tbuckley/cabot-search huggingface dataset:
Mate pair sequencing outperforms fluorescence in situ hybridization in the genomic characterization of multiple myeloma
Authors: James Smadbeck, Jess F. Peterson, Kathryn E. Pearce, Beth A. Pitel, Andrea Lebron Figueroa, Michael Timm, Dragan Jevremovic, Min Shi, A. Keith Stewart, Esteban Braggio, Daniel L. Riggs, P. Leif Bergsagel, George Vasmatzis, Hutton M. Kearney, Nicole L. Hoppman, Rhett P. Ketterling, Shaji Kumar, S. Vincent Rajkumar, Patricia T. Greipp, Linda B. Baughn
Journal: Blood Cancer Journal (2019)

Abstract Fluorescence in situ hybridization (FISH) is currently the gold-standard assay to detect recurrent genomic abnormalities of prognostic significance in multiple myeloma (MM). Since most translocations in MM involve a position effect with heterogeneous breakpoints, we hypothesize that FISH has the potential to miss translocations involving these regions. We evaluated 70 bone marrow samples from patients with plasma cell dyscrasia by FISH and whole-genome mate-pair sequencing (MPseq). Thirty cases (42.9%) displayed at least one instance of discordance between FISH and MPseq for each primary and secondary abnormality evaluated. Nine cases had abnormalities detected by FISH that went undetected by MPseq including 6 tetraploid clones and three cases with missed copy number abnormalities. In contrast, 19 cases had abnormalities detected by MPseq that went undetected by FISH. Seventeen were MYC rearrangements and two were 17p deletions. MPseq identified 36 MYC abnormalities and 17 (50.0% of MYC abnormal group with FISH results) displayed a false negative FISH result. MPseq identified 10 cases (14.3%) with IgL rearrangements, a recent marker of poor outcome, and 10% with abnormalities in genes associated with lenalidomide response or resistance. In summary, MPseq was superior in the characterization of rearrangement complexity and identification of secondary abnormalities demonstrating increased clinical value compared to FISH.
What did the 2010s ever do for us?
Authors: Tom Moberly
Journal: BMJ (2019)

The past decade has been characterised largely by the fallout of the financial crash, a revolution in the way we use technology to buy goods and interact with one another, and the return of populism and nationalism as potent political forces.While these have affected all our lives, including our healthcare, they aren't the only issues that have shaped the decade.
Linking Branch Lengths across Sets of Loci Provides the Highest Statistical Support for Phylogenetic Inference
Authors: David A Duchêne, K Jun Tong, Charles S P Foster, Sebastián Duchêne, Robert Lanfear, Simon Y W Ho
Journal: Molecular Biology and Evolution (2019)

Abstract Evolution leaves heterogeneous patterns of nucleotide variation across the genome, with different loci subject to varying degrees of mutation, selection, and drift. In phylogenetics, the potential impacts of partitioning sequence data for the assignment of substitution models are well appreciated. In contrast, the treatment of branch lengths has received far less attention. In this study, we examined the effects of linking and unlinking branch-length parameters across loci or subsets of loci. By analyzing a range of empirical data sets, we find consistent support for a model in which branch lengths are proportionate between subsets of loci: gene trees share the same pattern of branch lengths, but form subsets that vary in their overall tree lengths. These models had substantially better statistical support than models that assume identical branch lengths across gene trees, or those in which genes form subsets with distinct branch-length patterns. We show using simulations and empirical data that the complexity of the branch-length model with the highest support depends on the length of the sequence alignment and on the numbers of taxa and loci in the data set. Our findings suggest that models in which branch lengths are proportionate between subsets have the highest statistical support under the conditions that are most commonly seen in practice. The results of our study have implications for model selection, computational efficiency, and experimental design in phylogenomics.
Granuloma annulare skin profile shows activation of T-helper cell type 1, T-helper cell type 2, and Janus kinase pathways
Authors: Michelle S. Min, Jianni Wu, Helen He, Juan Luis Sanz-Cabanillas, Ester Del Duca, Ning Zhang, Yael Renert-Yuval, Ana B. Pavel, Mark Lebwohl, Emma Guttman-Yassky
Journal: Journal of the American Academy of Dermatology (2019)
Somatostatin interneurons in the prefrontal cortex control affective state discrimination in mice
Authors: Diego Scheggia, Francesca Managò, Federica Maltese, Stefania Bruni, Marco Nigro, Daniel Dautan, Patrick Latuske, Gabriella Contarini, Marta Gomez-Gonzalo, Linda Maria Requie, Valentina Ferretti, Giulia Castellani, Daniele Mauro, Alessandra Bonavia, Giorgio Carmignoto, Ofer Yizhar, Francesco Papaleo
Journal: Nature Neuroscience (2019)
Hispanic race and outcome of metastatic (MET) colorectal cancer (CRC): Biology or health care (HC) setting?
Authors: Maryam Shabihkhani, Steven Yu, Dongyun Yang, Heinz-Josef Lenz, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2013)

e17559 Background: Hispanics (H) have lower CRC related mortality compared to Whites (W). However, over the past decade H have appreciated less improvement in CRC mortality. Given that treatments (TX) for early stage CRC is unchanged we speculate that the gap is due to poorer outcome in the MET setting. Delivery of HC is identified as one of the factor for poor outcomes. We examined the relationship between HC delivery (public or private hospital) and TX as the drivers of poorer outcome in H. Methods: We identified CRC patients (pts) with at least one cycle of chemotherapy (CT) in the first line MET setting at Los Angeles County Hospital (LAC-public hospital) and Norris Cancer Center (NCC-Private hospital) between 2004-2011. Demographics; tumor and TX related factors were collected. Primary endpoint was TTP (time from first day to progression on first line CT). Descriptive statistics were used to describe the population and where appropriate chi-square, Wilcoxon, and log-rank tests were used for comparison between the groups. Results: 251 pts, 45%H, 26%W, 20% Asian (A) and 9%Black (B) were included. The median age of the population was 55 (21-82) years. 55% of pts were male.74 % of pts had de-novo MET disease. 48% of pts had left sided, 27% right sided and 25% rectal cancer. 71% of pts treated at LAC and 29% at NCC. 46% of pts at LAC and 56% at NCC received bevacizumab (BEV) as part of their TX (p= 0.26). Median TTP in H was 10.2 months (m) (95% CI: 8.1-11.8), and in W was 16.8 m (95% CI: 11.2-27.2; P&lt;0.05). Hispanics who were TX at LAC had longer TTP in comparison to H at NCC (p= 0.01). In multivariate analysis, race remained a significant predictor of TTP (p=0.001). Conclusions: H are the largest and fastest growing minority in the US, identification of factors of disparate outcome is crucial. This study revealed a significant association between race and TTP. Use of BEV for MET CRC became a standard TX in 2004 and since then TX is mostly unchanged. Our cohort received homogenous TX with regards to use of BEV. The results show that H regardless of HC setting have shorter TTP than W suggesting an inherent biological difference in the tumor or response to TX. Future biomarker studies will shed light on the cause.
Abstract 15185: The Pattern of Atrial Fibrillation is Relevant to Predicting Thromboembolic Risk - is It Time to Rethink Risk Scores?
Authors: Jacob Y Cao, Ruilong Zhao, Kim H Chan, Ian Wilcox, Kevin Phan, Sean Lal
Journal: Circulation (2018)

Introduction: Atrial fibrillation (AF) is a major cause of stroke and premature death. Current AHA/ESC guidelines define subtypes of AF but these are not incorporated into risk scores of the compli...
18F-FDG PET/CT Findings in Metastatic Pilomatrix Carcinoma
Authors: Tarik Sengoz, Nilufer Avci
Journal: Clinical Nuclear Medicine (2019)

Abstract We describe a rare case of metastatic pilomatrix carcinoma with distant metastases 10 months after diagnosis. A 37-year-old woman was diagnosed with pilomatrix carcinoma by excisional biopsy from the occipital region and referred to us for 18 F-FDG PET/CT examinations at the time of diagnosis and 10 months after diagnosis. The first PET/CT did not show any pathological activity, whereas the second PET/CT showed multiple intensive 18 F-FDG uptakes in the right lung parenchyma, right hemithorax pleura, liver, and bones.
Pluripotent stem cell–derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity
Authors: Huang Zhu, Robert H. Blum, Ryan Bjordahl, Svetlana Gaidarova, Paul Rogers, Tom Tong Lee, Ramzey Abujarour, Gregory B. Bonello, Jianming Wu, Pei-Fang Tsai, Jeffrey S. Miller, Bruce Walcheck, Bahram Valamehr, Dan S. Kaufman
Journal: Blood (2019)

Antibody-dependent cellular cytotoxicity (ADCC) is a key effector mechanism of natural killer (NK) cells that is mediated by therapeutic monoclonal antibodies (mAbs). This process is facilitated by the Fc receptor CD16a on human NK cells. CD16a appears to be the only activating receptor on NK cells that is cleaved by the metalloprotease a disintegrin and metalloproteinase-17 upon stimulation. We previously demonstrated that a point mutation of CD16a prevents this activation-induced surface cleavage. This noncleavable CD16a variant is now further modified to include the high-affinity noncleavable variant of CD16a (hnCD16) and was engineered into human induced pluripotent stem cells (iPSCs) to create a renewable source for human induced pluripotent stem cell-derived NK (hnCD16-iNK) cells. Compared with unmodified iNK cells and peripheral blood-derived NK (PB-NK) cells, hnCD16-iNK cells proved to be highly resistant to activation-induced cleavage of CD16a. We found that hnCD16-iNK cells were functionally mature and exhibited enhanced ADCC against multiple tumor targets. In vivo xenograft studies using a human B-cell lymphoma demonstrated that treatment with hnCD16-iNK cells and anti-CD20 mAb led to significantly improved regression of B-cell lymphoma compared with treatment utilizing anti-CD20 mAb with PB-NK cells or unmodified iNK cells. hnCD16-iNK cells, combined with anti-HER2 mAb, also mediated improved survival in an ovarian cancer xenograft model. Together, these findings show that hnCD16-iNK cells combined with mAbs are highly effective against hematologic malignancies and solid tumors that are typically resistant to NK cell-mediated killing, demonstrating the feasibility of producing a standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies that are otherwise refractory.
A randomised, double‐blind, placebo‐controlled trial of metformin on myocardial efficiency in insulin‐resistant chronic heart failure patients without diabetes
Authors: Anders Hostrup Larsen, Niels Jessen, Helene Nørrelund, Lars Poulsen Tolbod, Hendrik Johannes Harms, Søren Feddersen, Flemming Nielsen, Kim Brøsen, Nils Henrik Hansson, Jørgen Frøkiær, Steen Hvitfeldt Poulsen, Jens Sörensen, Henrik Wiggers
Journal: European Journal of Heart Failure (2019)
Fall in male tobacco users is “turning point,” says WHO
Authors: Owen Dyer
Journal: BMJ (2019)

The director general of the World Health Organization has hailed the first measured decline in the number of male tobacco users worldwide as “a turning point in the fight against tobacco.”

“For many years now we have witnessed a steady rise in the number of males using tobacco products,” said Tedros Adhanom Ghebreyesus, announcing the findings of WHO’s third global report this century into tobacco use trends.1 “But now, for the first time, we are seeing a decline in male use, driven by governments being tougher on the tobacco industry.”

The decline is miniscule—there were 1.093 billion male tobacco users worldwide in 2018 and there will be two million fewer, or 1.091 billion, in 2020. But the …
FIREVAT: finding reliable variants without artifacts in human cancer samples using etiologically relevant mutational signatures
Authors: Hyunbin Kim, Andy Jinseok Lee, Jongkeun Lee, Hyonho Chun, Young Seok Ju, Dongwan Hong
Journal: Genome Medicine (2019)

Abstract Background Accurate identification of real somatic variants is a primary part of cancer genome studies and precision oncology. However, artifacts introduced in various steps of sequencing obfuscate confidence in variant calling. Current computational approaches to variant filtering involve intensive interrogation of Binary Alignment Map (BAM) files and require massive computing power, data storage, and manual labor. Recently, mutational signatures associated with sequencing artifacts have been extracted by the Pan-cancer Analysis of Whole Genomes (PCAWG) study. These spectrums can be used to evaluate refinement quality of a given set of somatic mutations. Results Here we introduce a novel variant refinement software, FIREVAT (FInding REliable Variants without ArTifacts), which uses known spectrums of sequencing artifacts extracted from one of the largest publicly available catalogs of human tumor samples. FIREVAT performs a quick and efficient variant refinement that accurately removes artifacts and greatly improves the precision and specificity of somatic calls. We validated FIREVAT refinement performance using orthogonal sequencing datasets totaling 384 tumor samples with respect to ground truth. Our novel method achieved the highest level of performance compared to existing filtering approaches. Application of FIREVAT on additional 308 The Cancer Genome Atlas (TCGA) samples demonstrated that FIREVAT refinement leads to identification of more biologically and clinically relevant mutational signatures as well as enrichment of sequence contexts associated with experimental errors. FIREVAT only requires a Variant Call Format file (VCF) and generates a comprehensive report of the variant refinement processes and outcomes for the user. Conclusions In summary, FIREVAT facilitates a novel refinement strategy using mutational signatures to distinguish artifactual point mutations called in human cancer samples. We anticipate that FIREVAT results will further contribute to precision oncology efforts that rely on accurate identification of variants, especially in the context of analyzing mutational signatures that bear prognostic and therapeutic significance. FIREVAT is freely available at https://github.com/cgab-ncc/FIREVAT
Effects of Tobacco Smoking on the Tumor Immune Microenvironment in Head and Neck Squamous Cell Carcinoma
Authors: Janis V. de la Iglesia, Robbert J.C. Slebos, Laura Martin-Gomez, Xuefeng Wang, Jamie K. Teer, Aik Choon Tan, Travis A. Gerke, Garrick Aden-Buie, Tessa van Veen, Jude Masannat, Ritu Chaudhary, Feifei Song, Michelle Fournier, Erin M. Siegel, Matthew B. Schabath, J. Trad Wadsworth, Jimmy Caudell, Louis Harrison, Bruce M. Wenig, Jose Conejo-Garcia, Juan C. Hernandez-Prera, Christine H. Chung
Journal: Clinical Cancer Research (2019)

Patients with head and neck squamous cell carcinoma (HNSCC) who actively smoke during treatment have worse survival compared with never-smokers and former-smokers. We hypothesize the poor prognosis in tobacco smokers with HNSCC is, at least in part, due to ongoing suppression of immune response. We characterized the tumor immune microenvironment (TIM) of HNSCC in a retrospective cohort of 177 current, former, and never smokers.Tumor specimens were subjected to analysis of CD3, CD8, FOXP3, PD-1, PD-L1, and pancytokeratin by multiplex immunofluorescence, whole-exome sequencing, and RNA sequencing. Immune markers were measured in tumor core, tumor margin, and stroma.Our data indicate that current smokers have significantly lower numbers of CD8+ cytotoxic T cells and PD-L1+ cells in the TIM compared with never- and former-smokers. While tumor mutation burden and mutant allele tumor heterogeneity score do not associate with smoking status, gene-set enrichment analyses reveal significant suppression of IFNα and IFNγ response pathways in current smokers. Gene expression of canonical IFN response chemokines, CXCL9, CXCL10, and CXCL11, are lower in current smokers than in former smokers, suggesting a mechanism for the decreased immune cell migration to tumor sites.These results suggest active tobacco use in HNSCC has an immunosuppressive effect through inhibition of tumor infiltration of cytotoxic T cells, likely as a result of suppression of IFN response pathways. Our study highlights the importance of understanding the interaction between smoking and TIM in light of emerging immune modulators for cancer management.
Activation of PI3K/AKT signaling pathway in malignant pleural mesothelioma cells
Authors: Yutaro Suzuki, Hideki Murakami, Koji Kawaguchi, Tetsuo Taniguchi, Yoshinori Hasegawa, Kaoru Shimokata, Yoshitaka Sekido
Journal: Cancer Research (2008)

2721   Background:  The phosphatidylinositol 3 kinase (PI3K) /AKT signaling pathway is important for cell survival and proliferation, and it has a significant role in carcinogenesis. Deregulated activation of this pathway has been found in many human common malignancies, either by loss of PTEN phosphatase, a negative regulator of PI3K pathway, or by constitutive activation of PI3K or downstream elements including AKT by genetic mutation.  Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm associated with asbestos exposure. Previous reports showed that the PI3K/AKT pathway was also frequently activated in MPM, but the molecular mechanisms of its pathway activation in MPM cells remain unclear. In the present study, to determine the frequency and key genetic mutations for the PI3K/AKT activation in MPM, we performed expression and/or mutation analyses of the molecules associated with this pathway including PIK3CA, PTEN, and LKB1, using MPM cell lines.  Methods:  Twenty MPM cell lines were investigated, 13 cell lines we established from Japanese patients and 7 cell lines from Caucasians. The expressions of AKT and PTEN in MPM cell lines were detected with Western blot analysis. Activated AKT was also analyzed with an anti-phospho-AKT antibody. Mutation analyses of PIK3CA, PTEN, and LKB1 were carried out by genomic PCR and direct sequencing.  Results:  Western blot analysis revealed that AKT was prominently activated in 10 (56%) of 18 cell lines studied compared to a normal mesothelial cell line, MeT-5A, under serum-starved condition. The loss of PTEN expression was observed in one cell line, and the following analysis using PTEN complementary DNA synthesized from this cell line showed the existence of an aberrant splicing transcript which lacked exon 2 of the PTEN gene. We demonstrated that this cell line had a homozygous deletion of approximately 40 kb, which encompassed exon 2 of PTEN, while no other mutation was detected in the remaining 19 cell lines. Moreover, no somatic mutation of PIK3CA and LKB1 was detected in the 20 cell lines.  Conclusion:  AKT activation was shown in more than half of the MPM cell lines investigated. Homozygous deletion of PTEN was detected in one cell line with elevated AKT activation. Somatic mutations of PIK3CA, LKB1, and PTEN appear to be infrequent in mesothelioma, suggesting that alterations of other upstream molecules of the PI3K/AKT pathway may be responsible for this signaling pathway activation. Thus, although the activation mechanism of the PI3K/AKT pathway in mesothelioma was not fully elucidated, this pathway may be a potential therapeutic target for mesothelioma due to its frequent activation in MPM cells.
Chemotherapeutic drugs stimulate the release and recycling of extracellular vesicles to assist cancer cells in developing an urgent chemoresistance
Authors: Xiaokun Wang, Dongjuan Qiao, Likun Chen, Meng Xu, Shupeng Chen, Liyan Huang, Fang Wang, Zhen Chen, Jiye Cai, Liwu Fu
Journal: Molecular Cancer (2019)

Abstract Background Chemotherapy is a widely used treatment for cancer. However, the development of acquired multidrug resistance (MDR) is a serious issue. Emerging evidence has shown that the extracellular vesicles (EVs) mediate MDR, but the underlying mechanism remains unclear, especially the effects of chemotherapeutic agents on this process. Methods Extracellular vesicles isolation was performed by differential centrifugation. The recipient cells that acquired ATP-binding cassette sub-family B member 1 (ABCB1) proteins were sorted out from co-cultures according to a stringent multi-parameter gating strategy by fluorescence-activated cell sorting (FACS). The transfer rate of ABCB1 was measured by flow cytometry. The xenograft tumor models in mice were established to evaluate the transfer of ABCB1 in vivo. Gene expression was detected by real-time PCR and Western blotting. Results Herein, we show that a transient exposure to chemotherapeutic agents can strikingly increase Rab8B-mediated release of extracellular vesicles (EVs) containing ABCB1 from drug-resistant cells, and accelerate these EVs to circulate back onto plasma membrane of sensitive tumor cells via the down-regulation of Rab5. Therefore, intercellular ABCB1 transfer is significantly enhanced; sensitive recipient cells acquire a rapid but unsustainable resistance to evade the cytotoxicity of chemotherapeutic agents. More fascinatingly, in the xenograft tumor models, chemotherapeutical drugs also locally or distantly increase the transfer of ABCB1 molecules. Furthermore, some Non-small-cell lung carcinoma (NSCLC) patients who are undergoing primary chemotherapy have a rapid increase of ABCB1 protein in their monocytes, and this is obviously associated with poor chemotherapeutic efficacy. Conclusions Chemotherapeutic agents stimulate the secretion and recycling of ABCB1-enriched EVs through the dysregulation of Rab8B and Rab5, leading to a significant increase of ABCB1 intercellular transfer, thus assisting sensitive cancer cells to develop an urgent resistant phenotype. Our findings provide a new molecular mechanism of how chemotherapeutic drugs assist sensitive cancer cells in acquiring an urgent resistance.
Transforming growth factor-β makes the key characteristics of the proteome CD133- differentiated cells closer to CD133+ cancer stem cells of glioblastoma
Authors: S. Zaitsev, V. Shevchenko, N. Arnotskaya, I.A. Lyakhova, Y. Khotimchenko, I.S. Bryukhovetskiy
Journal: Annals of Oncology (2019)
Association Between Recreational Cannabis Use and Cardiac Structure and Function
Authors: Mohammed Y. Khanji, Magnus T. Jensen, Asmaa A. Kenawy, Zahra Raisi-Estabragh, Jose M. Paiva, Nay Aung, Kenneth Fung, Elena Lukaschuk, Filip Zemrak, Aaron M. Lee, Ahmet Barutcu, Edd Maclean, Jackie Cooper, Stefan K. Piechnik, Stefan Neubauer, Steffen E. Petersen
Journal: JACC. Cardiovascular imaging (2019)

Cannabis is one of the most widely produced and consumed recreational drugs in the world, with over 192 million global users ([1][1]). The World Health Organization has warned against the potential harmful health effects of nonmedicinal cannabis use and highlighted the need for more research
Multipotent Mesenchymal Stromal Cells for Poor Graft Function after Allogeneic Hematopoietic Cell Transplantation:a Multicenter Prospective Study
Authors: Sophie Servais, Frédéric Baron, Chantal Lechanteur, Etienne Baudoux, Alexandra Briquet, Dominik Selleslag, Johan A. Maertens, Xavier Poire, Wilfried Schroyens, Carlos Graux, Rik Schots, Pierre Zachée, Aurelie Ory, Julie Herman, Tessa Kerre, Yves Beguin
Journal: Blood (2019)