tbuckley/cabot-search huggingface dataset:
iPSC-derived familial Alzheimer’s PSEN2 N141I cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling
Authors: Cesar L. Moreno, Lucio Della Guardia, Valeria Shnyder, Maitane Ortiz-Virumbrales, Ilya Kruglikov, Bin Zhang, Eric E. Schadt, Rudolph E. Tanzi, Scott Noggle, Christoph Buettner, Sam Gandy
Journal: Molecular Neurodegeneration (2018)

Type 2 diabetes (T2D) is a recognized risk factor for the development of cognitive impairment (CI) and/or dementia, although the exact nature of the molecular pathology of T2D-associated CI remains obscure. One link between T2D and CI might involve decreased insulin signaling in brain and/or neurons in either animal or postmortem human brains as has been reported as a feature of Alzheimer’s disease (AD). Here we asked if neuronal insulin resistance is a cell autonomous phenomenon in a familial form of AD. We have applied a newly developed protocol for deriving human basal forebrain cholinergic neurons (BFCN) from skin fibroblasts via induced pluripotent stem cell (iPSC) technology. We generated wildtype and familial AD mutant PSEN2N141I (presenilin 2) BFCNs and assessed if insulin signaling, insulin regulation of the major AD proteins Aβ and/or tau, and/or calcium fluxes is altered by the PSEN2N141I mutation. We report herein that wildtype, PSEN2N141I and CRISPR/Cas9-corrected iPSC-derived BFCNs (and their precursors) show indistinguishable insulin signaling profiles as determined by the phosphorylation of canonical insulin signaling pathway molecules. Chronic insulin treatment of BFCNs of all genotypes led to a reduction in the Aβ42/40 ratio. Unexpectedly, we found a CRISPR/Cas9-correctable effect of PSEN2N141I on calcium flux, which could be prevented by chronic exposure of BFCNs to insulin. Our studies indicate that the familial AD mutation PSEN2N141I does not induce neuronal insulin resistance in a cell autonomous fashion. The ability of insulin to correct calcium fluxes and to lower Aβ42/40 ratio suggests that insulin acts to oppose an AD-pathophysiology. Hence, our results are consistent with a potential physiological role for insulin as a mediator of resilience by counteracting specific metabolic and molecular features of AD.
Erratum. Insulin Access and Affordability Working Group: Conclusions and Recommendations. Diabetes Care 2018;41;1299–1311
Authors: William T. Cefalu, Daniel E. Dawes, Gina Gavlak, Dana Goldman, William H. Herman, Karen Van Nuys, Alvin C. Powers, Simeon I. Taylor, Alan L. Yatvin
Journal: Diabetes Care (2018)

On page 1302 of the article cited above, the wording of the following sentence was incorrect: “In contrast, net prices received by the …
Abstract 14396: Purification of Cardiomyocytes From Differentiating Pluripotent Stem Cells Using Molecular Beacons Targeting Cardiomyocyte-specific mRNA
Authors: Kiwon Ban, Brian Wile, Sangsung Kim, Hun-Jun Park, Jaemin Byun, Kyu-Won Cho, Talib Saafir, Mary Wagner, Gang Bao, Young-Sup Yoon
Journal: Circulation (2013)

Background:  Pluripotent stem cells (PSCs) offer unprecedented hopes for myocardial repair; however, there are numerous technical hurdles for their clinical uses. While methods for generating cardiomyocytes (CMs) from PSCs have been reported, currently available methods produce only heterogeneous mixtures of CMs and non-CM cells may cause negative outcomes. Therefore, it has been highly required to develop strategies to purify homogeneous populations of CM for their further clinical applications. Here, we report an entirely novel system in which PSC-derived CMs can be purified by CM-specific molecular beacons (MBs). MBs are nano-scale probes that emit a fluorescence signal when hybridized to target mRNAs. We hypothesized that MBs targeting CM-specific mRNA can specifically bind to CMs and allow to sort MB positive CM population by FACS.   Method and Results:  Five MBs targeting mRNAs of either cardiac troponin T or myosin heavy chain 6 and -7 were generated. Among five MBs, a MB targeting myosin heavy chain 6 and -7 mRNA (MHC1-MB) identified up to 99% of HL-1 CMs, an immortalized mouse CM cell line, but less than 3% of four non-CM cell types in flow cytometry analysis, indicating that MHC1-MB is specific for identifying CMs. We delivered MHC1-MB into cardiomyogenically differentiated PSCs through nucleofection and found that the detection rate of CMs was similar to the percentages of cardiac troponin T (TNNT2) or cardiac troponin I (TNNI3)-positive CMs, supporting the specificity of MBs. Finally, ~97% of CMs from mouse and human PSC differentiating cultures FACS-sorted with MHC1-MBs expressed TNNT2- or TNNI3 determined by flow cytometry. These MB-based sorted cells maintained their CM characteristics verified by spontaneous beating, electrophysiologic studies, and expression of cardiac proteins by immunocytochemistry. When transplanted in a myocardial infarction model, while unpurified CMs derived from mESCs developed tumors, MB-based purified CMs improved cardiac function and demonstrated significant engraftment for 4 weeks without forming tumors.   Conclusion:  We developed a novel CM selection system that allows production of highly purified CMs. These purified CMs and this system can be valuable for cell therapy and drug discovery.
Abstract 4566: PD-L1 and B7-H3 expression in serous carcinoma of endometrium
Authors: Masato Nishimura, Ayuka Mineda, Akiko Abe, Minoru Irahara
Journal: Cancer Research (2018)

Abstract Endometrial cancer keeps increasing in Japan explosively. In endometrial cancer, the prognosis of serous carcinoma is very poor, because of early progression to abdominal cavity. Remedy for endometrial cancer is limited, so new therapy has been required for a long time. Immunotherapy is very promising in various cancers recently. PD-L1 (programmed cell death ligand 1) and B7-H3 are factors of immunoresponse between cancer cells and lymphcyte. Purpose: The purpose of this study is to investing the expression of PD-L1 and B7-H3, moreover, relationship with clinicopathological factors in serous carcinoma of endometrium. We immunohistochemically evaluated PD-L1 and B7-H3 expression in 21 serous carcinoma. The result was graded as positive in case stained more than 10% area. Result: 2/21(9.5%) for PD-L1 and 10/21(47.6%) for B7-H3 were positive. There was no correlation with tumor diameter, lymphnode metastasis, advanced stage and recurrence in PD-L1, however, B7-H3 expression had trend node metastasis, 3/10 in positive cases vs 0/11 in negative cases (p=0.05). In 4 recurrent cases treated with taxane and carboplatin as second line therapy, one case with B7-H3 negative got complete remission, however 3 cases with B7-H3 positive got partial improvement once, but finally got progression. Conclusion: PD-L1 expression was limited in serous carcinoma, so immunotherapy targeted for PD-1 and PD-L1 may be limited. The expression of B7-H3 is related to chemotherapy resistance. B7-H3 may be a biomarker for chemotherapy and target of new immunotherapy for serous carcinoma of endometrium. Citation Format: Masato Nishimura, Ayuka Mineda, Akiko Abe, Minoru Irahara. PD-L1 and B7-H3 expression in serous carcinoma of endometrium [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 4566.
Standardization of Continuous Renal Replacement Therapy—Reply
Authors: Rodrigo F. Alban, Joshua Tseng, Hector Rodriguez
Journal: JAMA Internal Medicine (2018)

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The Improved Delivery to Breast Cancer Based on a Novel Nanocarrier Modified with High‐Affinity Peptides Discovered by Phage Display
Authors: Haoran Zhang, Zhaoming Guo, Bing He, Wenbing Dai, Hua Zhang, Xueqing Wang, Qiang Zhang
Journal: Advanced Healthcare Materials (2018)

Abstract Ligand‐targeted nanosystems have the potential to realize site‐specific tumor therapy and alleviate unwanted side effects of many chemotherapeutic agents, and one of the most key issues seems to be the construction of an effective nanocarrier. Based on different processes of phage display techniques, 38 cell‐binding peptides and 32 cell‐internalizing peptides are discovered. Four of these ligand peptides [FIPFDPMSMRWE (FIP), NASSFPTNSRWA (NAS), GLHTSATNLYLH (GLH), and ALAVAPSRWWNE (ALA), respectively] exhibit high affinity to MCF7 human breast cancer cells. Among them, NAS and ALA are reported for the first time, whose affinities are 20.6 and 76.3 times that of the random peptide control, respectively. Both NAS and ALA modifications to doxorubicin‐loaded lipid nanosytems [LP(DOX)] show stronger tumor inhibition, longer animal survival time, and less body weight loss, compared to unmodified or control peptide modified nanosystems, on an MCF7 tumor‐bearing mouse model. In conclusion, the cell‐binding peptide NAS and cell‐internalizing peptide ALA can be used for ligand‐targeted delivery of antitumor drugs. It seems that the in vivo antitumor effect of these ligand‐targeted nanosystems is closely related to their ligand–cell affinity, but fairly tolerant of the ligand types.
Comprehensive molecular classification of localized prostate adenocarcinoma reveals a tumour subtype predictive of non-aggressive disease
Authors: A. Kamoun, G. Cancel-Tassin, G. Fromont, N. Elarouci, L. Armenoult, M. Ayadi, J. Irani, X. Leroy, A. Villers, G. Fournier, L. Doucet, S. Boyault, L. Brureau, L. Multigner, A. Diedhiou, M. Roupret, E. Compérat, P. Blanchet, A. de Reyniès, O. Cussenot
Journal: Annals of Oncology (2018)

Management of localized prostate cancer (PCa) is a major clinical challenge since most of these cancers would not evolve but a majority of patients will still undergo a life-changing radical surgery. Molecular studies have shown that PCa can be classified according to their genomic alterations but none of the published PCa molecular classifications could identify a subtype corresponding to non-evolutive tumours.Multi-omics molecular profiling was carried out on post-radical prostatectomy material from a cohort of 130 patients with localized PCa. We used unsupervised classification techniques to build a comprehensive classification of prostate tumours based on three molecular levels: DNA copy number, DNA methylation, and mRNA expression. Merged data from our cohort and The Cancer Genome Atlas cohort were used to characterize the resulting tumour subtypes. We measured subtype-associated risks of biochemical relapse using Cox regression models and survival data from five cohorts including the two aforementioned.We describe three PCa molecular subtypes associated with specific molecular characteristics and different clinical outcomes. Particularly, one subtype was strongly associated with the absence of biochemical recurrence. We validated this finding on 746 samples from 5 distinct cohorts (P = 3.41 × 10-8, N = 746 tumour samples), and showed that our subtyping approach outperformed the most popular prognostic molecular signatures to accurately identify a subset of patients with a non-evolutive disease. We provide a set of 36 transcriptomic biomarkers to robustly identify this subtype of non-evolutive cases whose prevalence was estimated to 22% of all localized PCa tumours.At least 20% of patients with localized PCa can be accurately predicted to have a non-evolutive disease on the basis of their molecular subtype. Those patients should not undergo immediate surgery and rather be placed under active surveillance.
The NHS is no longer safe for patients and staff, say doctors
Authors: Abi Rimmer
Journal: BMJ (2018)

Doctors have expressed their worry that the NHS can no longer provide safe patient care and is no longer a safe place for doctors to work.

Delegates at the BMA’s annual representative meeting in Brighton on 25 June voted in favour of a motion which stated, “the NHS is no longer a safe place for patients and staff.”

The motion was passed despite calls from Jeeves Wijesuriya, chair of the BMA Junior Doctors Committee, for doctors …
HmmUFOtu: An HMM and phylogenetic placement based ultra-fast taxonomic assignment and OTU picking tool for microbiome amplicon sequencing studies
Authors: Qi Zheng, Casey Bartow-McKenney, Jacquelyn S. Meisel, Elizabeth A. Grice
Journal: Genome biology (2018)

Culture-independent analysis of microbial communities frequently relies on amplification and sequencing of the prokaryotic 16S ribosomal RNA gene. Typical analysis pipelines group sequences into operational taxonomic units (OTUs) to infer taxonomic and phylogenetic relationships. Here, we present HmmUFOtu, a novel tool for processing microbiome amplicon sequencing data, which performs rapid per-read phylogenetic placement, followed by phylogenetically informed clustering into OTUs and taxonomy assignment. Compared to standard pipelines, HmmUFOtu more accurately and reliably recapitulates microbial community diversity and composition in simulated and real datasets without relying on heuristics or sacrificing speed or accuracy.
Sympathetic Neuronal Activation Triggers Myeloid Progenitor Proliferation and Differentiation
Authors: Sathish Babu Vasamsetti, Jonathan Florentin, Emilie Coppin, Lotte C.A. Stiekema, Kang H. Zheng, Muhammad Umer Nisar, John Sembrat, David J. Levinthal, Mauricio Rojas, Erik S.G. Stroes, Kang Kim, Partha Dutta
Journal: Immunity (2018)
Abstract 2012: The generation of a NSCLC EMT reporter cell line for metastatic lung cancer drug discovery and development
Authors: Metewo S. Enuameh, Sangeeta Kumari, Chauzhong Zou, John Foulke, Elizabeth Turner, Weiguo Shu, Robert Newman
Journal: Cancer Research (2018)

Abstract Cancer metastasis continues to be the leading cause of mortality in cancer patients around the world. One of the prominent biological processes implicated in cancer metastasis is epithelial-to-mesenchymal transition (EMT). EMT has also been shown to have roles in many aspects of cancer initiation and progression, including tumorigenesis and drug resistance. Despite the accumulation of a large body of data on the association of EMT with cancer, to date, EMT has not been an active target for therapeutic development partly due to the lack of appropriate in vitro models. Utilizing some of the basic biology of EMT, we have created a novel advanced in vitro model for use in both basic research and discovery of new anti-EMT drugs. In lung cancer, vimentin (VIM) intermediate filament (IF) proteins are associated with EMT, and the metastatic spread of cancer. Vimentin expression is generally upregulated when epithelial cells transition to the mesenchymal phenotype. We capitalized on this biological phenomenon, using CRISPR/Cas9 gene editing to generate a VIM RFP (red fluorescent protein) reporter cell line in the A549 non-small cell lung cancer (NSCLC) cell line; one of the most widely used and recognized lung cancer cell lines. The A549 VIM RFP cell line harbors a C-terminal red fluorescent protein (RFP) tag on the vimentin gene which enables end-point or real-time tracking of the EMT status as cells transition from epithelial to mesenchymal phenotype under defined conditions. The EMT reporter cell line was verified at the nucleic acid (genomic and mRNA) and protein levels as well as in cell-based assays. Bio-functional evaluation of the A549 VIM RFP cell line shows sensitivity to metastatic NSCLC drugs PP1 (SRC inhibitor) and A83-01 (ALK5 inhibitor). These results provide the foundation for the use of this cell line in high throughput screening (HTS) applications including the identification of new anti-EMT drugs for metastatic NSCLC. Furthermore, the A549 Vim RFP reporter cell line is also a convenient and sensitive model for basic science research on the mechanisms of metastasis. Citation Format: Metewo S. Enuameh, Sangeeta Kumari, Chauzhong Zou, John Foulke, Elizabeth Turner, Weiguo Shu, Robert Newman. The generation of a NSCLC EMT reporter cell line for metastatic lung cancer drug discovery and development [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 2012.
Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma (ccRCC) and its association with PD-L1 expression.
Authors: Aly-Khan A. Lalani, Laurence Albiges, Kathryn P. Gray, Soumitro Pal, Jean-Christophe Pignon, Mamta Gupta, Rupal Satish Bhatt, David F. McDermott, Michael B. Atkins, George Franklin Vande Woude, Sabina Signoretti, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

4573 Background: Preclinical models show that c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). The relationship between c-Met and PD-L1 in human ccRCC is not well characterized. We compared c-Met expression between primary and metastatic sites in ccRCC tissues and evaluated the association with PD-L1 expression. Methods: Pairedprimary and metastatic samples from 45 ccRCC patients were included. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab, VARI) and calculated by a combined score (CS, 0-300) as: intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression was previously assessed by IHC (PMID: 26014095). c-Met expression (average c-Met CS) between paired primary and metastatic samples were compared using Wilcoxon signed-rank test. Associations of c-Met expression with PD-L1 expression (+/-) and other clinical features were assessed with Wilcoxon rank-sum tests. Results: Our cohort included 45 primary ccRCCs and 54 corresponding metastases. c-Met expression was higher in metastatic sites compared to primary (c-Met CS: 55 vs. 28, p=0.0003) and was numerically-greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression was associated with higher FNG and T-stage in both primary and metastatic sites (Table). Conclusions: Higher c-Met expression in metastases compared to paired primary tumors in our cohort of ccRCC suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. Although the observation of higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination trials. [Table: see text]
Dilation catheter-guided mini-forceps biopsy improves the diagnostic accuracy of malignant biliary strictures
Authors: Ying-Chun Ren, Chun-Lan Huang, Su-Min Chen, Qiu-Yan Zhao, Xin-Jian Wan, Bai-Wen Li
Journal: Endoscopy (2018)

Abstract Background Tissue sampling for biliary stricture is important for differential diagnosis and further treatment. The aim of this study was to assess a novel dilation catheter-guided mini-forceps biopsy (DCMB) method in the diagnosis of malignant biliary strictures. Methods 42 patients with malignant biliary stricture who underwent both brush cytology and DCMB during endoscopic retrograde cholangiopancreatography between October 2014 and November 2015 were retrospectively included. During DCMB, the mini biopsy forceps was introduced into the biliary stricture through the dilation catheter, and then the position and direction of the forceps were adjusted to obtain tissue samples. Results The positive rate of DCMB was significantly higher than that of brush cytology (81.0 % [34/42] vs. 38.1 % [16/42]; P &lt; 0.001). No severe complications occurred; three patients (7.1 %) experienced mild procedure-related acute pancreatitis. Conclusions The novel DCMB technique was a practical, safe, efficient, and low-costing method for diagnosing malignant biliary stricture with a high accuracy rate.
Abstract 560: Identification of a novel <i>MUTYH</i> mutation in non-small cell lung cancer
Authors: Alvin Hong-Wai Fong, Eunice Yuen-Ting Lau, William Ka-Chun Cheung, William Chi-Shing Cho
Journal: Cancer Research (2018)

Abstract Introduction: Lung cancer is the leading cause of death from cancer in Hong Kong and worldwide. Nearly 80-85% of lung cancers are diagnosed with non-small cell lung cancer (NSCLC). Treatment strategies can be refined according to the distinct difference of NSCLC molecular profiling among different ethnic populations. Moreover, oncogenic driver mutations are closely linked to NSCLC in non-smokers and young people. Therefore, the urge of finding pathogenic mutations is inevitable. This study aims to discover novel mutations in NSCLC patients in Hong Kong by next-generation sequencing and characterize the clinical significance of these mutations. Methods: In order to identify mutations, DNA was purified from 6 pairs of lung tumor-normal tissues from 2 stage I adenocarcinoma (LUAD), 2 stage III LUAD and 2 stage I squamous cell carcinoma (LUSC) patients. Samples were sequenced by targeted sequencing with the TOMA OS-Seq 130 cancer gene panel. Sequence alignment and variant calling were performed by combining TOMA Stratus and in-house pipelines. Results: The mean aligned reads exceeded 14 million and the mean coverage of target region was over 1000X. MUTYH deletion was found in 66.7% (4/6) of the patients. Data from The Cancer Genome Atlas (TCGA) revealed that MUTYH deletion is significantly associated with poorer disease-free survival (DFS) (p=0.0063) and overall survival (p=0.022) in LUAD patients. TCGA data also showed that MUTYH copy number correlates with gene expression (r=0.473) and LUAD patients with MUTYH mRNA overexpression have better DFS (p=0.0205). However, such correlations were not observed in LUSC patients. MUTYH is a DNA glycosylase which involves in the base excision repair and it repairs oxidative DNA damage by preventing G:C to T:A transversion. Numerous studies indicated that biallelic mutations in MUTYH cause MUTYH-associated polyposis and increase the lifetime risk of colorectal cancer. MUTYH mutations could be associated with increased risk of endometrial and breast cancer. Conclusion: To elucidate the clinical significance of MUTYH in LUAD, an independent cohort will be sequenced to validate the primary result. Immunohistochemistry, RT-qPCR and functional assays will be performed to examine the protein expression, the gene expression and the functional role. All these findings suggested that MUTYH deletion may play a crucial role in LUAD and potentially lead to the development of biomarker and therapeutic target. Citation Format: Alvin Hong-Wai Fong, Eunice Yuen-Ting Lau, William Ka-Chun Cheung, William Chi-Shing Cho. Identification of a novel MUTYH mutation in non-small cell lung cancer [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 560.