tbuckley/cabot-search huggingface dataset:
Personal Mutanomes Meet Modern Oncology Drug Discovery and Precision Health
Authors: Feixiong Cheng, Han Liang, Atul J. Butte, Charis Eng, Ruth Nussinov
Journal: Pharmacological Reviews (2018)

Recent remarkable advances in genome sequencing have enabled detailed maps of identified and interpreted genomic variation, dubbed "mutanomes." The availability of thousands of exome/genome sequencing data has prompted the emergence of new challenges in the identification of novel druggable targets and therapeutic strategies. Typically, mutanomes are viewed as one- or two-dimensional. The three-dimensional protein structural view of personal mutanomes sheds light on the functional consequences of clinically actionable mutations revealed in tumor diagnosis and followed up in personalized treatments, in a mutanome-informed manner. In this review, we describe the protein structural landscape of personal mutanomes and provide expert opinions on rational strategies for more streamlined oncological drug discovery and molecularly targeted therapies for each individual and each tumor. We provide the structural mechanism of orthosteric versus allosteric drugs at the atom-level via targeting specific somatic alterations for combating drug resistance and the "undruggable" challenges in solid and hematologic neoplasias. We discuss computational biophysics strategies for innovative mutanome-informed cancer immunotherapies and combination immunotherapies. Finally, we highlight a personal mutanome infrastructure for the emerging development of personalized cancer medicine using a breast cancer case study.
Androgen receptor signaling induces prostate cancer cell proliferation through mTOR activation and post-transcriptional increases in cyclin D proteins
Authors: Youyuan Xu, Shaoyong Chen, Steven P. Balk
Journal: Cancer Research (2006)

2925   Androgen receptor (AR) plays a central role in prostate cancer (PCa) growth, with most PCa being androgen dependent and responding to androgen deprivation therapies. Previous studies using PCa cell lines and xenografts have shown that androgens (testosterone or dihydrotestosterone, DHT) can stimulate cell cycle progression, and that androgen withdrawal results in a pRb dependent G0/G1dependent cell cycle arrest. However, the molecular targets of AR that mediate androgen stimulated proliferation have not been established. Using the LNCaP PCa cell line as a model, we initially confirmed in time course studies that increased phosphorylation of the pRb protein on a CDK4/cyclin D dependent site correlated with cell cycle progression after DHT stimulation. Significantly, there was no increase in cyclin D1 or D2 mRNA, and only a small increase in cyclin D3. Nonetheless, DHT stimulated a dramatic increase in cyclin D1, D2 and D3 proteins, indicating post-transcriptional regulation of D-type cyclin protein. This post-transcriptional mechanism was identified as mTOR activation, as demonstrated by increased phosphorylation of p70 S6 kinase 1 and ribosomal S6 protein in response to DHT. Importantly, this increase in mTOR activity was observed despite the high basal level in LNCaP cells due to PTEN loss and subsequent activation of the PI3 kinase/Akt pathway (which enhances mTOR activity through phosphorylation of tuberin). Activation of mTOR by amino acids supplementation similarly increased mTOR activity and cyclin D levels, while inhibition of mTOR by rapamycin decreased D-type cyclin protein levels in LNCaP cells and blocked the DHT stimulated D-type cyclin protein accumulation. Significantly, mTOR activation in response to DHT occurred after approximately 8 hours and did not reflect the previously described androgen stimulated rapid nontranscriptional activation of PI3 kinase and Akt. The DHT mediated mTOR activation was similarly independent of the Erk/Rsk and AMPK pathways, but was blocked by actinomycin D, indicating that it was dependent on new mRNA synthesis. Affymetrix oligonucleotide microarrays identified a series of genes that were rapidly induced by DHT, including amino acid transporters, which may contribute to mTOR activation. Finally, the basal level of mTOR activity was increased, and the DHT response was decreased, in an “androgen independent” subline of LNCaP cells (C4-2 cells). Taken together, these results indicate that the androgen liganded AR stimulates the expression of one or more proteins that activate mTOR downstream of Akt, potentially through increasing nutrient levels, and that increased expression of these proteins may be a mechanism for the progression to androgen independent PCa.
Abstract 16234: Promising in vitro Resveratrol Treatment for the Reduction in the Induced Pluripotent Stem (iPS) Cell Tumorigenicity to Confirm the Safety of iPS Cell-Based Cardiomyogenesis Therapy
Authors: Motoko Shiozaki, Shigeru Miyagawa, Satsuki Fukushima, Shin Yajima, Emiko Ito, Atsuhiro Saito, Yoshiki Sawa
Journal: Circulation (2017)

Background: Transplantation of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) into the heart is promising for cardiac regeneration, but clinical trial may be limited by tumorigenic...
REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A)
Authors: Eleni Frangou, Akrivi Chrysanthopoulou, Alexandros Mitsios, Konstantinos Kambas, Stella Arelaki, Iliana Angelidou, Athanasios Arampatzioglou, Hariklia Gakiopoulou, George K Bertsias, Panayotis Verginis, Konstantinos Ritis, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2018)

Objectives The release of neutrophil extracellular traps (NETs) represents a novel neutrophil effector function in systemic lupus erythematosus (SLE) pathogenesis. However, the molecular mechanism underlying NET release and how NETs mediate end-organ injury in SLE remain elusive. Methods NET formation and NET-related proteins were assessed in the peripheral blood and biopsies from discoid lupus and proliferative nephritis, using immunofluorescence, immunoblotting, quantitative PCR and ELISA. Autophagy was assessed by immunofluorescence and immunoblotting. The functional effects of NETs in vitro were assessed in a primary fibroblast culture. Results Neutrophils from patients with active SLE exhibited increased basal autophagy levels leading to enhanced NET release, which was inhibited in vitro by hydroxychloroquine. NETosis in SLE neutrophils correlated with increased expression of the stress-response protein REDD1. Endothelin-1 (ET-1) and hypoxia-inducible factor-1α (HIF-1α) were key mediators of REDD1-driven NETs as demonstrated by their inhibition with bosentan and L-ascorbic acid, respectively. SLE NETs were decorated with tissue factor (TF) and interleukin-17A (IL-17A), which promoted thrombin generation and the fibrotic potential of cultured skin fibroblasts. Notably, TF-bearing and IL-17A-bearing NETs were abundant in discoid skin lesions and in the glomerular and tubulointerstitial compartment of proliferative nephritis biopsy specimens. Conclusions Our data suggest the involvement of REDD1/autophagy/NET axis in end-organ injury and fibrosis in SLE, a likely candidate for repositioning of existing drugs for SLE therapy. Autophagy-mediated release of TF-bearing and IL-17A-bearing NETs provides a link between thromboinflammation and fibrosis in SLE and may account for the salutary effects of hydroxychloroquine.
The effect of tumor derived HMBG1 on intra-tumoral B cells in esophageal squamous cell carcinoma
Authors: D.L.W. Kwong, Y.N. Kam, X.Y. Guan
Journal: Annals of Oncology (2018)

Background: Tumor microenvironment (TME) is often hypoxic and characterized by diverse cell populations (tumor cells and lymphocytes). An intranuclear architectural protein termed high mobility group box chromosomal protein 1 (HMGB-1) is enriched in hypoxic environment, where it acts as a chemokine to promote recruitment of inflammatory cells. We studied the effect of tumor derived HMBG1 on B cell migration and phenotype differentiation in esophageal squamous cell carcinoma (ESCC). Methods: Immunohistochemistry (IHC) staining for HMGB-1 was performed on tissue microarray (TMA) of ESCC and correlated with survival outcome. An immunostaining scoring system corresponding to total staining intensity as follows; (strong staining score =3; moderate staining score=2; weak staining scores= 1; no staining scores= 0). Co-staining with CD20+B was also performed to study B cells distribution in the tumor. ESCC cell lines were transfected with HMGB-1 and transwell migration of B cells were studied. Results: TMA containing 78 paired primary tumors and normal tissue from ESCC patients was analyzed by IHC using an anti-HMGB1 antibody. We found that HMGB1 was expressed at a higher level as compared to paired normal tissue. Survival curves were estimated by the Kaplan-Meier method and compared with log-rank test to evaluate the relationship between biomarker HMGB1 and survival outcomes. Patients were divided into two groups based on the optimal cutoffs of low (score 0-1), high (score 2-3) staining of HMGB1, we found out that HMGB1 staining were not correlated to patient survivals (p = 0.363). We then performed double-staining and demonstrated that B cells were located in the stroma along HMGB1-stained tumor. Stable HMGB1 ESCC cell lines were established where boyden chamber and wound-healing assays demonstrated that B cells migrated and proliferated at higher rates towards HMGB1-overexpressing cell lines. Conclusions: Our findings indicate that HMGB1 was over-expressed in tumor compared with normal tissue. HMGB1 expression per se was not correlated to survival in our log-rank analysis. HMGB1 expression has probable role in B cells recruitment, migration/proliferation. Legal entity responsible for the study: Dora LW Kwong. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Abstract 18212: Unique Exonic RNA Polymerase II Pausing in the Hypoxia Inducible Factor-1 Alpha Gene is Associated With Alternative Splicing
Authors: Hyewon Shin, Jessica Toli, Minzhen He, Danish Sayed, Maha Abdellatif
Journal: Circulation (2013)

Hypoxia-inducible factor 1α (Hif-1α) is the primary transcription factor that promptly increases upon exposure of the cells to hypoxia. It is mainly regulated by posttranscriptional and posttranslational mechanisms involving miR-199a and prolyl hydroxylase, respectively. In addition, the discovery of multiple Hif-1α isoforms suggests that alternative splicing may play a role in regulating its activity, although little is known about this in the heart. We, thus, hypothesized, that in addition to the known mechanisms, Hif-1α is activated by an alternative splicing step, a process that is tightly coupled to transcription. To test this, we treated myocytes with antimiR-199a, which robustly induces Hif-1α expression, and analyzed its effects on gene transcription using RNA polymerase II Chromatin immunoprecipitation-deep sequencing. The analysis revealed that antimiR-199a induced 1) the upregulation of genes that are predominantly Hif-1α targets including Pdk1, Glut3, Vegfa, Bnip3, Ndrg1, and Gys1, in addition to Pfkm, G0s2 and Sdpr, which are a subject of an independent study, and 2) a unique, very precise RNA pol II pausing (accumulation of pol II at a very precise sites with a density &gt;2x of its flanking sequence) within the exons of only the Hif-1α gene, while RNA pol II at the transcription start site, and within other regions of the gene body, was similar to the control myocytes. In particular, all exons except for exons 1, 10, and 11, exhibited some degree of pausing, where exon 15 had a pol II pausing peak that was 20 fold higher than the flanking pol II density. Deceleration of transcriptional elongation has been associated with RNA splicing, however, these very precise exonic pausing peaks are quite unique. Using quantitative PCR, were able to confirm that during normoxia, Hif-1α was abundant as determined by primers specific for exons 10, 11, and 12, which increased by ~2 folds with miR-199a treatment. On the other hand, exon 15, which encodes part of the transactivation domain, was relatively lower during normoxia but increased 300x with antimiR-199a treatment. The result suggests that alternative splicing of exon 15 is a critical regulatory step required for the transcriptional activity of Hif-1α, which is associated with the increase in its protein.
Chronic urticaria and osteoporosis: a longitudinal, community‐based cohort study of 11 944 patients
Authors: G. Shalom, K. Kridin, M. Babaev, E. Magen, S. Tiosano, J. Dreiher, A. Horev, R. Khury, D. Comaneshter, N. Agmon‐Levin, A.D. Cohen
Journal: British Journal of Dermatology (2018)

Chronic urticaria (CU) carries many risk factors for osteoporosis, but data on the relationships between CU and osteoporosis are lacking. To evaluate the association between CU and osteoporosis in a large community‐based study. A nationwide observational longitudinal cohort study was conducted. CU was defined as four pairs of urticaria diagnoses; each pair was recorded within a period of 6 weeks and was registered by physicians in a primary‐care setting. Patients with CU and their age‐ and sex‐ matched controls were followed for the incidence of osteoporosis and other laboratory data between 2002 and 2017. Data regarding systemic steroid exposure and other relevant risk factors for osteoporosis were obtained. Analyses of risk for osteoporosis were performed in Cox regression models adjusted for age, sex, exposure to systemic corticosteroids, obesity, smoking and hyper‐ and hypothyroid disease. The study included 11 944 patients with CU and 59 829 controls. During the study's observation period, 1035 (8·7%) patients with CU were diagnosed with osteoporosis, compared with 4046 (6·8%) controls. The adjusted multivariate analysis demonstrated that CU was significantly associated with a higher risk for osteoporosis (hazard ratio 1·23, 95% confidence interval 1·10–1·37, P < 0·001). CU may impose a risk for osteoporosis. Appropriate targeted screening should be considered.
Abstract MP48: Ascertainment of Newly-Diagnosed Atrial Fibrillation Using Cohort Follow up Versus Centers for Medicare and Medicaid Services Data in the Atherosclerosis Risk in Communities Study
Authors: Lindsay G Smith, Anna Kucharska-Newton, Lisa Wruck, Laura Loehr, Aaron Folsom, Lin Chen, Wayne Rosamond, Sue Duval, Pamela Lutsey, Sally Stearns, Carla Sueta, Jessica Yeh, Ervin Fox, Alvaro Alonso
Journal: Circulation (2013)

Background: Increasingly, administrative data are being used for epidemiologic studies to identify atrial fibrillation (AF) patients. Despite data indicating that administrative data could be a promising source for identifying AF patients, the ability to identify incident AF is not well understood. We examined the concordance of incident AF diagnosis based on Centers for Medicare and Medicaid Services (CMS) data and cohort follow up in the Atherosclerosis Risk in Communities (ARIC) study. Methods: ARIC cohort participants enrolled in fee-for-service (FFS) Medicare, both Parts A and B, for at least 12 continuous months between January 1, 1991, and December 31, 2009, were eligible for inclusion. Individuals with diagnosed AF before January 1, 1992, were excluded. Additionally, AF diagnoses occurring simultaneously with cardiac surgery, without a subsequent AF diagnosis, were excluded. In the ARIC cohort follow up, incident cases of AF were ascertained through hospital discharge codes and death certificates ...
ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma
Authors: Rani Ojha, Nektaria M. Leli, Angelique Onorati, Shengfu Piao, Ioannis I. Verginadis, Feven Tameire, Vito W. Rebecca, Cynthia I. Chude, Sengottuvelan Murugan, Colin Fennelly, Estela Noguera-Ortega, Charleen T. Chu, Shujing Liu, Xiaowei Xu, Clemens Krepler, Min Xiao, Wei Xu, Zhi Wei, Dennie T. Frederick, Genevieve Boland, Tara C. Mitchell, Giorgos C. Karakousis, Lynn M. Schuchter, Keith T. Flaherty, Gao Zhang, Meenhard Herlyn, Constantinos Koumenis, Ravi K. Amaravadi
Journal: Cancer Discovery (2018)

Abstract Resistance to BRAF and MEK inhibitors (BRAFi + MEKi) in BRAF-mutant tumors occurs through heterogeneous mechanisms, including ERK reactivation and autophagy. Little is known about the mechanisms by which ERK reactivation or autophagy is induced by BRAFi + MEKi. Here, we report that in BRAF-mutant melanoma cells, BRAFi + MEKi induced SEC61-dependent endoplasmic reticulum (ER) translocation of the MAPK pathway via GRP78 and KSR2. Inhibition of ER translocation prevented ERK reactivation and autophagy. Following ER translocation, ERK exited the ER and was rephosphorylated by PERK. Reactivated ERK phosphorylated ATF4, which activated cytoprotective autophagy. Upregulation of GRP78 and phosphorylation of ATF4 were detected in tumors of patients resistant to BRAFi + MEKi. ER translocation of the MAPK pathway was demonstrated in therapy-resistant patient-derived xenografts. Expression of a dominant-negative ATF4 mutant conferred sensitivity to BRAFi + MEKi in vivo. This mechanism reconciles two major targeted therapy resistance pathways and identifies druggable targets, whose inhibition would likely enhance the response to BRAFi + MEKi. Significance: ERK reactivation and autophagy are considered distinct resistance pathways to BRAF + MEK inhibition (BRAFi + MEKi) in BRAFV600E cancers. Here, we report BRAFi + MEKi–induced ER translocation of the MAPK pathway is necessary for ERK reactivation, which drives autophagy. The ER translocation mechanism is a major druggable driver of resistance to targeted therapy. This article is highlighted in the In This Issue feature, p. 305
Inflammatory back pain criteria perform well in subset of patients with active axial psoriatic arthritis but not among patients with established axial disease
Authors: Muhammad Haroon, Phil Gallagher, Oliver FitzGerald
Journal: Annals of the Rheumatic Diseases (2018)

Psoriatic arthritis (PsA) is a progressive, potentially destructive and disabling immune-mediated inflammatory joint disease and is characterised by involvement of both the appendicular and axial skeleton. Inflammatory spinal disease is one of three inflammatory musculoskeletal (MSK) manifestations that frequently occur in PsA. The reported prevalence of axial disease in patients with PsA is quite variable, and has been reported to be as high as up to 78%.1 Axial involvement is typically characterised by chronic lower back pain, and a significant proportion of such patients develop disabilities due to spinal inflammation. The early identification of patients with axial involvement among patients with psoriasis (PsO) therefore assumes considerable importance.

There are limited data about the utility of inflammatory back pain (IBP) criteria among patients with axial PsA (AxPsA). Previous studies have described low sensitivity of IBP criteria among AxPsA (around 68%).2 We read with interest the article of Yap et al , where authors report that IBP criteria may not perform well for axial involvement in PsA.3 The authors also report the low sensitivity and high specificity of IBP criteria among AxPsA. We also aimed to assess the diagnostic performance of back pain features among a much larger cohort of patients with PsA.

We have previously reported clinical and genetic association of sacroiliitis (SI) among 283 patients with PsA.4 …
High Modulus Conductive Hydrogels Enhance In Vitro Maturation and Contractile Function of Primary Cardiomyocytes for Uses in Drug Screening
Authors: Fengxin Wu, Aijun Gao, Jian Liu, Yaoyi Shen, Panpan Xu, Jie Meng, Tao Wen, Lianghua Xu, Haiyan Xu
Journal: Advanced Healthcare Materials (2018)

Effective and quick screening and cardiotoxicity assessment are very crucial for drug development. Here, a novel composite hydrogel composed of carbon fibers (CFs) with high conductivity and modulus with polyvinyl alcohol (PVA) is reported. The conductivity of the composite hydrogel PVA/CFs is similar to that of natural heart tissue, and the elastic modulus is close to that of natural heart tissue during systole, due to the incorporation of CFs. PVA/CFs remarkably enhance the maturation of neonatal rat cardiomyocytes (NRCM) in vitro by upregulating the expression of α-actinin, troponin T, and connexin-43, activating the signaling pathway of α5 and β1 integrin-dependent ILK/p-AKT, and increasing the level of RhoA and hypoxia-inducible factor-1α. As a result, the engineered cell sheet-like constructs NRCM@PVA/CFs display much more synchronous, stable, and robust beating behavior than NRCM@PVA. When exposed to doxorubicin or isoprenaline, NRCM@PVA/CFs can retain effective beating for much longer time or change the contractile rate much faster than NRCM@PVA, respectively, therefore representing a promising heart-like platform for in vitro drug screening and cardiotoxicity assessment.
Data mining for health: staking out the ethical territory of digital phenotyping
Authors: Nicole Martinez-Martin, Thomas R. Insel, Paul Dagum, Henry T. Greely, Mildred K. Cho
Journal: npj Digital Medicine (2018)

Digital phenotyping uses smartphone and wearable signals to measure cognition, mood, and behavior. This promising new approach has been developed as an objective, passive assessment tool for the diagnosis and treatment of mental illness. Digital phenotyping is currently used with informed consent in research studies but is expected to expand to broader uses in healthcare and direct-to-consumer applications. Digital phenotyping could involve the collection of massive amounts of individual data and potential creation of new categories of health and risk assessment data. Because existing ethical and regulatory frameworks for the provision of mental healthcare do not clearly apply to digital phenotyping, it is critical to consider its possible ethical, legal, and social implications. This paper addresses four major areas where guidelines and best practices will be helpful: transparency, informed consent, privacy, and accountability. It will be important to consider these issues early in the development of this new approach so that its promise is not limited by harmful effects or unintended consequences.