tbuckley/cabot-search huggingface dataset:
Benefits of functional assays in personalized cancer medicine: more than just a proof-of-concept
Authors: Christophe Bounaix Morand du Puch, Mathieu Vanderstraete, Stéphanie Giraud, Christophe Lautrette, Niki Christou, Muriel Mathonnet
Journal: Theranostics (2021)

As complex and heterogeneous diseases, cancers require a more tailored therapeutic management than most pathologies. Recent advances in anticancer drug development, including the immuno-oncology revolution, have been too often plagued by unsatisfying patient response rates and survivals. In reaction to this, cancer care has fully transitioned to the "personalized medicine" concept. Numerous tools are now available tools to better adapt treatments to the profile of each patient. They encompass a large array of diagnostic assays, based on biomarkers relevant to targetable molecular pathways. As a subfamily of such so-called companion diagnostics, chemosensitivity and resistance assays represent an attractive, yet insufficiently understood, approach to individualize treatments. They rely on the assessment of a composite biomarker, the ex vivo functional response of cancer cells to drugs, to predict a patient's outcome. Systemic treatments, such as chemotherapies, as well as targeted treatments, whose efficacy cannot be fully predicted yet by other diagnostic tests, may be assessed through these means. The results can provide helpful information to assist clinicians in their decision-making process. We explore here the most advanced functional assays across oncology indications, with an emphasis on tests already displaying a convincing clinical demonstration. We then recapitulate the main technical obstacles faced by researchers and clinicians to produce more accurate, and thus more predictive, models and the recent advances that have been developed to circumvent them. Finally, we summarize the regulatory and quality frameworks surrounding functional assays to ensure their safe and performant clinical implementation. Functional assays are valuable in vitro diagnostic tools that already stand beyond the "proof-of-concept" stage. Clinical studies show they have a major role to play by themselves but also in conjunction with molecular diagnostics. They now need a final lift to fully integrate the common armament used against cancers, and thus make their way into the clinical routine.
Cardiometabolic Benefits of Intermittent Fasting
Authors: Krista A. Varady, Sofia Cienfuegos, Mark Ezpeleta, Kelsey Gabel
Journal: Annual Review of Nutrition (2021)

This review aims to summarize the effects of intermittent fasting on markers of cardiometabolic health in humans. All forms of fasting reviewed here—alternate-day fasting (ADF), the 5:2 diet, and time-restricted eating (TRE)—produced mild to moderate weight loss (1–8% from baseline) and consistent reductions in energy intake (10–30% from baseline). These regimens may benefit cardiometabolic health by decreasing blood pressure, insulin resistance, and oxidative stress. Low-density lipoprotein cholesterol and triglyceride levels are also lowered, but findings are variable. Other health benefits, such as improved appetite regulation and favorable changes in the diversity of the gut microbiome, have also been demonstrated, but evidence for these effects is limited. Intermittent fasting is generally safe and does not result in energy level disturbances or increased disordered eating behaviors. In summary, intermittent fasting is a safe diet therapy that can produce clinically significant weight loss (&gt;5%) and improve several markers of metabolic health in individuals with obesity.
P57.11 The Role of Serum Proteomic Signature in Predicting Survival by PD-L1 Status in Patients With Non-Small Cell Lung Cancer Receiving Immunotherapy
Authors: L. Kim, E. Yu, A. Lee, C.M. Jung, J. Park, S. Fridland, M. Nam, Y.K. Chae
Journal: Journal of Thoracic Oncology (2021)
Electrolyte-free gel immersion endoscopic submucosal dissection of gastric lesions
Authors: Tsevelnorov Khurelbaatar, Yoshimasa Miura, Tomonori Yano, Chihiro Iwashita, Haruo Takahashi, Alan Kawarai Lefor, Hiroyuki Osawa, Hironori Yamamoto
Journal: Endoscopy (2021)

Gel immersion endoscopy was developed to secure the visual field during ongoing gastrointestinal bleeding using the viscous rehydration supplement "OS-1 jelly" (Otsuka Pharmaceutical Factory, Tokushima, Japan) [1]. However, this includes electrolytes and needs replacement with gas or pure water before cauterization using monopolar devices to avoid electrical dispersion [1]. A new, dedicated electrolyte-free gel (Viscoclear; Otsuka Pharmaceutical Factory) allows effective coagulation within the gel [2], enabling usage during endoscopic submucosal dissection (ESD).
Bortezomib (PS-341) downregulates the androgen receptor (AR) and induces growth arrest and apoptosis in human prostate cancer cell lines
Authors: Vasily J. Assikis, Yanjuan He, Shin-Yong Sun
Journal: Cancer Research (2005)

2287  Proteasome inhibitor bortezomib (PS-341) has been shown to confer antitumor activity in a number of malignancies including prostate cancer. Its primary mechanism of action is postulated to be mitigated through the inhibition of the nuclear translocation/activation of the nuclear factor kB (NF-kB). However, additional mechanisms may account for the drug’s potent cytotoxic activity. In this report we set out to investigate possible additional mechanisms that could account for bortezomib’s activity in prostate cancer. Bortezomib was very effective in inhibiting the growth of both PC-3 and LNCaP human prostate cancer cell lines with IC50s (approximately 15 to 25 nM) that are clinically relevant. When these cells were exposed to bortezomib, cells rapidly underwent G2/M arrest at 24 h followed by a dramatic increase of apoptotic cell death at 48 h, indicating that bortezomib inhibited cell growth through induction of growth arrest and apoptosis. In conjunction with growth arrest and apoptosis, we found that bortezomib inhibited the levels of phosphorylated Akt in these cell lines, suggesting that suppression of Akt signaling pathway may play a role in mediating bortezomib-induced growth arrest and apoptosis. In addition, we found that bortezomib reduced the levels of the androgen receptor (AR) and its downstream target PSA in a dose dependent fashion in the AR-expressing LNCaP cell line. Down regulation of the AR may be central to the drug’s activity in advanced prostate cancer since functional AR is reported in the vast majority of clinical specimens from patients with androgen independent prostate cancer. Therefore, we are currently investigating how bortezomib down-regulates AR expression. Furthermore, we are interested in probing the potential synergy of bortezomib with non-cytotoxic steroids as it relates to the inhibition of redundant signaling pathways that allow survival and proliferation in androgen independent prostate cancer.
Predicting Survival in Repaired Tetralogy of Fallot
Authors: Sarah Ghonim, Michael A. Gatzoulis, Sabine Ernst, Wei Li, James C. Moon, Gillian C. Smith, Ee Ling Heng, Jennifer Keegan, Siew Yen Ho, Karen P. McCarthy, Darryl F. Shore, Anselm Uebing, Aleksander Kempny, Francisco Alpendurada, Gerhard P. Diller, Konstantinos Dimopoulos, Dudley J. Pennell, Sonya V. Babu-Narayan
Journal: JACC. Cardiovascular imaging (2021)

This study sought to identify patients with repaired tetralogy of Fallot (rTOF) at high risk of death and malignant ventricular arrhythmia (VA).To date there is no robust risk stratification scheme to predict outcomes in adults with rTOF.Consecutive patients were prospectively recruited for late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) to define right and left ventricular (RV, LV) fibrosis in addition to proven risk markers.The primary endpoint was all-cause mortality. Of the 550 patients (median age 32 years, 56% male), 27 died (mean follow-up 6.4 ± 5.8; total 3,512 years). Mortality was independently predicted by RVLGE extent, presence of LVLGE, RV ejection fraction ≤47%, LV ejection fraction ≤55%, B-type natriuretic peptide ≥127 ng/L, peak exercise oxygen uptake (V02) ≤17 mL/kg/min, prior sustained atrial arrhythmia, and age ≥50 years. The weighted scores for each of the preceding independent predictors differentiated a high-risk subgroup of patients with a 4.4%, annual risk of mortality (area under the curve [AUC]: 0.87; P < 0.001). The secondary endpoint (VA), a composite of life-threatening sustained ventricular tachycardia/resuscitated ventricular fibrillation/sudden cardiac death occurred in 29. Weighted scores that included several predictors of mortality and RV outflow tract akinetic length ≥55 mm and RV systolic pressure ≥47 mm Hg identified high-risk patients with a 3.7% annual risk of VA (AUC: 0.79; P < 0.001) RVLGE was heavily weighted in both risk scores caused by its strong relative prognostic value.We present a score integrating multiple appropriately weighted risk factors to identify the subgroup of patients with rTOF who are at high annual risk of death who may benefit from targeted therapy.
Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan
Authors: Amrendra Mishra, Hamed Mirzaei, Novella Guidi, Manlio Vinciguerra, Alice Mouton, Marina Linardic, Francesca Rappa, Rosario Barone, Gerardo Navarrete, Min Wei, Sebastian Brandhorst, Stefano Di Biase, Todd E. Morgan, S. Ram Kumar, Peter S. Conti, Matteo Pellegrini, Michel Bernier, Rafael de Cabo, Valter D. Longo
Journal: Nature Metabolism (2021)
P27.06 Multiscale NSCLC Tumor Growth Knowledge-Based Model Reproduces Tumor-Non-Progression under Gefitinib
Authors: A. L'Hostis, J. Palgen, N. Ceres, E. Peyronnet, A. Perrillat-Mercerot, A. Schneider, M. Margreiter, E. Jacob, R. Kahoul, B. Illigens, M. Hommel, J. Boissel, J. Bosley, C. Monteiro
Journal: Journal of Thoracic Oncology (2021)
Racial and Ethnic Disparities in Rates of Invasive Secondary Breast Cancer Among Women With Ductal Carcinoma In Situ in Hawaiʻi
Authors: Linda Lindström
Journal: JAMA Network Open (2021)

Kekoa Taparra, MD, PhD; Jami Fukui, MD; Jeffrey Killeen, MD; Kenneth Sumida, MD; Lenora W. M. Loo, PhD; Brenda Y. Hernandez, PhD, MPH
DDX3X loss is an adverse prognostic marker in diffuse large B-cell lymphoma and is associated with chemoresistance in aggressive non-Hodgkin lymphoma subtypes
Authors: Atish Kizhakeyil, Nurmahirah Binte Mohammed Zaini, Zhi Sheng Poh, Brandon Han Siang Wong, Xinpeng Loh, Aik Seng Ng, Zun Siong Low, Praseetha Prasannan, Chun Gong, Michelle Guet Khim Tan, Chandramouli Nagarajan, Dachuan Huang, Pang Wan Lu, Jing Quan Lim, Sharon Barrans, Choon Kiat Ong, Soon Thye Lim, Wee Joo Chng, George Follows, Daniel J. Hodson, Ming Qing Du, Yeow Tee Goh, Suat Hoon Tan, Nicholas Francis Grigoropoulos, Navin Kumar Verma
Journal: Molecular Cancer (2021)
Modeling the Recommended Age for Initiating Coronary Artery Calcium Testing Among At-Risk Young Adults
Authors: Omar Dzaye, Alexander C. Razavi, Zeina A. Dardari, Leslee J. Shaw, Daniel S. Berman, Matthew J. Budoff, Michael D. Miedema, Khurram Nasir, Alan Rozanski, John A. Rumberger, Carl E. Orringer, Sidney C. Smith, Ron Blankstein, Seamus P. Whelton, Martin Bødtker Mortensen, Michael J. Blaha
Journal: Journal of the American College of Cardiology (2021)
Intra-patient stability of tumor mutational burden from tissue biopsies at different time points in advanced cancers
Authors: Timothy V. Pham, Aaron M. Goodman, Smruthy Sivakumar, Garrett Frampton, Razelle Kurzrock
Journal: Genome Medicine (2021)

Abstract Background Tumor mutational burden (TMB) may be a predictive biomarker of immune checkpoint inhibitor (ICI) responsiveness. Genomic landscape heterogeneity is a well-established cancer feature. Molecular characteristics may differ even within the same tumor specimen and undoubtedly evolve with time. However, the degree to which TMB differs between tumor biopsies within the same patient has not been established. Methods We curated data on 202 patients enrolled in the PREDICT study (NCT02478931), seen at the University of California San Diego (UCSD), who had 404 tissue biopsies for TMB (two per patient, mean of 722 days between biopsies) to assess difference in TMB before and after treatment in a pan-cancer cohort. We also performed an orthogonal analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database to examine difference in TMB between first and last biopsies. Results The mean (95% CI) TMB difference between samples was 0.583 [− 0.900–2.064] ( p = 0.15). Pearson correlation showed a flat line for time elapsed between biopsies versus TMB change indicating no correlation ( R 2 = 0.0001; p = 0.8778). However, in 55 patients who received ICIs, there was an increase in TMB (before versus after mean mutations/megabase [range] 12.50 [range, 0.00–98.31] versus 14.14 [range, 0.00–100.0], p = 0.025). Analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database also indicated largely stable TMB patterns; TMB increases were only observed in specific tumors (e.g., breast, colorectal, glioma) within certain time intervals. Conclusions Overall, our results suggest that tissue TMB remains stable with time, though specific therapies such as immunotherapy may correlate with an increase in TMB. Trial registration NCT02478931 , registered June 23, 2015.
Human resident memory T cells exit the skin and mediate systemic Th2-driven inflammation
Authors: Johanna Strobl, Laura Marie Gail, Lisa Kleissl, Ram Vinay Pandey, Valerie Smejkal, Julian Huber, Viktoria Puxkandl, Luisa Unterluggauer, Ruth Dingelmaier-Hovorka, Denise Atzmüller, Thomas Krausgruber, Christoph Bock, Philipp Wohlfarth, Werner Rabitsch, Georg Stary
Journal: The Journal of Experimental Medicine (2021)

Emigration of tissue-resident memory T cells (TRMs) was recently introduced in mouse models and may drive systemic inflammation. Skin TRMs of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) can coexist beside donor T cells, offering a unique human model system to study T cell migration. By genotyping, mathematical modeling, single-cell transcriptomics, and functional analysis of patient blood and skin T cells, we detected a small consistent population of circulating skin-derived T cells with a TRM phenotype (cTRMs) in the blood and unveil their skin origin and striking resemblance to skin TRMs. Blood from patients with active graft-versus-host disease (GVHD) contains elevated numbers of host cTRMs producing pro-inflammatory Th2/Th17 cytokines and mediating keratinocyte damage. Expression of gut-homing receptors and the occurrence of cTRMs in gastrointestinal GVHD lesions emphasize their potential to reseed and propagate inflammation in distant organs. Collectively, we describe a distinct circulating T cell population mirroring skin inflammation, which could serve as a biomarker or therapeutic target in GVHD.
Spinal Cord Neuronal Network Formation in a 3D Printed Reinforced Matrix—A Model System to Study Disease Mechanisms (Adv. Healthcare Mater. 19/2021)
Authors: Natalie Fischhaber, Jessica Faber, Ezgi Bakirci, Paul D. Dalton, Silvia Budday, Carmen Villmann, Natascha Schaefer
Journal: Advanced Healthcare Materials (2021)

In article number 2100830, Natascha Schaefer and co-workers show an immunocytochemical z-stack of a two week old three dimensional primary spinal cord composit.Proteins marked are VGAT (cyan), GlyR (magenta), and Nuclei (DAPI).The MEW-scaffold shows an autofluorescence in the DAPI-channel.
Abstract 16173: NFTAc1 is a Novel Atrial Fibrillation Susceptibility Gene
Authors: Natalia S Torres, Meganne Ferrel, Chuanchau J Jou, Cammon B Arrington, Neil E Bowles, Derek Lundahl, Alexandra Acuna, Karishma Shah, Scott Cho, Christopher Kauffman, Mark Yandell, Martin Tristani-Firouzi
Journal: Circulation (2019)

Atrial fibrillation (AF) is a common cardiac arrhythmia with a strong component of heritability. Genome-wide association and family studies have identified ion channel genes and transcription facto...
OA15.01 Mobocertinib in EGFR Exon 20 Insertion–Positive Metastatic NSCLC Patients With Disease Control on Prior EGFR TKI Therapy
Authors: A. Spira, S. Ramalingam, J. Neal, Z. Piotrowska, T. Mekhail, A. Tsao, R. Gentzler, G. Riely, L. Bazhenova, S. Gadgeel, D. Nguyen, M. Johnson, S. Vincent, S. Jin, C. Griffin, V. Bunn, J. Lin, E. Churchill, M. Mehta, P. Janne
Journal: Journal of Thoracic Oncology (2021)
Quantifying and Benchmarking Disparities in COVID-19 Vaccination Rates by Race and Ethnicity
Authors: Marissa B. Reitsma, Jeremy D. Goldhaber-Fiebert, Joshua A. Salomon
Journal: JAMA Network Open (2021)

This decision analytical model quantifies disparities in uptake of COVID-19 vaccination by race and ethnicity and models alternative scenarios of persistent differential uptake and reduced barriers to access.
MA11.02 Targeting HER2 Exon 20–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor, Mobocertinib
Authors: H. Han, S. Li, T. Chen, M. Fitzgerald, S. Liu, C. Peng, K. Tang, S. Cao, J. Chouitar, J. Wu, D. Peng, J. Deng, Z. Gao, T. Baker, F. Li, H. Zhang, Y. Pan, H. Ding, H. Hu, V. Pyon, C. Thakurdin, E. Papadopoulos, S. Tang, F. Gonzalvez, H. Chen, V. Rivera, R. Brake, S. Vincent, K. Wong
Journal: Journal of Thoracic Oncology (2021)
Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion
Authors: Matthew Jensen, Anastasia Tyryshkina, Lucilla Pizzo, Corrine Smolen, Maitreya Das, Emily Huber, Arjun Krishnan, Santhosh Girirajan
Journal: Genome Medicine (2021)

Abstract Background Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in &gt; 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional “second-hit” variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. Methods We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and “second-hit” variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. Results We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1 , ANK3 , and MEF2 . Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of “second-hit” variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1 , gene expression was synergistically altered by both the deletion and inherited “second-hits” in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying “second-hits” and genes with transcriptome alterations in deletion carriers. Conclusions Our results suggest a potential mechanism for how “second-hit” variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.
MA01.07 Prognostic Value of STK11 &amp; KRAS Mutations and irAE Incidence in Response to Immunotherapy in Hispanics: A Multicenter Analysis
Authors: F. Basher, L. Raez, D. Saravia, E. Rodriguez, R. Uba, A. Arora, J. Ocejo, K. Khan, K. Meiyappan, K. Dvir, G. Galarza Fortuna, A. North, K. Dumais, H. Powery, P. Izquierdo, G. De Lima Lopes
Journal: Journal of Thoracic Oncology (2021)
OA07.01 Signatures of Plasticity and Immunosuppression in a Single-Cell Atlas of Human Small Cell Lung Cancer
Authors: J. Chan, A. Quintanal-Villalonga, V. Gao, Y. Xie, V. Allaj, O. Chaudhary, I. Masilionis, J. Egger, A. Chow, T. Walle, M. Ciampricotti, M. Offin, V. Lai, M. Bott, D. Jones, T. Hollmann, T. Nawy, L. Mazutis, T. Sen, D. Pe'Er, C. Rudin
Journal: Journal of Thoracic Oncology (2021)
Covid-19: Antibody levels fall after second Pfizer dose, but protection against severe disease remains, studies indicate
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Covid-19: Antibody levels fall after second Pfizer dose, but protection against severe disease remains, studies indicate Elisabeth MahaseSix months after the second dose of the Pfizer-BioNTech covid-19 vaccine, antibody concentrations in healthcare workers had decreased substantially, especially among older men and immunosuppressed people, a study has found.
OA13.04 Chromosomal Rearrangements and Antigen Presentation as Predictors of Survival in Mesothelioma Treated With Immune Checkpoint Inhibitors
Authors: F. Kosari, M. Disselhorst, J. Yin, T. Peikert, J. Udell, S. Johnson, J. Smadbeck, S. Murphy, A. Mccune, G. Karagouga, A. Desai, J. Schaefer Klein, M. Borad, J. Cheville, G. Vasmatzis, P. Baas, A. Mansfield
Journal: Journal of Thoracic Oncology (2021)
Abstract 18802: Transcriptome Profiles of Chronically Closed or Cycling Aortic Valve Leaflets are Highly Similar Compared to Chronically Open Valves: Distention Drives Leaflet Homeostasis
Authors: Katsuhide Maeda, Xiaoyuan Ma, Frank Hanley, R. Kirk Riemer
Journal: Circulation (2015)

Introduction: Throughout the valve cycle mechanical forces of multiple types and intensities are exerted on the leaflets, sinus and annulus. The mechanisms through which these forces regulate the homeostatic maintenance of valve leaflet architecture are still poorly understood. Ventricular mechanical support with a continuous flow device results in chronic closure of the outflow valve. Whether chronic valve closure affects valve leaflet homeostasis is a significant but unsettled clinical concern. Hypothesis: We asked if chronic closure of the aortic valve (AV) impairs leaflet homeostasis by comparing the transcriptome profiles of AV cultured under different mechanical force conditions: Normally cycling (Flow); Not cycling but open (Static); or Not cycling but closed (Static-Closed, SC). Methods: Ex vivo culture of native rat aortic valves, (8 valves per bioreactor, 4 valves per condition) was conducted in a flow bioreactor for seven days at 37C in endothelial cell culture media under conditions approximating the normal stroke volume of the rat heart. In each of 4 independent experiments, flow-induced valve cycling (Flow) was compared with either Static or SC condition in paired groups. After culture, leaflets were dissected from 3 valves/condition and pooled, mRNA was extracted and expression was evaluated using whole genome microarrays. Results: Statistical-based unsupervised hierarchical clustering analysis of the leaflet transcriptome profiles revealed only two distinct patterns of leaflet gene expression between the three groups of AV. Flow and SC groups had nearly identical profiles whereas the Static valve group was distinctly different (p&lt;0.05). Conclusions: These results reveal that the stretching of valve leaflets by a filling volume inducing full coaptation is apparently sufficient to largely preserve their architecture and phenotypic gene expression in the seven day culture period tested. In contrast, the absence of valve closure produces a markedly different pattern of gene expression. Therefore, the absence of flow through the closed AV valve does not appear to be inherently destructive compared with conditions in which the valve remains open.