trial design.
Blood biomarkers for the diagnosis of hepatic steatosis in metabolic dysfunction-associated fatty liver disease
Authors: Zhou Xu, Hao Li, Shen Tian, Juan Wu, Xin Li, Zi-li Liu, Shu Li, Yu-ling Chen, Jun Xiao, Jia-ying Wei, Xin-yu Liang, Liang Ran, Ling-quan Kong
Journal: Journal of Hepatology (2020)
Response To: 'Effectiveness of Low-Dose Radiation Therapy on Symptoms in Patients With Knee Osteoarthritis'
Authors: E.A. Mahler, M.J.M. Minten, M.M. Leseman-Hoogenboom, P.M.P. Poortmans, J.W.H. Leer, S.S. Boks, F.H.J. van den Hoogen, A.A. den Broeder, C.H.M. van den Ende
Journal: Annals of the Rheumatic Diseases (2020)
Transarterial chemoembolization (TACE) of liver metastases (LM) from colorectal carcinoma (CRC) adopting drug eluting beads preloaded with irinotecan (DEBIRI): Results of a phase II study on 82 patients
Authors: C. Aliberti, G. Benea, M. Tilli, G. Fiorentini
Journal: Journal of Clinical Oncology (2009)

4092 Background: DC beads are new embolic microspheres capable to load IRI. The present phase II study investigated response and side effects after TACE adopting DEBIRI in 82 patients with LM from CRC not resectable and in progression after two lines of chemtherapy. Methods: A total of 185 TACE procedures were performed. A suspension of polyvinyl-alcohol beads (DC Bead) preloaded with Irinotecan ( 81 TACE procedures with 2ml of microspheres preloaded with 100mgr of Irinotecan and 104 with 4ml loaded with 200mgr of Irinotecan) was delivered selectively into hepatic arteries. All pts received a well defined prophylactic treatment against nausea and vomiting, infections, and upper quadrant right pain (UQRP).Tropisetron, hydration, antibiotics, morphine and intra-arterial lidocaine was delivered as reported in previous experiences ( ASCO GI abs 356,2007; IN VIVO. 21, 6, 2007). Follow-up studies were performed by contrast enhanced spiral multislice computed tomography (MsCT) 1 month after the procedures and every 3 months or when clinically required. Quality of life (QoL) was assessed by Edmonton SAS improvement scale before, after TACE and then monthly. Results: We obtained 100% technical success in TACEs performed, and no complications due to the procedure occurred. Patients developed a postembolization-syndrome with the following side effects : UQRP (G2), fever (G2), nausea (G2) and increased transaminases (G2–3) in 40%,80%,80%,70% respectively out of 185 procedures done. One pt presented acute pancreatitis. The median follow-up was 18.2 months. Within 1 month after treatment, CT scan showed significant ( 75–100%) reduction of metastatic contrast enhancement in all lesions treated. Therapeutic response (according to RECIST was observed in 78% of patients. After TACE. 75 out 82 pts (90%) declare a general improvement of QoL long lasting. Conclusions: We suggest that TACE with DEBIRI could be a palliative therapy for LM from CRC. Our promising experience need to be confirmed with further phase III studies. Mid and long-term results need to be carefully evaluated comparing them with systemic chemotherapy. No significant financial relationships to disclose.
Diabetes Impairs Cellular Cholesterol Efflux From ABCA1 to Small HDL Particles
Authors: Yi He, Graziella E. Ronsein, Chongren Tang, Gail P. Jarvik, W. Sean Davidson, Vishal Kothari, Hyun D. Song, Jere P. Segrest, Karin E. Bornfeldt, Jay W. Heinecke
Journal: Circulation Research (2020)

Rationale: HDL (high-density lipoprotein) may be cardioprotective because it accepts cholesterol from macrophages via the cholesterol transport proteins ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1). The ABCA1-specific cellular cholesterol efflux capacity (ABCA1 CEC) of HDL strongly and negatively associates with cardiovascular disease risk, but how diabetes mellitus impacts that step is unclear. Objective: To test the hypothesis that HDL’s cholesterol efflux capacity is impaired in subjects with type 2 diabetes mellitus. Methods and Results: We performed a case-control study with 19 subjects with type 2 diabetes mellitus and 20 control subjects. Three sizes of HDL particles, small HDL, medium HDL, and large HDL, were isolated by high-resolution size exclusion chromatography from study subjects. Then we assessed the ABCA1 CEC of equimolar concentrations of particles. Small HDL accounted for almost all of ABCA1 CEC activity of HDL. ABCA1 CEC―but not ABCG1 CEC―of small HDL was lower in the subjects with type 2 diabetes mellitus than the control subjects. Isotope dilution tandem mass spectrometry demonstrated that the concentration of SERPINA1 (serpin family A member 1) in small HDL was also lower in subjects with diabetes mellitus. Enriching small HDL with SERPINA1 enhanced ABCA1 CEC. Structural analysis of SERPINA1 identified 3 amphipathic α-helices clustered in the N-terminal domain of the protein; biochemical analyses demonstrated that SERPINA1 binds phospholipid vesicles. Conclusions: The ABCA1 CEC of small HDL is selectively impaired in type 2 diabetes mellitus, likely because of lower levels of SERPINA1. SERPINA1 contains a cluster of amphipathic α-helices that enable apolipoproteins to bind phospholipid and promote ABCA1 activity. Thus, impaired ABCA1 activity of small HDL particles deficient in SERPINA1 could increase cardiovascular disease risk in subjects with diabetes mellitus.
Use of independent genome-wide assays to discover HOXA signature in colon and rectal cancers and validate a role in tumorigenesis
Authors: S. Pant, G. Hostetter, B. Armstrong, M. Bittner, S. Shack, S. Savage, G. J. Weiss, H. Ozer, R. Ramanathan
Journal: Journal of Clinical Oncology (2009)

e15014 Background: Rectal cancer differs from colon cancer in terms of prognosis. Here we present genome-wide expression analysis of 79 colon and rectal tumors and gene dosage analysis of 34 archival colorectal tumors in paraffin (FFPE). Methods: Expression data were acquired ( http://expo.intgen.org/geo/home.do ) from Affymetrix experiments analyzed with GeneSpring software version 7.3 (Silicon Genetics, CA). Expression data were normalized ’per chip’ normalized to the 50th percentile of all values; and ’per gene’ normalized to the median expression level across all samples. Expression Project for Oncology (expO) samples included colon (n=50) and rectum (n=29). Differentially expressed genes were identified by parametric test for which variances were not assumed equal (Welch ANOVA). Array comparative genomic hybridization (aCGH) were performed separately on an independent set of FFPE colorectal tumors (n=34) by 244 K microarrays for CGH, Agilent Technologies, CA and with platform embedded analyses tools of CGH Analytics software and ADM-1 bioinformatics. Functional assay by knockout of HOXA9 promoter by lentiviral sh-RNAi construct was performed on colon cancer cell lines shown to have increased HOXA9 dosage and expression. Results: The analysis of expO colon and rectal cancers generated 42 genes with significant differential expression, 26 showed an increased expression of &gt; 2 fold in colon versus rectal samples. Transcription factor family HOXA9 was the most highly expressed (3.8 fold) in colon versus rectal cancer. The aCGH data showed a low level gain of the HOXA gene to be the most frequent dosage alteration (38%). Validation by IHC and qRT-PCR showed 80% and 76% concordance, respectively. Functional assay by sh-RNAi in cell lines (compared to vehicle only) showed marked decrease in cellular viability (40 to 60%), marked morphologic change and a significantly increased apoptotic rate. Conclusion: Multiple genome-wide assays have identified HOXA9 as differentially dosed and expressed in colon and rectal tumors. Compelling functional data from sh-RNAi experiments suggests a tumorigenic role for HOXA9 in altered apoptosis. No significant financial relationships to disclose.