tbuckley/cabot-search huggingface dataset:
Response to: ‘Development and initial validation of diagnostic gene signatures for systemic lupus erythematosus’ by Wang <i>et al</i>
Authors: Martin Aringer, Karen Costenbader, Thomas Dörner, Sindhu R Johnson
Journal: Annals of the Rheumatic Diseases (2019)

Response to: 'Development and initial validation of diagnostic gene signatures for systemic lupus erythematosus' by Wang et al In their letter, Dr Wang and colleagues 1 correctly remark that no novel molecular biomarkers were included in the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2019 classification criteria for systemic lupus erythematosus (SLE), although a variety of such markers were considered in the process, including the type I interferon signature. 2 3As cited by Wang et al, 1 sufficient evidence and worldwide availability were of importance for inclusion into the list of classification criteria items.Their approach presently is on the opposite side of the field, where early hypotheses are generated.Dr Wang and colleagues 1 used robust rank aggregation for analysing multiple transcriptome data sets.Essentially all hits in this approach were interferon-regulated genes.Accordingly, the authors worked at enriching for genes of other modules, and over several steps arrived at a five-gene score, which was superior to any single gene in distinguishing SLE from healthy individuals.This approach is interesting, and may in the end lead to markers relevant for diagnosis, as discussed by Dr Wang et al, 1 but eventually also for classification.However, testing against various other autoimmune diseases, such as in the EULAR/ ACR SLE classification project, 2 3 has not yet been shown.5][6] Once this is successfully done, it will be interesting to see whether the combination of established criteria and such novel markers further improve classification.
Reinterpreting Cardiorenal Protection of Renal Sodium–Glucose Cotransporter 2 Inhibitors via Cellular Life History Programming
Authors: Angelo Avogaro, Gian Paolo Fadini, Stefano Del Prato
Journal: Diabetes Care (2019)

Cardiovascular outcome trials have provided evidence that sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment is associated with remarkably favorable cardiovascular outcomes. Here, we offer a novel hypothesis that may encompass many of these hypothetical mechanisms, i.e., the ability of SGLT2i to modify the trajectory of cell response to a toxic environment through modifications of cellular life history programs, either the defense program or the dormancy program. The choice between these programs is mainly determined by the environment. Hyperglycemia can be considered a toxic determinant able to interfere with the basic programs of cell evolution. While the defense program is characterized by activation of the immune response and anabolic metabolism, the dormancy program is an energy-preserving state with high resistance to environmental stressors, and it has strong analogy with animal hibernation where fuel is stored, metabolic rate is suppressed, and insulin secretion is reduced. The metabolic changes that follow treatment with SGLT2i are reminiscent of the metabolic picture characteristic of the dormancy program. Therefore, we hypothesize that the beneficial cardioprotective effects of SGLT2i may be related to their ability to switch cell life programming from a defense to a dormancy state, thus lending additional benefit.
A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer
Authors: Amit M. Oza, Ursula A. Matulonis, Angeles Alvarez Secord, John Nemunaitis, Lynda D. Roman, Sarah P. Blagden, Susana Banerjee, William P. McGuire, Sharad Ghamande, Michael J. Birrer, Gini F. Fleming, Merry Jennifer Markham, Hal W. Hirte, Diane M. Provencher, Bristi Basu, Rebecca Kristeleit, Deborah K. Armstrong, Benjamin Schwartz, Patricia Braly, Geoff D. Hall, Kenneth P. Nephew, Simone Jueliger, Aram Oganesian, Sue Naim, Yong Hao, Harold Keer, Mohammad Azab, Daniela Matei
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. Patients and Methods: Patients received either G+C (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). Results: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. Conclusions: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.
Abstract A33: Single-cell profiling reveals subclonal vulnerabilities to therapy in patient-derived 2D and organoid models
Authors: Maria E. Monberg, Vincent B. Pagan, Alexander Semaan, Jaewon J. Lee, Paola A. Guerrero, Senthil K. Muthuswamy, Anirban Maitra
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related deaths in the United States. This is largely due to the fact of high propensity of patients presenting at metastatic stages resulting from symptom ambiguity and a complete lack of general population screening programs. As the overwhelming majority of patients (85%) present with surgically unresectable disease, the 5-year survival rate is dire at only ~8%. Outside of what is known of the commonly mutated genes in PDAC, which include KRAS, TP53, SMAD4, and CDKN2A, little molecular information exists that has yielded clinical knowledge that may have an impact on survival outcomes. Therefore, a concerted clinical and research paradigm shift towards higher-resolution investigations of the genomics of PDAC is an area of highest public health significance. In our laboratory, we have leveraged single-cell sequencing approaches in both cell lines and patient-derived tissues to develop models for molecular underpinnings of PDAC and as potential tools for therapeutic stratification. First, to demonstrate the ability to model cellular heterogeneity of tumor populations, single-cell RNA and DNA sequencing was applied to widely used patient-derived PDAC cell lines. Using a bioinformatics pipeline, were able to differentiate between supposedly identical cell lines that had evolved rich subclonal architecture that may provide insight into complex in silico landscapes that naturally evolve as these cells are continuously used by laboratories. We then characterized single-cell gene expression profiles of patient-derived organoids (PDOs) to understand their heterogeneous composition and applied an in silico therapeutic drug prediction model to identify and validate combinatorial strategies targeting subpopulations. These present multiple phenotypic traits similar to that of the parental tumor including histoarchitecture, oxygen biology, epigenetic marking, and differentiation status. Orthogonal validation of predicted drugs was confirmed through a high-throughput drug screen of 764 agency-approved candidates on two PDOs. This strategy demonstrated the utility of single-cell transcriptomic profiling from PDOs in effectively identifying heterogeneous enriched pathways and molecular subtypes within cultures to predict viable treatment options using a pharmacogenomic approach. Citation Format: Maria E. Monberg, Vincent B. Pagan, Alexander Semaan, Jaewon J. Lee, Paola A. Guerrero, Senthil K. Muthuswamy, Anirban Maitra. Single-cell profiling reveals subclonal vulnerabilities to therapy in patient-derived 2D and organoid models [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 A33.
Correction to: Immunostimulatory RNA leads to functional reprogramming of myeloid-derived suppressor cells in pancreatic cancer
Authors: Philipp Metzger, Sabrina V. Kirchleitner, Michael Kluge, Lars M. Koenig, Christine Hörth, Carlotta A. Rambuscheck, Daniel Böhmer, Julia Ahlfeld, Sebastian Kobold, Caroline C. Friedel, Stefan Endres, Max Schnurr, Peter Duewell
Journal: Journal for ImmunoTherapy of Cancer (2019)

Following publication of the original article [1], the authors have reported that Fig. 2 and Additional file 1: Figure S1, S2 partially show red scripts.
Non-transdermal microneedles for advanced drug delivery
Authors: KangJu Lee, Marcus J. Goudie, Peyton Tebon, Wujin Sun, Zhimin Luo, Junmin Lee, Shiming Zhang, Kirsten Fetah, Han-Jun Kim, Yumeng Xue, Mohammad Ali Darabi, Samad Ahadian, Einollah Sarikhani, WonHyoung Ryu, Zhen Gu, Paul S. Weiss, Mehmet R. Dokmeci, Nureddin Ashammakhi, Ali Khademhosseini
Journal: Advanced Drug Delivery Reviews (2019)
A Runaway PRH/HHEX-Notch3–Positive Feedback Loop Drives Cholangiocarcinoma and Determines Response to CDK4/6 Inhibition
Authors: Philip Kitchen, Ka Ying Lee, Danielle Clark, Nikki Lau, Jomnarong Lertsuwan, Anyaporn Sawasdichai, Jutamaad Satayavivad, Sebastian Oltean, Simon Afford, Kevin Gaston, Padma-Sheela Jayaraman
Journal: Cancer Research (2019)

Aberrant Notch and Wnt signaling are known drivers of cholangiocarcinoma (CCA), but the underlying factors that initiate and maintain these pathways are not known. Here, we show that the proline-rich homeodomain protein/hematopoietically expressed homeobox (PRH/HHEX) transcription factor forms a positive transcriptional feedback loop with Notch3 that is critical in CCA. PRH/HHEX expression is elevated in CCA, and depletion of PRH reduces CCA tumor growth in a xenograft model. Overexpression of PRH in primary human biliary epithelial cells is sufficient to increase cell proliferation and produce an invasive phenotype. Interrogation of the gene networks regulated by PRH and Notch3 reveals that unlike Notch3, PRH directly activates canonical Wnt signaling. These data indicate that hyperactivation of Notch and Wnt signaling is independent of the underlying mutational landscape and has a common origin in dysregulation of PRH. Moreover, they suggest new therapeutic options based on the dependence of specific Wnt, Notch, and CDK4/6 inhibitors on PRH activity. SIGNIFICANCE: The PRH/HHEX transcription factor is an oncogenic driver in cholangiocarcinoma that confers sensitivity to CDK4/6 inhibitors.
Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Hironobu Hashimoto, Masakazu Abe, Osamu Tokuyama, Hideaki Mizutani, Yosuke Uchitomi, Takuhiro Yamaguchi, Yukari Hoshina, Yasuhiko Sakata, Takako Yanai Takahashi, Kazuhisa Nakashima, Masahiko Nakao, Daisuke Takei, Sadamoto Zenda, Koki Mizukami, Satoru Iwasa, Michiru Sakurai, Noboru Yamamoto, Yuichiro Ohe
Journal: The Lancet Oncology (2019)
Abstract I22: New players and unique features of cancer lysosomes
Authors: Rushika M Perera
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDA) cells and tumors constitutively activate nutrient scavenging pathways, namely, autophagy (cellular self-catabolism) and macropinocytosis (bulk uptake of extracellular material) in order to maintain metabolic homeostasis. Importantly, both of these pathways converge on the lysosome, an acidic organelle that harbors within its lumen a complex series of enzymatic reactions that enable degradation of incoming cargo material. Our prior work has shown that the lysosome is greatly expanded and qualitatively different in PDA cells compared to normal tissue. PDA tumors are effectively “addicted” to enhanced catabolic activity as blocking lysosome function specifically inhibits in vitro and in vivo growth of PDA cell lines and tumor xenografts with minimal effects on normal cells. How key changes in lysosome composition and content contribute to the aggressive nature of PDA remains an open question. We have optimized methodologies to isolate and purify lysosomes from normal human pancreatic epithelial cells and several established patient-derived PDA cancer cell lines, using affinity-based capture techniques that isolate 50-80% intact lysosomes free of cytoplasm and other contaminating organelles. By systematically implementing lysosome purification from normal, primary, and metastatic PDA tumors combined with mass spectrometry-based proteomics, we have identified both resident and substrate proteins that are uniquely associated with PDA lysosomes. Several cancer-specific lysosomal membrane proteins emerged from this analysis that may endow cancer lysosomes with enhanced functionality, including rapid membrane repair in the face of sustained mechanical and chemical insults. Similarly, we find that PDA lysosomes degrade select cellular proteins to enable dynamic remodeling of the cellular proteome in a manner that favors tumor growth and progression. Collectively, our data provide strong evidence in support of the lysosome as a central mediator of cellular adaptation to stress and promoter of tumorigenesis. Citation Format: Rushika M Perera. New players and unique features of cancer lysosomes [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 I22.
Comment on Jakubowicz et al. Reduction in Glycated Hemoglobin and Daily Insulin Dose Alongside Circadian Clock Upregulation in Patients With Type 2 Diabetes Consuming a Three-Meal Diet: A Randomized Clinical Trial. Diabetes Care 2019;42:2171–2180
Authors: Ivan E. Saraiva
Journal: Diabetes Care (2019)

I read with great interest the clinical trial report by Jakubowicz et al. recently published in Diabetes Care (1). The authors demonstrated a large benefit in a group of patients with type 2 diabetes just by manipulating the frequency and distribution of meals throughout the day. The interesting findings were explained as suggestive of clock gene expression correction by means of shifting carbohydrate intake to the morning time. They performed mRNA expression assays to support this hypothesis.

I want to point to an alternative explanation that, although inextricably associated with the protocol of the study, may be …
Leading the Call for Reform of Medical Device Safety Surveillance
Authors: James W. Salazar, Rita F. Redberg
Journal: JAMA Internal Medicine (2019)

Jay Sengupta, MD; Katelyn Storey, BA; Susan Casey, RN; Lena Trager, BA; Melissa Buescher, MPH; Mark Horning, RN; Charles Gornick, MD; Raed Abdelhadi, MD; Chuen Tang, MD; Suzanne Brill, RN; Laura Ashbach, RN; Robert G. Hauser, MD
ALDEFLUOR-positive populations in breast cell lines: evidence for cancer stem cells properties and gene expression profile (GEP)
Authors: Emmanuelle Charafe-jauffret, Christophe Ginestier, Min Hee Hur, Florence Monville, Nathalie Cervera, Pascal Finetti, Julie Dutcher, Julien Wicinsky, Marthy Brown, Luc Xerri, Francois Bertucci, Daniel Birnbaum, Gabriela Dontu, Max Wicha
Journal: Cancer Research (2007)

1307  Evidence for the cancer stem cell concept has emerged recently in many fields of cancerous pathology. As in leukemia, myeloma, melanoma, brain, colon and prostate malignancies, it was shown that breast tumors derive from and are driven by a small population of cancer stem cells. The extension of this concept to different kinds of tumors suggests that some same markers will identify cancer stem cells in different malignancies. One approach to find these “universal” markers is to rely on conserved stem or progenitor cells functions. Aldehyde dehydrogenase1 (ALDH1), a detoxifying enzyme implicated in retinoic acid metabolism, fits this description is enzymatic activity has been associated with the identification of cancer stem cells in multiple myeloma and leukemia. Here, we have aimed at characterizing in breast cell lines, a population of cells sorted by flow cytometry using an enzymatic fluorescent assay, ALDEFLUOR, based on ALDH activity.  First, we showed that the presence of ALDEFLUOR-positive cells was more frequent and higher in the 15 basal-like breast cell lines than in the 13 luminal ones in which only 5 cell lines contained ALDEFLUOR-positive cells. We had previously established the subtype of the 29 cell lines using DNA microarrays.  Second, we demonstrated the ability of the ALDEFLUOR-positive to form much more spheres in suspension cultures compared to the negative populations in the same cell lines.  Third, we proved the tumorigenic properties of the ALDEFLUOR-positive population compared to ALDEFLUOR-negative and whole cell line, by injecting orthotopically limiting dilution of each population in cleared and humanized NOD/SCID mice fat pads. These in vitro and in vivo analyses confirmed the cancer stem cell properties of the ALDEFLUOR-positive population.Finally, we profiled the ALDEFLUOR-positive and negative cells from ten cell lines with Affymetrix U133 Plus 2.0 human oligonucleotide microarrays. We compared the gene expression profile (GEP) of the ALDEFLUOR-positive population with previously established stem cell signatures, and determined the molecular subtype by comparison to the ALDELFUOR-negative or the whole cell line population. The GEP of ALDEFLUOR-positive cells will help discover other potential cancer stem cell markers and develop the field of new targeted therapies for breast cancers.
Нутритивный статус больных хроническими воспалительными заболеваниями кишечника и методы его оценки
Authors: Yu.M. Stepanov, M.V. Titova, M.V. Stoikevich
Journal: GASTROENTEROLOGY (2019)

Хронические воспалительные заболевания кишечника, а именно неспецифический язвенный колит и болезнь Крона, остаются одной из наиболее сложных и актуальных проблем гастроэнтерологии и колопроктологии. Широкая распространенность хронических воспалительных заболеваний кишечника и постоянный рост заболеваемости побуж­дают ученых всего мира к более глубокому изучению клинических особенностей и механизмов развития системных поражений у больных неспецифическим язвенным колитом и болезнью Крона, разработке новых схем диагностики и лечения таких больных. Проблемой является недостаточное внимание врачей к выявлению нарушений нутритивного статуса у данной категории пациентов. Одной из причин этого является отсутствие единых стандартов оценки нутритивного статуса и риска его нарушения, что снижает возможности анализа, обобщения результатов исследований и разработки алгоритмов коррекции этих нарушений. В статье освещены основные методы диагностики нарушений нутритивного статуса. Показаны возможности инструментальных и лабораторных методов исследования. Уделено внимание методам исследования микробиоты кишечника, поскольку известно, что синдром избыточного бактериального роста в тонкой кишке и нарушение микрофлоры в толстой кишке играют важную роль и способствуют прогрессированию мальнутриции. Поиск проводился с применением баз данных PubMed, MedLine, EMBASE.
Anxiety and Depression Prevalence in Children, Adolescents, and Young Adults With Life-Limiting Conditions
Authors: Kyoung-Sae Na
Journal: JAMA Pediatrics (2019)

To the Editor I read the meta-analysis article by Barker et al1 on anxiety and depression among children, adolescents, and young adults with life-limiting conditions (LLCs). Two critical issues affecting the considerably high prevalence of depression in the HIV subgroup were observed.
Abstract 20012: Histone Methylation in Distressed Cardiomyocytes Indicates Clinical Outcome After Autologous Myoblast Cell Sheet Transplantation in Non-ischemic Dilated Cardiomyopathy
Authors: Keitaro Domae, Shigeru Miyagawa, Yasushi Yoshikawa, Hiroki Hata, Shunsuke Saito, Tetsuya Saito, Noriyuki Kashiyama, Emiko Ito, Akima Harada, Yuri Ide, Koichi Toda, Yoshiki Sawa
Journal: Circulation (2017)

Background: We have introduced skeletal myoblast cell sheet (SMBs) transplantation for treating severe heart failure (HF) to maximize the paracrine effects, which enhance the native regenerative pr...
Timers from birth: Early timing abilities exceed limits of the temporal updating system
Authors: Karina Hamamouche
Journal: Behavioral and Brain Sciences (2019)

Abstract Hoerl &amp; McCormack argue that children are incapable of reasoning about time until age 5. However, their dual timing perspective does not address non-symbolic timing, or timing in the absence of symbols/language. Given substantial evidence that infants and children are capable of non-symbolic timing, I argue that infants and children are well-tuned timers prior to age 5.
Applicability of the LIPI score to metastatic microsatellite instability high cancer patients treated with immune checkpoint inhibitors
Authors: P. Vuagnat, E. Auclin, L. Mezquita, J. Adeva Alfonso, M.R. Vidal Tocino, F. Longo Munoz, Y. El Dakdouki, P. Martin Romano, C. Baldini, A. Varga, R. Garcia-Carbonero, B. Besse, C. Massard, A. Hollebecque
Journal: Annals of Oncology (2019)