tbuckley/cabot-search huggingface dataset:
A Reliable Diagnostic Test for Hypotonic Polyuria
Authors: Clifford J. Rosen, Julie R. Ingelfinger
Journal: New England Journal of Medicine (2018)

Pinpointing the cause of hypotonic polyuria in a patient poses a diagnostic and therapeutic challenge, particularly in distinguishing primary polydipsia (either psychogenic or nonpsychogenic) from partial pituitary insufficiency due to injury or neoplasm. Diabetes insipidus is one cause of hypotonic polyuria and previously was classified as either central or nephrogenic, on the basis of a water-deprivation test and the administration of vasopressin.1 But in 1970, Miller et al. noted that some patients who underwent water deprivation had a urine osmolality greater than their plasma osmolality and that the urine osmolality further increased, albeit modestly, after the injection of vasopressin — . . .
Abstract 12414: The Impact of Frailty on Cause Specific Mortality Among Elderly Patients Undergoing PCI
Authors: Nicholas M Orme, Ryan J Lennon, Bradley R Lewis, Rajiv Gulati, Gurpreet Sandhu, John Spertus, Veronique L Roger, Mandeep Singh
Journal: Circulation (2015)

Background: The presence of frailty increases the risk of long-term mortality for a myriad of reasons, but its association with cardiac-specific mortality among the elderly undergoing percutaneous coronary intervention (PCI) is unknown. We sought to determine the relationship between frailty and cause-specific (cardiac versus non-cardiac) mortality among elderly patients undergoing PCI. Methods: A prospective cohort of elderly (&gt;65 years) patients undergoing PCI at Mayo Clinic between October 2005 and September 2008 were tested for frailty using the Fried criteria. Vital status was prospectively monitored including evaluation of death certificates, telephone interviews and review of autopsy/medical records. Results: Frailty data was obtained in 428 (84%) of 508 elderly patients (median age 74.2 years [SD 6.4, range 65-100]; 59% male). Of these, 92 (21%) patients were frail while 231 (54%) had intermediate frailty and 105(25%) were not frail. Frail patients were older than intermediate and non-frail patients (77.6 vs 74.3 vs 71.0 years; p&lt;0.001) and had more comorbidities (mean Charlson index 4.6 vs 3.9 vs 2.8; p&lt;0.001). There were 113 deaths (26% of cohort) during 5.1 median years of follow-up, of which 77 (68%) were classified as non-cardiac and 36 (32%) which were classified as cardiac. Frailty at baseline was associated with poor overall survival compared to non-frail patients (HR 6.1, 95% CI 3.2, 11.6; p&lt;0.001). The estimated effect of frailty was nearly 3 times greater for cardiac mortality (HR 13.1, 95% CI 3.0, 57.0; p=0.001) than non-cardiac mortality (HR 4.6, 95% CI 2.2, 9.7; p&lt;0.001). These findings remained significant following multivariable adjustment. Conclusions: Frailty is common among elderly patients undergoing PCI and is associated with poor overall survival and both cardiac and non-cardiac causes of death.
Abstract 5345: Somatic mutation status in cfDNA between therapy responders and non-responders of oropharyngeal squamous cell carcinoma patients
Authors: Alok R. Khandelwal, Adam Greer, Rhett Orgeron, Mickie Hamiter, Xiaohui Ma, Tara Moore-Medlin, Hong Yin, Glenn Mills, Cherie-Ann O. Nathan
Journal: Cancer Research (2018)

Abstract Circulating tumor DNA (ctDNA) could potentially be utilized as a biomarker in Oropharyngeal Squamous Cell Carcinoma (SCC) patients. The objective of this study was to determine if somatic variants could be detected in circulating cell-free DNA (cfDNA) of Oropharyngeal SCC patients using Next Generation Sequencing (NGS). Somatic mutations have been reported in Orophayngeal SCC cases. The identification and detection of somatic variants in circulating cell-free DNA in patient's plasma may predict response to therapy, help monitor disease progression, guide therapy, and determine likelihood of recurrence. In this study, we compared the somatic mutation status between therapy responders and non-responders among Orophayngeal SCC patients. IRB approval was obtained and 23 Oropharyngeal SCC patients were identified in our patient database. Genomic DNA was isolated from frozen tumor tissue using NucleoSpin Tissue kit by Clontech. Cell-Free (cfDNA) was then extracted from patient's plasma samples using Zymo's Quick-cfDNATM serum and plasma kit. The quality and size of DNA was determined by Agilent 2200 TapeStation. If genomic DNA contamination was identified it was removed with Zymo Select-a-Size DNA kit. Libraries were prepared with 10 to 25 ηg of cfDNA using Accel-Amplicon 56G Oncology Panel of Swift Biosciences. DNA sequencing was then performed on MiSeq platform with Miseq Reagent Kit. Variants were identified using Biomedical Genomic Workbench and Genialis's online data analysis platform for Swift Biosciences's Accel-amplicon panels. From the 23 matched samples, 8 somatic non-synonymous variants were found in both tissue and plasma, 7 of which were present in non-responders. The variants and their allele frequencies in the non-responder group were as follows (tumor DNA /cfDNA in %) HRAS Gly12Cys (36.54/0.45), TP53 Glu298* (5.48/0.21), CDKN2A Pro114Arg (48.11/1.52), TP53 Arg282Trp (46.47/1.77), FBXW7 Arg505Gly (30.17/0.58), FBXW7 Arg505Leu (30.46/0.64), TP53 Arg273Cys (38.91/2.51), and one variant in the responder group PTEN (21.07/0.67) Arg130Gln. In conclusion, somatic non-synonymous variants can be identified in cfDNA from Oropharyngeal SCC patients using NGS. The number of detected variants is far greater in the non-responder group suggesting somatic variant detection could be a prognostic marker for Oropharyngeal SCC patients. Citation Format: Alok R. Khandelwal, Adam Greer, Rhett Orgeron, Mickie Hamiter, Xiaohui Ma, Tara Moore-Medlin, Hong Yin, Glenn Mills, Cherie-Ann O. Nathan. Somatic mutation status in cfDNA between therapy responders and non-responders of oropharyngeal squamous cell carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5345.
Abstract 5306: SAUCIE: Sparse autoencoder for unsupervised clustering, imputation, and embedding
Authors: Matthew Amodio, Krishnan Srinivasan, David van Dijk, Hussein Mohsen, Kristina Yim, Rebecca Muhle, Kevin Moon, Ruth Montgomery, James Noonan, Guy Wolf, Smita Krishnaswamy
Journal: Cancer Research (2018)

Abstract Handling the vast amounts of single-cell RNA-sequencing and CyTOF data, now being generated in patient cohorts, presents a computational challenge due to the noise, complexity, sparsity and batch effects present. Here, we propose a unified deep neural network approach to automatically process and extract structure from these massive datasets. Our unsupervised architecture, called SAUCIE (Sparse Autoencoder for Unsupervised Clustering, Imputation, and Embedding), simultaneously performs several key tasks for single-cell data analysis including 1) clustering, 2) batch correction, 3) visualization, and 4) denoising/imputation. SAUCIE is trained to recreate its own input after reducing its dimensionality in a 2-D embedding layer which can be used to visualize the data. Additionally, it uses two novel regularizations: (1) an information dimension regularization to penalize entropy as computed on normalized activation values of the layer, and thereby encourage binary-like encodings that are amenable to clustering and (2) a Maximal Mean Discrepancy penalty to correct batch effects. Thus SAUCIE has a single architecture that denoises, batch-corrects, visualizes and clusters data using a unified representation. We show results on artificial data where ground truth is known, as well as mass cytometry data from patients undergoing immunotherapy, dengue-infected patients, and single-cell RNA-sequencing data from embryonic mouse brain. Citation Format: Matthew Amodio, Krishnan Srinivasan, David van Dijk, Hussein Mohsen, Kristina Yim, Rebecca Muhle, Kevin Moon, Ruth Montgomery, James Noonan, Guy Wolf, Smita Krishnaswamy. SAUCIE: Sparse autoencoder for unsupervised clustering, imputation, and embedding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5306.
Abstract 293: Heterogeneous nucleocytoplasmic regulation of an incompletely penetrant ErbB2 onco-phenotype
Authors: Lixin Wang, Kevin A. Janes
Journal: Cancer Research (2018)

Abstract Perturbation of cancer cells often leads to heterogeneous outcomes, in that most cells exhibit a dominant phenotype, but the rest appear resistant or hypersensitive to the perturbation. If the penetrance of such a phenotype is heritably incomplete, then it becomes extremely difficult to decipher the upstream molecular events that heterogenize the population and cause response variability. By combining quantitative measurements with dynamical models, systems approaches should be useful if provided with a core network of important biomolecules. The daunting hurdle lies in identifying phenotype-relevant regulatory heterogeneities that define the network for penetrance at the single-cell level. Here, we exploit a new approach, called stochastic frequency matching (SFM), which elaborates the molecular networks upstream of incompletely penetrant phenotypes. SFM identifies and parameterizes single-cell heterogeneities—which emerge after a uniform perturbation but before the appearance of a variable phenotype—to hone in on regulatory states corresponding to future penetrance. For a multi-acinar onco-phenotype incompletely triggered by ErbB receptor tyrosine kinase signaling in 3D cultured breast epithelia, we implemented SFM using microarrays to uncover a network of critical nucleocytoplasmic regulators, including the inner-ring nucleoporin NUP37 and the exportin CSE1L. Gain- and loss-of-function perturbations of NUP37 and CSE1L alter the frequency of ErbB2-triggered multiacinus formation, supporting that SFM can identify mechanisms of incompletely penetrant phenotypes. In addition, population-level transcriptomics revealed other ErbB2-induced changes in nucleocytoplasmic shuttling proteins: KPNA2, RANBP1, and XPO1. The net result of these alterations on shuttling is complicated, and the specific cargo relocalized by ErbB2 signaling is not known. We hypothesize that ErbB signaling heterogeneously reconfigures the nucleocytoplasmic shuttling state of cells to determine incomplete penetrance of the onco-phenotype. Using proximity labeling, we seek to identify novel ErbB2-induced NUP37 and CSE1L interactors that may serve as effectors for the multiacinar phenotype. Systems models of the nucleocytoplasmic shuttling network will evaluate the impact of observed abundance changes and identify characteristics of cargo predicted to be most sensitive to network reconfiguration. The importance of key effectors will ultimately be tested in vivo with murine cells engineered for spontaneous Erbb2 amplification and in patient samples with HER2 amplification. Citation Format: Lixin Wang, Kevin A. Janes. Heterogeneous nucleocytoplasmic regulation of an incompletely penetrant ErbB2 onco-phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 293.
The continuum of screening and early detection, awareness and faster diagnosis of lung cancer
Authors: Michael D Peake, Neal Navani, David R Baldwin
Journal: Thorax (2018)

The principal reason lung cancer outcomes are poor is that most patients are diagnosed with what, with current technologies, is incurable disease. Despite unprecedented recent advances in the understanding of the biology, oncogenesis and immunology of cancer, and the subsequent development of innovative systemic therapies for lung cancer, the long-term prognosis for patients beyond stages I and II remains poor. The cost of the new agents, largely indicated for people with advanced disease and good performance status (PS), is such that the International Agency for Research on Cancer recently said that ‘No country can afford to treat its way out of the cancer problem’.1 In any case, many patients with advanced disease are ineligible because of poor performance status.

Although lung cancer survival rates have been improving in England since 2006,2 the latest data from the Concord study still rate the UK behind many other nations.3 Later diagnosis is likely a major factor explaining the consistent observation that the proportion of patients that have early stage disease at the time of diagnosis in the UK is less than in many comparator countries.4 In a recent study comparing older patients with non-small cell lung cancer (NSCLC) in England with those in the USA, 15% were diagnosed at stage I in England compared with 25% in the USA.5 

To address these issues, we need to consider ways in which we can detect lung cancer at an earlier stage to increase the curative treatment rate, and where cancer is detected at a later stage, provide rapid work-up to minimise deterioration in fitness to maximise the impact of systemic therapy. Essentially this means: screening of people at relatively high risk of lung cancer; using public and professional awareness campaigns to promote the earlier referral of patients with symptoms suspicious …
Abstract 18122: Mir-206 Plays an Important Role in Mediating Pressure Overload-induced Cardiac Hypertrophy
Authors: Sebstiano Sciarretta, Yanfei Yang, Dominic P Del Re, Junichi Sadoshima
Journal: Circulation (2015)

Introduction: Expression of miR-206 is upregulated by YAP, a key transcription co-factor controlled by the Hippo signaling pathway, and mediates YAP-induced hypertrophy and survival of cardiomyocytes. Although miR-206 is known to promote hypertrophy of skeletal muscle, the role of miR-206 in the heart under clinically relevant conditions in vivo remains unknown. We investigated the role of miR-206 in mediating cardiac hypertrophy in response to pressure overload (PO). Results: The level of miR-206 in the mouse heart, as evaluated by qRT-PCR, was upregulated 2.9 fold (p&lt;0.05) 7 days after transverse aortic constriction (TAC) compared to sham operation. In order to evaluate the involvement of miR-206 in cardiac hypertrophy, wild-type C57B/6J mice were administered LNA inhibitor designed to selectively inhibit miR-206, or control scrambled LNA, by tail vein injection. Specificity of the LNA inhibitor was confirmed by qRT-PCR analysis of miRNA expression 48 hours after treatment. Notably, the LNA inhibitor did not affect the level of miR-1, which has a sequence similarity with miR-206. After 48 hours, mice from both treatment groups were subjected to sham operation or TAC. After 7 days of TAC, echocardiography was performed and mice were sacrificed. Upregulation of myocardial miR-206 expression levels after 7 days TAC observed in LNA control-treated mice was completely abolished in LNA-anti-206 -treated mice. A significant increase in left ventricular weight/tibial length (mg/mm) in LNA control-treated mice following TAC was observed (sham vs TAC: 3.7, 4.8, p&lt;0.05); however, no increase was observed in LNA-anti-206 -treated mice (3.8, 3.8). We also noted significant differences in chamber wall thickness (mm) between the LNA-control and LNA-anti-206-treated TAC groups (diastolic posterior wall 0.91, 0.61, p&lt;0.05). Additionally, cardiomyocyte cross sectional area (1.23, 0.9, p&lt;0.05) and ANF expression (2.5, 1.3, P&lt;0.05) were significantly increased in the LNA control-treated TAC group, and these responses were attenuated in the LNA-anti-206-treated mice. Conclusions: These data demonstrate that inhibition of miR-206 impairs PO-induced hypertrophy and indicates that miR-206 is an important endogenous mediator of heart growth in response to PO.
Abstract 4496: Myofibroblast-secreted follistatin-like 1 promotes hepatocellular carcinoma formation and metastasis
Authors: Natalie Tsz Wai Li, Man Tong, Lei Zhou, Wen Ning, Chung-Mau Lo, Kwan Man, Terence Kin-Wah Lee, Stephanie Kwai-Yee Ma
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) develops in the setting of fibrosis/cirrhosis, a progressive process in which chronic inflammation and hepatocellular regeneration result in the malignant transformation of hepatocytes. Enrichment of stromal myofibroblasts in this pathological stage is commonly observed, which constitutes the bulk of the tumor microenvironment and contributes to disease progression. Cancer cells are regulated by signals generated intrinsically and extrinsically from the tumor microenvironment. Targeting critical factors involved in this process may offer important therapeutic opportunities. Follistatin-like 1 (FSTL1) has been widely reported as a pro-inflammatory mediator in different fibrosis-related and inflammatory diseases. Here, we report that FSTL1 is either absent or expressed at very low levels in HCC cells, but preferentially secreted from the myofibroblasts of peri-tumor liver and HCC tissue as well as in the liver following acute injury. FSTL1 was found to co-localize and positively correlate with α-SMA, marker of myofibroblasts, in both human HCC as well as in a DEN+CCl4-induced HCC mouse model. High FSTL1 expression in myofibroblast FAP+ cells (FAP+/FSTL1high) also correlated with advanced TNM stages as compared to HCC patients in the FAP+/FSTL1low subgroup. Functional investigations revealed that FSTL1 can induce HCC cell proliferation, metastasis and sorafenib resistance; while FSTL1 attenuation by neutralizing antibody elicited the opposite effects. These observations were further validated in HCC patient-derived organoid cultures in which FSTL1 can enhance the metastatic effect of the cells. Transcriptome sequencing analysis is now currently underway to delineate the underlying molecular mechanism by which myofibroblast-secreted FSTL1 drives carcinogenesis and tumor progression in HCC. Citation Format: Natalie Tsz Wai Li, Man Tong, Lei Zhou, Wen Ning, Chung-Mau Lo, Kwan Man, Terence Kin-Wah Lee, Stephanie Kwai-Yee Ma. Myofibroblast-secreted follistatin-like 1 promotes hepatocellular carcinoma formation and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4496.
Abstract 3376: Early onset of chromosomal instability in breast preneoplasia detected by single-cell genomics
Authors: Katerina Fagan-Solis, Dennis A. Simpson, Luciano Martelotto, Jorge S. Reis-Filho, John H. Petrini, Gaorav P. Gupta
Journal: Cancer Research (2018)

Abstract Chromosomal rearrangements and copy number aberrations are a major mechanism for driver gene alterations in breast cancer. However, the origins of chromosomal instability during breast tumorigenesis are poorly understood. We have recently shown that oncogene expression in normal mammary epithelial cells induces replication stress and a DNA damage response (DDR). The double-strand break sensor Mre11 is required for the oncogene-induced DDR, and suppression of Mre11 is sufficient to promote the development of Her2/Neu-driven breast cancer in a transgenic mouse model. Here we have applied single-cell genomics to primary mammary epithelial cells from this mouse model and demonstrate a profound effect of oncogene expression on chromosomal instability in preneoplastic cells, which is further augmented in Mre11-mutant cells. Her2/Neu-induced chromosomal breakpoints are highly enriched in the vicinity of large genes, suggesting a possible role for gene transcription and/or R-loops in the origin of oncogene-induced genomic fragility. Mre11 hypomorphism does not affect the number of chromosomal breakpoints but alters the genomic aberration signature to one that is over-represented by larger-size deletions. These findings indicate that chromosomal instability is an early event during Her2/Neu-initiated breast neoplasia. Furthermore, DDR perturbation—in the form of Mre11 hypomorphism—is not required for oncogene-induced genomic instability but rather alters the pattern of observed copy number aberrations and promotes the proliferative expansion of genomically unstable clones. Thus, single-cell genomics applied to murine models of breast preneoplasia reveals insights into the origins of chromosomal instability in breast cancer that may inform novel strategies to prognosticate or prevent the progression of high-risk premalignant breast lesions. Citation Format: Katerina Fagan-Solis, Dennis A. Simpson, Luciano Martelotto, Jorge S. Reis-Filho, John H. Petrini, Gaorav P. Gupta. Early onset of chromosomal instability in breast preneoplasia detected by single-cell genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3376.
Abstract 3160: The actin-binding protein Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization
Authors: Xiaoze Wang, Atsushi Enomoto, Liang Weng, Hisashi Haga, Sumire Ishida, Masahide Takahashi
Journal: Cancer Research (2018)

Abstract Pathological observations show that cancer cells frequently invade the surrounding stroma in collective groups rather than through single cell migration. The identification of genes and proteins that are specifically involved in the collective behavior of cancer cells has thus far been limited. Here, we studied the role of the actin-binding protein Girdin in collective cancer cell migration. This protein is a specific regulator of collective migration of neuroblasts born in the subventricular zone of the postnatal and adult brains and participates in the progression of cancer. We found that Girdin was essential for the collective migration of the skin cancer cell line A431 on collagen gels as well as their fibroblast-led collective invasion in an organotypic culture model. We provide evidence that Girdin binds to β-catenin that plays important roles in the Wnt signaling pathway and in E-cadherin-mediated cell-cell adhesion. Girdin-depleted cells displayed scattering and impaired E-cadherin-specific cell-cell adhesion. Importantly, Girdin depletion led to impaired cytoskeletal association of the β-catenin complex, which was accompanied by changes in the supracellular actin cytoskeletal organization of cancer cell cohorts on collagen gels. Although the underlying mechanism is unclear, this observation is consistent with the established role of the actin cytoskeletal system and cell-cell adhesion in the collective behavior of cells. Citation Format: Xiaoze Wang, Atsushi Enomoto, Liang Weng, Hisashi Haga, Sumire Ishida, Masahide Takahashi. The actin-binding protein Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3160.