tbuckley/cabot-search huggingface dataset:
RIG-I activation is critical for responsiveness to checkpoint blockade
Authors: Simon Heidegger, Alexander Wintges, Florian Stritzke, Sarah Bek, Katja Steiger, Paul-Albert Koenig, Sascha Göttert, Thomas Engleitner, Rupert Öllinger, Tatiana Nedelko, Julius C. Fischer, Vladimir Makarov, Christof Winter, Roland Rad, Marcel R.M. van den Brink, Jürgen Ruland, Florian Bassermann, Timothy A. Chan, Tobias Haas, Hendrik Poeck
Journal: Science Immunology (2019)

Aberrant tumor-intrinsic RIG-I signaling is a crucial mechanism underlying cancer resistance to anti–CTLA-4 immunotherapy.
Mitochondrial membrane anchored photosensitive nano-device for lipid hydroperoxides burst and inducing ferroptosis to surmount therapy-resistant cancer
Authors: Mangmang Sang, Renjie Luo, Yidan Bai, Jun Dou, Zhongtao Zhang, Fulei Liu, Feng Feng, Jian Xu, Wenyuan Liu
Journal: Theranostics (2019)

Rationale: Ferroptosis is a regulated process of cell death caused by iron-dependent accumulation of lipid hydroperoxides (LPO). It is sensitive to epithelial-to-mesenchymal transition (EMT) cells, a well-known therapy-resistant state of cancer. Previous studies on nanomaterials did not investigate the immense value of ferroptosis therapy (FT) in epithelial cell carcinoma during EMT. Herein, we describe an EMT-specific nanodevice for a comprehensive FT strategy involving LPO burst. Methods: Mitochondrial membrane anchored oxidation/reduction response and Fenton-Reaction-Accelerable magnetic nanophotosensitizer complex self-assemblies loading sorafenib (CSO-SS-Cy7-Hex/SPION/Srfn) were constructed in this study for LPO produced to overcome the therapy-resistant state of cancer. Both in vitro and in vivo experiments were performed using breast cancer cells to investigate the anti-tumor efficacy of the complex self-assemblies. Results: The nano-device enriched the tumor sites by magnetic targeting of enhanced permeability and retention effects (EPR), which were disassembled by the redox response under high levels of ROS and GSH in FT cells. Superparamagnetic iron oxide nanoparticles (SPION) released Fe2+ and Fe3+ in the acidic environment of lysosomes, and the NIR photosensitizer Cy7-Hex anchored to the mitochondrial membrane, combined sorafenib (Srfn) leading to LPO burst, which was accumulated ~18-fold of treatment group in breast cancer cells. In vivo pharmacodynamic test results showed that this nanodevice with small particle size and high cytotoxicity increased Srfn circulation and shortened the period of epithelial cancer treatment. Conclusion: Ferroptosis therapy had a successful effect on EMT cells. These findings have great potential in the treatment of therapy-resistant epithelial cell carcinomas.
Prognostic impact of miR-146 polymorphism in patients with resected colorectal cancer.
Authors: Jong Gwang Kim, Yee Soo Chae, Soo Jung Lee, Byung Woog Kang, Joon Ho Moon, Sang Kyun Sohn, Jun Young Choi
Journal: Journal of Clinical Oncology (2012)

3554 Background: MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. The rs2910164 is a C to G polymorphism located within the sequence of miR-164a precursor, which leads to a change from a C:U pair to a G:U mismatch in its stem region. Recent evidence suggested that the rs2910164 SNP in miR-146a was associated with development of familial breast and ovarian cancers, and prostatic cancer. The aim of this study was to investigate the association between this genetic variant and prognosis of colorectal cancer (CRC) operated curatively. Methods: A total of 343 CRC patients underwent curative surgery were consecutively enrolled between 2004 and 2006. DNA was extracted from fresh frozen normal tissue and miR-146 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: With a median follow up of 42.3 months, the combined GG+CG genotype demonstrated a better survival outcome compared with the CC genotype in a Kaplan-Meier survival analysis. Multivariate analysis showed that the G allele of miR-146 was associated with better progression-free and disease-specific survival as a dominant model adjusted to age, sex, histologic grade and stage [HR=0.54 and 0.49; p = 0.018 and 0.025, respectively]. Moreover, the tumors containing the G allele were histologically associated with more prominent lymphovascular invasion. Conclusions: Our results suggest that miR-146 polymorphism is possible prognostic marker in operated CRC patients in Korean.
Cancer-associated adipocytes: key players in breast cancer progression
Authors: Qi Wu, Bei Li, Zhiyu Li, Juanjuan Li, Si Sun, Shengrong Sun
Journal: Journal of Hematology & Oncology (2019)

Adipocytes are one of the primary stromal cells in many tissues, and they are considered to play an active role in the tumor microenvironment. Cancer-associated adipocytes (CAAs) are not only found adjacent to cancer cells, but also communicate with cancer cells through releasing various factors that can mediate local and systemic effects. The adipocyte-cancer cell crosstalk leads to phenotypical and functional changes of both cell types, which can further enhance tumor progression. Indeed, obesity, which is associated with an increase in adipose mass and an alteration of adipose tissue, is becoming pandemic in some countries and it is now considered to be an independent risk factor for cancer progression. In this review, we focus on the potential mechanisms involved with special attention to the adipocyte-cancer cell circle in breast cancer. We envisage that besides having a direct impact on tumor cells, CAAs systemically preconditions the tumor microenvironment by favoring anti-tumor immunity. A better understanding of cancer-associated adipocytes and the key molecular events in the adipocyte-cancer cell crosstalk will provide insights into tumor biology and permit the optimization of therapeutic strategies.
Adherence to Biopsy and Follow-Up Guidelines in a Population-Based Cohort of Children With Eosinophilic Esophagitis
Authors: Amber McClain, Molly O’Gorman, Carlos Barbagelata, Raza Patel, Amy Lowichik, Kathryn Peterson, Stephen Guthery, Jacob Robson
Journal: Clinical Gastroenterology and Hepatology (2019)
Hippocampal-Prefrontal Theta Transmission Regulates Avoidance Behavior
Authors: Nancy Padilla-Coreano, Sarah Canetta, Rachel M. Mikofsky, Emily Alway, Johannes Passecker, Maxym V. Myroshnychenko, Alvaro L. Garcia-Garcia, Richard Warren, Eric Teboul, Dakota R. Blackman, Mitchell P. Morton, Sofiya Hupalo, Kay M. Tye, Christoph Kellendonk, David A. Kupferschmidt, Joshua A. Gordon
Journal: Neuron (2019)
Abstract 15692: Comparison of Registered and Published Primary Outcomes in Cardiovascular Randomized Controlled Trials
Authors: Karim Abdur Rehman, Haris Riaz, Muhammad Shahzeb Khan, Safi Khan, Sara Salim, Mohamed M Gad, Haitham Ahmed
Journal: Circulation (2018)

Introduction: Selective reporting can confound the interpretation and validity of randomized controlled trials (RCT). Therefore in 2005, the International Committee of Medical Journal Editors manda...
Metformin in diabetic pancreatic cancer patients: Benefit or not—Multicenter experience.
Authors: Onur Esbah, Berna Oksuzoglu, Tulay Eren, Kaan Helvaci, Tunc Guler, Ayse Ocak Duran, Oznur Bal, Nurıye Yıldırım Ozdemir, Sercan Aksoy
Journal: Journal of Clinical Oncology (2013)

e15110 Background: Risk factors for the pancreatic cancer are cigarette smoking, obesity, family history, chronic pancreatitis and type 2 diabetes mellitus. Diabetes mellitus is associated with 2-3 fold increase in the risk of pancreas cancer development. Down-regulation of mTOR pathway which begins with the insulin signaling is the possible protective effect of metformin in the oncogenesis of pancreatic cancer. In this study, we aimed to evaluate whether the use of metformin in diabetic pancreas cancer patients has an advantage or not. Methods: The data of 467 patients with the diagnosis of pancreas cancer in from 2003 to 2012 were analyzed, retrospectively. Results: Four hundred and sixty seven patients with the median age of 62 (20-85) were reviewed Median tumour size was 42 mm (14-145 mm). According to 2010 TNM staging, 23 patients had stage 1 (4.9%), 97 patients stage 2 (20.8%), 70 patients stage 3 (15%) and 277 patients had stage 4 disease (59.3%). Diabetes mellitus was detected in 173 (37%) patients. In this group 23 patients had stage 1 (4.9%), 97 patients stage 2 (20.8%), 70 patients stage 3 (15%) and 98 patients had stage 4 disease (56.6%). Thirty seven percent (64 patients) of the patients with diabetes were using metformin. Median time for metformin usage was 14±2,3 months. Median follow-up time was 7 months (1-88 months). Median overall survival (OS) of all pancreas cancer patients was 8 months. Surprisingly, median OS of diabetic pancreas cancer patients and non-diabetics was 9 and 8 months, respectively (statistically not significant). Median OS of diabetic patient subgroup who use metformin or not was 7 versus 10 months, respectively (statistically not significant). In the subgroup of stage 3 pancreatic cancer patients with diabetes mellitus, the median OS were 16 months and 10 months according to metformin usage or not, respectively (p=02). Conclusions: In this study, the median OS of diabetic pancreas cancer patients was superior from the non-diabetics. Multi-center prospective trials including large number of patients are needed to understand well enough the benefit of metformin in diabetic pancreas carcinoma patients.
Machine learning analysis of DNA methylation profiles distinguishes primary lung squamous cell carcinomas from head and neck metastases
Authors: Philipp Jurmeister, Michael Bockmayr, Philipp Seegerer, Teresa Bockmayr, Denise Treue, Grégoire Montavon, Claudia Vollbrecht, Alexander Arnold, Daniel Teichmann, Keno Bressem, Ulrich Schüller, Maximilian von Laffert, Klaus-Robert Müller, David Capper, Frederick Klauschen
Journal: Science Translational Medicine (2019)

A DNA methylation–based classifier facilitates the differentiation of primary lung and metastatic head and neck cancer with diagnostic accuracy.
Subset-Specific Recurrence of Mutations and Identification of Functional Modules Provides New Clues about the Pathogenesis of Large Granular Lymphocyte Leukemia
Authors: Alessandro Coppe, Emma I Andersson, Andrea Binatti, Vanessa R Gasparini, Sabrina Bortoluzzi, Michael J. Clemente, Marco Herling, Jaroslaw P. Maciejewski, Satu Mustjoki, Stefania Bortoluzzi
Journal: Blood (2016)
Abstract 17865: The Presence of Left Ventricular Scar in Atrial Fibrillation is associated with Major Adverse Cardiovascular Events
Authors: Promporn Suksaranjit, Nazem Akoum, Brent D Wilson, Joseph Biskupiak, Lowell Chang, Krishna Velagapudi, Leenhapong Navaravong, Kavitha Damal, Allen Rassa, Erik Bieging, Nassir Marrouche, Christopher J McGann
Journal: Circulation (2014)

Introduction: Left ventricular (LV) scar identified by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) imaging is associated with adverse cardiovascular outcomes in patients with coronary artery disease (CAD) and cardiomyopathies. We studied the prognostic significance of LV-LGE in patients with atrial fibrillation (AF). Methods: We studied 778 consecutive patients referred for radiofrequency ablation of AF who underwent CMR exams between June 2006 and January 2013. Patients with history of CAD, prior myocardial infarction (MI), hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) were excluded (24 patients). The presence of LV-LGE was assessed by two independent observers who were blinded to the clinical data and outcomes. The endpoint of interest was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, MI and ischemic stroke. MACE was determined by systematic retrospective review of electronic medical records and ICD-9 codes. Univariate and multivariate analysis were performed to identify predictors of MACE. Results: Of the 754 patients who met the inclusion criteria, 60% were male with an average age of 64 years and 87% had LV ejection fraction ≥ 55%. LV-LGE was found in 46 (6%) patients. There were 32 MACE over the mean follow up period of 53 months. The MACE rate was 13% in AF patient with LV-LGE compared to 3.7% in patient without LV-LGE (p = 0.002). In univariable analysis, age (HR 1.05, CI 1.01-10.9, p = 0.005), prior stroke (HR 1.64, CI 1.08-2.49, p = 0.021), CHADS2 (HR 1.75, CI 1.34-2.27, p &lt; 0.001), CHA2DS2-VASc (HR 1.32, CI 1.15-1.52, p &lt; 0.001), left atrial fibrosis (HR 1.66, CI 1.41-1.96, p &lt; 0.001) and LV-LGE (HR 3.68, CI 1.52-8.95, p = 0.004) were significantly associated with MACE. In multivariate analysis, age and LV-LGE were independent predictors of MACE. Conclusions: In this large cohort of AF patients, LV -LGE is shown to be an independent predictor of MACE.
EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks
Authors: Laurent Gouya, Paolo Ventura, Manisha Balwani, D. Montgomery Bissell, David C. Rees, Ulrich Stölzel, John D. Phillips, Raili Kauppinen, Janneke G. Langendonk, Robert J. Desnick, Jean‐Charles Deybach, Herbert L. Bonkovsky, Charles Parker, Hetanshi Naik, Michael Badminton, Penelope E. Stein, Elisabeth Minder, Jerzy Windyga, Radan Bruha, Maria Domenica Cappellini, Eliane Sardh, Pauline Harper, Sverre Sandberg, Aasne K. Aarsand, Janice Andersen, Félix Alegre, Aneta Ivanova, Neila Talbi, Amy Chan, William Querbes, John Ko, Craig Penz, Shangbin Liu, Tim Lin, Amy Simon, Karl E. Anderson
Journal: Hepatology (2019)

Background and Aims Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long‐term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and Results EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0‐52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0‐37.0]). Elevated levels of hepatic δ‐aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ‐aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day‐to‐day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.
Podoplanin Expression in the Bleeding Complications of Acute Promyelocytic Leukemias
Authors: Vincent-Philippe Lavallee, Jalila Chagraoui, MacRae Tara, Miriam Marquis, Bonnefoy Arnaud, Jana Krosl, Sébastien Lemieux, Georges-Étienne Rivard, Josée Hébert, Guy Sauvageau
Journal: Blood (2017)
Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis
Authors: Kazuki Tajima, Kenji Ikeda, Hsin-Yi Chang, Chih-Hsiang Chang, Takeshi Yoneshiro, Yasuo Oguri, Heejin Jun, Jun Wu, Yasushi Ishihama, Shingo Kajimura
Journal: Nature Metabolism (2019)
Global, regional and national burden of osteoarthritis 1990-2017: a systematic analysis of the Global Burden of Disease Study 2017
Authors: Saeid Safiri, Ali-Asghar Kolahi, Emma Smith, Catherine Hill, Deepti Bettampadi, Mohammad Ali Mansournia, Damian Hoy, Ahad Ashrafi-Asgarabad, Mahdi Sepidarkish, Amir Almasi-Hashiani, Gary Collins, Jay Kaufman, Mostafa Qorbani, Maziar Moradi-Lakeh, Anthony D Woolf, Francis Guillemin, Lyn March, Marita Cross
Journal: Annals of the Rheumatic Diseases (2020)

To report the level and trends of prevalence, incidence and years lived with disability (YLDs) for osteoarthritis (OA) in 195 countries and territories from 1990 to 2017 by age, sex and Socio-demographic index (SDI; a composite of sociodemographic factors).Publicly available modelled data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 were used. The burden of OA was estimated for 195 countries and territories from 1990 to 2017, through a systematic analysis of prevalence and incidence modelled data using the methods reported in the GBD 2017 Study. All estimates were presented as counts and age-standardised rates per 100 000 population, with uncertainty intervals (UIs).Globally, the age-standardised point prevalence and annual incidence rate of OA in 2017 were 3754.2 (95% UI 3389.4 to 4187.6) and 181.2 (95% UI 162.6 to 202.4) per 100 000, an increase of 9.3% (95% UI 8% to 10.7%) and 8.2% (95% UI 7.1% to 9.4%) from 1990, respectively. In addition, global age-standardised YLD rate in 2017 was 118.8 (95% UI 59.5 to 236.2), an increase of 9.6% (95% UI 8.3% to 11.1%) from 1990. The global prevalence was higher in women and increased with age, peaking at the >95 age group among women and men in 2017. Generally, a positive association was found between the age-standardised YLD rate and SDI at the regional and national levels. Age-standardised prevalence of OA in 2017 ranged from 2090.3 to 6128.1 cases per 100 000 population. United States (6128.1 (95% UI 5729.3 to 6582.9)), American Samoa (5281 (95% UI 4688 to 5965.9)) and Kuwait (5234.6 (95% UI 4643.2 to 5953.6)) had the three highest levels of age-standardised prevalence. Oman (29.6% (95% UI 24.8% to 34.9%)), Equatorial Guinea (28.6% (95% UI 24.4% to 33.7%)) and the United States 23.2% (95% UI 16.4% to 30.5%)) showed the highest increase in the age-standardised prevalence during 1990-2017.OA is a major public health challenge. While there is remarkable international variation in the prevalence, incidence and YLDs due to OA, the burden is increasing in most countries. It is expected to continue with increased life expectancy and ageing of the global population. Improving population and policy maker awareness of risk factors, including overweight and injury, and the importance and benefits of management of OA, together with providing health services for an increasing number of people living with OA, are recommended for management of the future burden of this condition.
Valuation mechanisms in moral cognition
Authors: Julia Haas
Journal: Behavioral and Brain Sciences (2019)

Abstract May cites a body of evidence suggesting that participants take consequences, personal harm, and other factors into consideration when making moral judgments. This evidence is used to support the conclusion that moral cognition relies on rule-based inference. This commentary defends an alternative interpretation of this evidence, namely, that it can be explained in terms of domain general valuation mechanisms .
68Ga-PSMA-HBED-CC PET/CT and 18F-FDG PET/CT in Ewing Sarcoma
Authors: Ashwin Singh Parihar, Apurva Sood, Bhagwant Rai Mittal, Rajender Kumar, Harmandeep Singh, Sarvdeep Singh Dhatt
Journal: Clinical Nuclear Medicine (2019)

We present a case of a 19-year-old woman with Ewing sarcoma of the iliac bone in whom Ga-PSMA-HBED-CC PET/CT showed high radiotracer activity in the primary tumor. The present case documents the in vivo expression of PSMA in Ewing sarcoma family of tumors and adds on to the list of nonprostatic malignancies showing PSMA expression.
Discovery and Validation of a Biomarker Model (PRESERVE) Predictive of Renal Outcomes After Liver Transplantation
Authors: Josh Levitsky, Sumeet K. Asrani, Goran Klintmalm, Thomas Schiano, Adyr Moss, Kenneth Chavin, Charles Miller, Kexin Guo, Lihui Zhao, Linda W. Jennings, Merideth Brown, Brian Armstrong, Michael Abecassis
Journal: Hepatology (2019)

Background and Aims A high proportion of patients develop chronic kidney disease (CKD) after liver transplantation (LT). We aimed to develop clinical/protein models to predict future glomerular filtration rate (GFR) deterioration in this population. Approach and Results In independent multicenter discovery (CTOT14) and single‐center validation (BUMC) cohorts, we analyzed kidney injury proteins in serum/plasma samples at month 3 after LT in recipients with preserved GFR who demonstrated subsequent GFR deterioration versus preservation by year 1 and year 5 in the BUMC cohort. In CTOT14, we also examined correlations between serial protein levels and GFR over the first year. A month 3 predictive model was constructed from clinical and protein level variables using the CTOT14 cohort (n = 60). Levels of β‐2 microglobulin and CD40 antigen and presence of hepatitis C virus (HCV) infection predicted early (year 1) GFR deterioration (area under the curve [AUC], 0.814). We observed excellent validation of this model (AUC, 0.801) in the BUMC cohort (n = 50) who had both early and late (year 5) GFR deterioration. At an optimal threshold, the model had the following performance characteristics in CTOT14 and BUMC, respectively: accuracy (0.75, 0.8), sensitivity (0.71, 0.67), specificity (0.78, 0.88), positive predictive value (0.74, 0.75), and negative predictive value (0.76, 0.82). In the serial CTOT14 analysis, several proteins, including β‐2 microglobulin and CD40, correlated with GFR changes over the first year. Conclusions We have validated a clinical/protein model (PRESERVE) that early after LT can predict future renal deterioration versus preservation with high accuracy. This model may help select recipients at higher risk for subsequent CKD for early, proactive renal sparing strategies.
A Family of Dual-Activity Glycosyltransferase-Phosphorylases Mediates Mannogen Turnover and Virulence in Leishmania Parasites
Authors: M. Fleur Sernee, Julie E. Ralton, Tracy L. Nero, Lukasz F. Sobala, Joachim Kloehn, Marcel A. Vieira-Lara, Simon A. Cobbold, Lauren Stanton, Douglas E.V. Pires, Eric Hanssen, Alexandra Males, Tom Ward, Laurence M. Bastidas, Phillip L. van der Peet, Michael W. Parker, David B. Ascher, Spencer J. Williams, Gideon J. Davies, Malcolm J. McConville
Journal: Cell Host & Microbe (2019)

Parasitic protists belonging to the genus Leishmania synthesize the non-canonical carbohydrate reserve, mannogen, which is composed of β-1,2-mannan oligosaccharides. Here, we identify a class of dual-activity mannosyltransferase/phosphorylases (MTPs) that catalyze both the sugar nucleotide-dependent biosynthesis and phosphorolytic turnover of mannogen. Structural and phylogenic analysis shows that while the MTPs are structurally related to bacterial mannan phosphorylases, they constitute a distinct family of glycosyltransferases (GT108) that have likely been acquired by horizontal gene transfer from gram-positive bacteria. The seven MTPs catalyze the constitutive synthesis and turnover of mannogen. This metabolic rheostat protects obligate intracellular parasite stages from nutrient excess, and is essential for thermotolerance and parasite infectivity in the mammalian host. Our results suggest that the acquisition and expansion of the MTP family in Leishmania increased the metabolic flexibility of these protists and contributed to their capacity to colonize new host niches.