tbuckley/cabot-search huggingface dataset:
The evolving landscape of predictive biomarkers of response to PARP inhibitors
Authors: Anish Thomas, Junko Murai, Yves Pommier
Journal: Journal of Clinical Investigation (2018)

Poly(ADP-ribose) polymerase inhibitors (PARPis) are DNA-damaging agents that trap PARP-DNA complexes and interfere with DNA replication. Three PARPis — olaparib, niraparib, and rucaparib — were recently approved by the FDA for the treatment of breast and ovarian cancers. These PARPis, along with 2 others (talazoparib and veliparib), are being evaluated for their potential to treat additional malignancies, including prostate cancers. While lack of PARP-1 confers high resistance to PARPis, it has not been established whether or not the levels of PARP-1 directly correlate with tumor response. In this issue of the JCI, Makvandi and coworkers describe an approach to address this question using [18F]FluorThanatrace, an [18F]-labeled PARP-1 inhibitor, for PET. The tracer was taken up by patient tumor tissue and appeared to differentiate levels of PARP-1 expression; however, future studies should be aimed at determining if this tracer can be used to stratify patient response to PARPi therapy.
Theodore Lawless—A Physician-Scientist, Philanthropist, and Champion of the African American Community
Authors: Manthan Patel, Varun Ayyaswami, Arpan V. Prabhu
Journal: JAMA Dermatology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Estimating long-term survival of PD-L1-expressing, previously treated, non-small cell lung cancer patients who received pembrolizumab in KEYNOTE-001 and -010.
Authors: Matthew David Hellmann, Junshui Ma, Edward B. Garon, Rina Hui, Leena Gandhi, Jean-Charles Soria, Keaven M. Anderson, Gregory M. Lubiniecki, Bilal Piperdi, Roy S. Herbst
Journal: Journal of Clinical Oncology (2017)

77 Background: Pembrolizumab showed promising activity in patients with advanced non–small cell lung cancer (NSCLC) in the KEYNOTE-001 study (NCT01295827) and significantly prolonged overall survival (OS) compared with docetaxel in the randomized KEYNOTE-010 study (NCT01905657). Responses to pembrolizumab appear to be remarkably durable, making long-term survival possible in some patients. Typical parametric survival models do not account for the possibility of long-term survival. An alternative, well-established class of statistical models called long-term survival models can be used to directly estimate the percentage of patients achieving long-term survival (&gt;5 years), called “long-term survival rate.” (Berkson J, Gage RP. J Am Stat Assoc. 1952;47:501-515.)(Tsodikov AD et al. J Am Stat Assoc. 2003;98:1063-1078.) Methods: Data from patients with PD-L1–expressing (tumor proportion score ≥1%), previously treated, advanced NSCLC in KEYNOTE-001 and KEYNOTE-010 were used. KEYNOTE-001 data were used to initially estimate the long-term survival rate of pembrolizumab, while KEYNOTE-010 data were used for subsequent independent validation. Point estimates of long-term survival rates with their 95% CIs based on the model described above are reported. Results: Based on the long-term survival model, the estimated long-term survival rate in pembrolizumab-treated population in KEYNOTE-001 (n = 306) is 25.4% (95% CI, 15.2%-33.3%) and the intention-to-treat population who received pembrolizumab in KEYNOTE-010 (n = 690) is 25.3% (95% CI, 8.9%-36.9%). In contrast, the long-term survival rate of docetaxel arm (n = 343) in KEYNOTE-010 is estimated to be 3.2% (95% CI, 0%-17.4%). Conclusions: In 2 independent data sets, it is estimated that 25% of patients with previously treated PD-L1–expressing NSCLC may achieve long-term benefit from pembrolizumab monotherapy. Long-term survival models can provide an early estimate of long-term benefit from pembrolizumab using data with limited follow-up time. Long-term follow-up from these trials will further validate this finding. MDH and JM are co-first authors.
Influence of protein properties and protein modification on biodistribution and tumor uptake of anticancer antibodies, antibody derivatives, and non‐Ig scaffolds
Authors: Frank‐Jan Warnders, Marjolijn N. Lub‐de Hooge, Elisabeth G. E. de Vries, Jos G. W. Kosterink
Journal: Medicinal Research Reviews (2018)

Abstract Newly developed protein drugs that target tumor‐associated antigens are often modified in order to increase their therapeutic effect, tumor exposure, and safety profile. During the development of protein drugs, molecular imaging is increasingly used to provide additional information on their in vivo behavior. As a result, there are increasing numbers of studies that demonstrate the effect of protein modification on whole body distribution and tumor uptake of protein drugs. However, much still remains unclear about how to interpret obtained biodistribution data correctly. Consequently, there is a need for more insight in the correct way of interpreting preclinical and clinical imaging data. Summarizing the knowledge gained to date may facilitate this interpretation. This review therefore provides an overview of specific protein properties and modifications that can affect biodistribution and tumor uptake of anticancer antibodies, antibody fragments, and nonimmunoglobulin scaffolds. Protein properties that are discussed in this review are molecular size, target interaction, FcRn binding, and charge. Protein modifications that are discussed are radiolabeling, fluorescent labeling drug conjugation, glycosylation, humanization, albumin binding, and polyethylene glycolation.
Targeted methylation sequencing of plasma cell-free DNA for cancer detection and classification
Authors: L. Liu, J.M. Toung, A.F. Jassowicz, R. Vijayaraghavan, H. Kang, R. Zhang, K.M. Kruglyak, H.J. Huang, T. Hinoue, H. Shen, N.S. Salathia, D.S. Hong, A. Naing, V. Subbiah, S.A. Piha-Paul, M. Bibikova, G. Granger, B. Barnes, R. Shen, K. Gutekunst, S. Fu, A.M. Tsimberidou, C. Lu, C. Eng, S.L. Moulder, E.S. Kopetz, R.N. Amaria, F. Meric-Bernstam, P.W. Laird, J.-B. Fan, F. Janku
Journal: Annals of Oncology (2018)

BackgroundTargeted methylation sequencing of plasma cell-free DNA (cfDNA) has a potential to expand liquid biopsies to patients with tumors without detectable oncogenic alterations, which can be potentially useful in early diagnosis.Patients and methodsWe developed a comprehensive methylation sequencing assay targeting 9223 CpG sites consistently hypermethylated according to The Cancer Genome Atlas. Next, we carried out a clinical validation of our method using plasma cfDNA samples from 78 patients with advanced colorectal cancer, non-small-cell lung cancer (NSCLC), breast cancer or melanoma and compared results with patients' outcomes.ResultsMedian methylation scores in plasma cfDNA samples from patients on therapy were lower than from patients off therapy (4.74 versus 85.29; P = 0.001). Of 68 plasma samples from patients off therapy, methylation scores detected the presence of cancer in 57 (83.8%), and methylation-based signatures accurately classified the underlying cancer type in 45 (78.9%) of these. Methylation scores were most accurate in detecting colorectal cancer (96.3%), followed by breast cancer (91.7%), melanoma (81.8%) and NSCLC (61.1%), and most accurate in classifying the underlying cancer type in colorectal cancer (88.5%), followed by NSCLC (81.8%), breast cancer (72.7%) and melanoma (55.6%). Low methylation scores versus high were associated with longer survival (10.4 versus 4.4 months, P < 0.001) and longer time-to-treatment failure (2.8 versus 1.6 months, P = 0.016).ConclusionsComprehensive targeted methylation sequencing of 9223 CpG sites in plasma cfDNA from patients with common advanced cancers detects the presence of cancer and underlying cancer type with high accuracy. Methylation scores in plasma cfDNA correspond with treatment outcomes.
Transcripts of immune cell surface proteins from tumor samples to predict patient clinical outcome.
Authors: Aiwu Ruth He, Yuriy Gusev, Krithika Bhuvaneshwar, Coleman Smith, Alexander H Kroemer, Petra Prins
Journal: Journal of Clinical Oncology (2017)

32 Background: Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, and its incidence and mortality are rapidly increasing in the US. Treatments for advanced HCC are limited despite best efforts to develop therapeutics that target the deregulated pathways of HCC. Recent studies reveal a direct causal relationship between cancer and immune dysfunction, whereby tumor cells and their microenvironment can evade immune attack by exploiting various immunoregulatory mechanisms in a process termed cancer immune editing. This study objective is to determine the relationship between immune cell surface protein transcripts from tumor samples and the clinical outcome of pts by performing exploratory analyses of liver cancer data from the cancer genome atlas (TCGA). Methods: We analyzed RNAseq data from a cohort of 75 HCC samples in the TCGA collection. We explored the association of expression of a group of specific markers for infiltrating lymphocytes (several subtypes) with overall survival (OS) and tumor immune infiltrates (IHC data). Results: Among the 75 HCC cases analyzed, 25 pts had Hepatitis C (HCV), 25 had Hepatitis B (HBV), and 25 had HCV and HBV co-infection. Fourteen of the 75 cases were found to express the CD8B isoform. The LOG RANK survival test showed a significant association between CD8B level and OS (ChiSq = 5.2, 1df; p= 0.0222), as did the Cox proportional hazard model for survival. The latter test showed that pts who’s HCC did not express the CD8B were at higher risk of death compared with those who did. Additional immune cell subtype specific transcripts are being tested. Based on analysis of differentially expressed genes between immune cell subtype "Low" and vs. "High" groups, pathways highly relevant to lymphocyte signaling and immune response and infiltration are identified. Conclusions: Immune cell specific transcripts in tumor samples may serve as a predictor of response to treatments that target immune evasion in cancer pts.
Abstract 12714: Aldosterone Activates Raptor to Promote Pulmonary Artery Smooth Muscle Cell Proliferation and Pulmonary Arterial Hypertension
Authors: Thomas E Stephens, Elena Arons, Ying-Yi Zhang, Paula Zaman, Reza Aghamohammadzadeh, Kevin J Polach, Majed Matar, Marcel G Brown, Joseph Loscalzo, Jane A Leopold, Bradley A Maron
Journal: Circulation (2015)

In pulmonary arterial hypertension (PAH), elevated levels of aldosterone (ALDO) induce a vasculopathy that is characterized by dysregulated pulmonary artery smooth muscle cell (PSMC) growth. Upregulation of the mammalian target of rapamycin complex 1 subunit Raptor induces PSMC growth; however, the factors regulating Raptor in PAH are not known. We hypothesized that Raptor activation by ALDO induces PSMC proliferation, hypertrophic vascular remodeling, and PAH. To test this hypothesis, PSMCs were exposed to vehicle (V) control or ALDO (10 -7 mol/l) for 1 h. Compared to V-treated cells, ALDO increased expression of P-Raptor(Ser792) and the Raptor target P-p70S6K(Thr389) by 68% (P&lt;0.01) and 50% (P&lt;0.01), respectively, without affecting total Raptor/p70S6K levels. Raptor upregulation in ALDO-treated cells also increased PSMC proliferation by 19% (P&lt;0.01), assessed by BrdU incorporation. To explore the relevance of ALDO-Raptor signaling in vivo , we studied the monocrotaline (MCT) model of PAH, which is characterized by hyperALDO. In a prevention protocol, MCT-PAH rats were treated with spironolactone (SP)(25 mg/kg/d) in the drinking water to inhibit ALDO and/or intravenous Staramine-mPEG labeled with Raptor-siRNA (2 mg/kg dose x4)(si-Raptor). Anti-Raptor and anti-α-SM actin immunohistochemistry showed that compared to controls (N=4), Raptor expression and vessel thickness was increased in MCT-PAH rats (N=5) by 87% (P&lt;0.01) and 5.8-fold (P&lt;0.01), respectively, and pulmonary artery systolic pressure (PASP) was increased significantly (25 ± 4 vs. 77 ± 12 mmHg, P&lt;0.01) as assessed by catheterization. Compared to MCT-PAH, MCT-si-Raptor (N=5) decreased Raptor levels by 31% (P&lt;0.05), arteriole thickness by 41% (P&lt;0.05), and PASP (77 ± 12 vs. 46 ± 5 mmHg, P&lt;0.05) without affecting central blood pressure significantly. A further benefit was observed in MCT-si-Raptor+SP rats (N=5) for arterial thickness (-57%, P&lt;0.01) and PASP (46 ± 5 vs. 39 ± 5 mmHg, P&lt;0.05) compared to MCT-si-Raptor. Taken together, Raptor activation by ALDO induces PSMC proliferation in vitro to promote PAH in vivo . Identifying ALDO-Raptor signaling as a pathobiological mechanism underlying pulmonary vascular remodeling may have novel therapeutic implications for PAH patients.
An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression
Authors: Yufeng Qin, John D. Roberts, Sara A. Grimm, Fred B. Lih, Leesa J. Deterding, Ruifang Li, Kaliopi Chrysovergis, Paul A. Wade
Journal: Genome biology (2018)

The gut microbiome, a key constituent of the colonic environment, has been implicated as an important modulator of human health. The eukaryotic epigenome is postulated to respond to environmental stimuli through alterations in chromatin features and, ultimately, gene expression. How the host mediates epigenomic responses to gut microbiota is an emerging area of interest. Here, we profile the gut microbiome and chromatin characteristics in colon epithelium from mice fed either an obesogenic or control diet, followed by an analysis of the resultant changes in gene expression. The obesogenic diet shapes the microbiome prior to the development of obesity, leading to altered bacterial metabolite production which predisposes the host to obesity. This microbiota–diet interaction leads to changes in histone modification at active enhancers that are enriched for binding sites for signal responsive transcription factors. These alterations of histone methylation and acetylation are associated with signaling pathways integral to the development of colon cancer. The transplantation of obesogenic diet-conditioned microbiota into germ free mice, combined with an obesogenic diet, recapitulates the features of the long-term diet regimen. The diet/microbiome-dependent changes are reflected in both the composition of the recipient animals' microbiome as well as in the set of transcription factor motifs identified at diet-influenced enhancers. These findings suggest that the gut microbiome, under specific dietary exposures, stimulates a reprogramming of the enhancer landscape in the colon, with downstream effects on transcription factors. These chromatin changes may be associated with those seen during colon cancer development.
A cluster of two human cases of tick-borne encephalitis (TBE) transmitted by unpasteurised goat milk and cheese in Germany, May 2016
Authors: SO Brockmann, R Oehme, T Buckenmaier, M Beer, A Jeffery-Smith, M Spannenkrebs, S Haag-Milz, C Wagner-Wiening, C Schlegel, J Fritz, S Zange, M Bestehorn, A Lindau, D Hoffmann, S Tiberi, U Mackenstedt, G Dobler
Journal: Eurosurveillance (2018)

In May 2016, two cases of tick-borne encephalitis (TBE) were confirmed by serology (positive IgM and IgG antibodies against TBE virus (TBEV) in serum), with a possible link to raw milk and cheese from a goat farm in a region in Baden-Württemberg, Germany not previously known as TBE-endemic. The outbreak investigation identified 32 consumers of goat dairy products (29 consumers, one farm employee, two owners) of whom none had IgM antibodies against TBEV 3–8 weeks after consumption. Of the 27 notified TBE cases in the State, none reported consumption of raw goat milk or cheese from the suspected farm. Five of 22 cheese samples from 18 different batches were RT-qPCR-positive for TBEV -genome, and two of the five samples were confirmed by virus isolation, indicating viability of TBEV in the cheese. Nine of the 45 goats had neutralising TBEV antibodies, two of them with a high titre indicating recent infection. One of 412 Ixodes ricinus was RT-qPCR-positive, and sequencing of the E gene from nucleic acid extracted from the tick confirmed TBEV. Phylogenetic analyses of tick and cheese isolates showed 100% amino acid homology in the E gene and a close relation to TBEV strains from Switzerland and Austria.
Cost-effectiveness of Continuous Glucose Monitoring for Adults With Type 1 Diabetes Compared With Self-Monitoring of Blood Glucose: The DIAMOND Randomized Trial
Authors: Wen Wan, M. Reza Skandari, Alexa Minc, Aviva G. Nathan, Aaron Winn, Parmida Zarei, Michael O’Grady, Elbert S. Huang
Journal: Diabetes Care (2018)

This study evaluated the societal cost-effectiveness of continuous glucose monitoring (CGM) in patients with type 1 diabetes (T1D) using multiple insulin injections.
Abstract 18677: Correlation of Cytokine Levels After Cardiac Arrest With Clinical Outcomes and Brain Regional Saturation of Oxygen (rSO2)
Authors: Niraj Sinha, Vikram Chabra, Shreyas T Ravishankar, Robert T Nguyen, Brian A Suarez, Caitlin O’Neill, Dmitri Gnatenko, Henry C Thode, Sam Parnia
Journal: Circulation (2016)

Introduction: The Post Cardiac Arrest syndrome (PCAS) cytokine storm is associated with mortality and neurological deficits. The magnitude of PCAS cytokine storm reflects the ischemic burden during...
What Hippocrates called ‘Man’s best medicine’: walking is humanity’s path to a better world
Authors: Emmanuel Stamatakis, Mark Hamer, Marie H Murphy
Journal: British Journal of Sports Medicine (2018)

Whether it is a stroll on a sunny day, walking to and from work, or walking down to the local shops, the act of putting one foot in front of the other in a rhythmic manner is as much human nature as breathing, thinking, and loving.This Walking and Health special issue of BJSM celebrates the 21 st anniversary of Morris and Hardman's seminal Walking to Health review published in 1997 1 .This Special Issue is an opportunity to celebrate three decades of exciting multidisciplinary research on this seemingly mundane activity -walking.The member society lead on this Special Issue, the International Society of Physical Activity and Health (ISPAH), has been instrumental to the growth of this area of research and global advocacy for physical activity that has culminated in the development of the WHO Global Physical Activity Action Plan 2 .The forthcoming 7 th ISPAH Congress (October 15 th -17 th 2018, London) -the first ISPAH conference in the UK --is a wonderful opportunity
Approach for Achieving Effective Care for High-Need Patients
Authors: Jose F. Figueroa, Ashish K. Jha
Journal: JAMA Internal Medicine (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase
Authors: Jianbiao Zhou, Sabrina Hui-Min Toh, Zit-Liang Chan, Jessie Yiying Quah, Jing-Yuan Chooi, Tuan Zea Tan, Phyllis S. Y. Chong, Qi Zeng, Wee-Joo Chng
Journal: Journal of Hematology & Oncology (2018)

Protein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor. In this study, we performed whole-genome lentiviral shRNA library screening to discover synthetic lethal target to PRL-3 in AML. We used specific small molecule inhibitors to validate the synthetic lethality in human PRL-3 high vs PRL-3 low human AML cell lines and primary bone marrow cells from AML patients. AML mouse xenograft model was used to examine the in vivo synergism. The list of genes depleted in TF1-hPRL3 cells was particularly enriched for members involved in WNT/β-catenin pathway and AKT/mTOR signaling. These findings prompted us to explore the impact of AKT/mTOR signaling inhibition in PRL-3 high AML cells in combination with WNT/β-catenin inhibitor. VS-5584, a novel, highly selective dual PI3K/mTOR inhibitor, and ICG-001, a WNT inhibitor, were used as a combination therapy. A synthetic lethal interaction between mTOR/AKT pathway inhibition and WNT/β-catenin was validated by a variety of cellular assays. Notably, we found that treatment with these two drugs significantly reduced leukemic burden and prolonged survival of mice transplanted with human PRL-3 high AML cells, but not with PRL-3 low AML cells. In summary, our results support the existence of cooperative signaling networks between AKT/mTOR and WNT/β-catenin pathways in PRL-3 high AML cells. Simultaneous inhibition of these two pathways could achieve robust clinical efficacy for this subtype of AML patient with high PRL-3 expression and warrant further clinical investigation.