tbuckley/cabot-search huggingface dataset:
Clinical validation of NGS workflow in myeloid neoplasms.
Authors: Céline Bourgne, Marc Berger, Alexander Kurze
Journal: Journal of Clinical Oncology (2019)

e18557 Background: The advent of NGS technologies revolutionized patient management. Compiling a comprehensive list of genomic alterations and summarizing the clinical implications is complex and time-consuming. One main difficulty lies in detecting relevant genomic alterations with actionable, diagnostic and prognostic value. The development of bioinformatic tools is essential to interpret genomic data. Here we describe the validation of an end-to-end genomic NGS workflow to diagnose myeloid disorders. Methods: Performed on 81 patients previously diagnosed using non-NGS diagnostic tests, this study aims at finding out if an NGS diagnostic approach can accelerate the diagnosis process. DNA was extracted from purified mononuclear cells (n = 54), polymorphonuclear cells (n = 50) and/or total leucocytes (n = 58) from peripheral blood and bone marrow (n = 9). Genomic analysis was performed using a capture-based solution (MYS by SOPHiA GENETICS) covering 30 relevant genes associated with MDS, MPN and Leukemia. Sequencing was performed on Illumina MiSeq and results were analyzed using the SOPHiA platform. Results: We performed 2 validation runs with high raw reads quality (Phred-score &gt; 35). Over 90% of reads were on-target and coverage was larger &gt; 1000x with a mean of 10 regions falling below this threshold for each sample. Repeatability and reproducibility were evaluated with 6 samples and showed a good correlation between intra (R = 0.993) and inter run (R = 0.97) replicates. Average number of driver mutation was 1.3 for patients with MPN (n = 38), 3 for patients with CMML (n = 9), 2.3 for patients with MDS (n = 10), 2.5 for patients with AML (n = 13) and 1.2 for other neoplasms (n = 11). Obtained NGS results supported previous diagnoses. However for patients where peripheral blood and bone marrow samples were used to perform the analysis, one patient with mastocytosis has a discrepancy of variants found in each sample type. We detected 4 variants in peripheral blood and one additional variant in DNA extracted from bone marrow. The mutation occurred in the RUNX1 gene and was associated to an unfavourable prognosis with higher risk of relapse. Conclusions: We described here the successful validation of a single NGS panel to diagnose multiple myeloid neoplasms. The workflow shows excellent reliability in terms of reproducibility and repeatability which is essential for clinical implementation. Each method has its own benefits and limitations and interpretation of results should be made taking into account the type of the sample used.
Matters Arising: Zhu et al, "A novel gene variation of TNFa associated with ankylosing spondylitis: A reconfirmed study"
Authors: Matthew Brown
Journal: Annals of the Rheumatic Diseases (2008)

In a recently published study1 involving 79 ankylosing spondylitis (AS) patients and 132 unrelated healthy blood donors, Zhu et al report association of a tumour necrosis factor α (TNFα) single nucleotide polymorphism (SNP), rs1799724, with AS.1 I have many concerns with this paper and its conclusions...
Abstract P6-05-08: Progesterone receptor membrane component 1 controls cellular proliferation and plays a key role in the molecular circuitry of both ER positive and triple negative breast cancers
Authors: Diego A Pedroza, Alejandra Bencomo, Adriana Galvez, Ramadevi Subramani, Venkatesh Rajamanickam, Rajkumar Lakshmanaswamy
Journal: Cancer Research (2020)

Abstract Introduction: Increased expression of progesterone receptor membrane component 1 (PGRMC1), has been linked to breast cancer cell proliferation and tumor growth via epidermal growth factor receptor (EGFR) dependent interaction. As estrogen receptor positive breast cancers receive endocrine therapy and triple negative breast cancers (TNBC) rely on chemotherapeutic agents and or small molecule inhibitors. PGRMC1 could be a potential therapeutic target for both estrogen receptor positive and TNBCs, however its mechanism of action remains elusive. We, aim to understand the signaling mechanism behind PGRMC1 and its potential as viable target for the treatment of breast cancers. Materials and Methods: A panel of non-malignant and malignant breast cell lines were cultured and screened for PGRMC1 expression. PGRMC1 overexpressing breast cancer cell lines were treated with AG-205 (PGRMC1 inhibitor) and PGRMC1 targeting siRNAs. MTS, qRT-PCR, Western blot, immunofluorescence, flow cytometry assays and phospho explorer antibody array analysis were performed. Results: Increased PGRMC1 mRNA and protein levels were observed in estrogen receptor positive ZR-75-1 and TNBC MDA-MB-468 cells, these results were validated and compared to online RNA-seq based gene expression analysis of breast cell lines and breast tumor data sets. Data from online databases also demonstrated PGRMC1 overexpression in multiple breast cancer subtypes (Luminal, Basal B and Basal A). Immunohistochemistry demonstrated strong staining for PGRMC1 in human breast cancer tissue compared to normal tissue. Both AG-205 treatment and PGRMC1 silencing decreased cell proliferation, induced cell cycle arrest at the G0/G1 phase, promoted apoptosis and reduced the capability of the cells to migrate and invade. Phospho-specific antibody array data demonstrated overall downregulation of the EGFR/PI3K/AKT signaling mechanisms following AG-205 and PGRMC1 silencing. Alteration in the expression of key markers of cell proliferation, apoptosis and cell cycle revealed that PGRMC1 inhibition decreases breast cancer proliferation. Conclusion: Our data demonstrate that PGRMC1 plays a prominent role in regulating breast cancer growth and progression by altering the EGFR/PI3K/AKT signaling mechanisms. Citation Format: Diego A Pedroza, Alejandra Bencomo, Adriana Galvez, Ramadevi Subramani, Venkatesh Rajamanickam, Rajkumar Lakshmanaswamy. Progesterone receptor membrane component 1 controls cellular proliferation and plays a key role in the molecular circuitry of both ER positive and triple negative breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-08.
Abstract 828: Accelerated epigenetic aging in bladder cancer patients
Authors: Yap Ching Chew, Wei Guo, Xiaojing Yang, Paolo Piatti, Mingda Jin, Keith Booher, Benjamin Jara, Xi-Yu Jia
Journal: Cancer Research (2019)

Abstract Aging represents the most important risk factor for many chronic diseases including cardiovascular diseases, diabetes, and cancer, therefore understanding the mechanisms of aging is a fundamental step for designing new treatments for chronic diseases. DNA methylation is the most reliable and accurate molecular marker for aging quantification, however, genome-wide DNA methylation profiling techniques, such as reduced representative bisulfite sequencing and Illumina Bead Array that are widely used in aging research are prohibitively expensive and have poor data quality at low-read coverage sites. Here we report a robust targeted bisulfite sequencing approach, called SWARM® (Simplified Whole-panel Amplification Reaction Method), for the accurate biological age determination. SWARM™ is flexible and low cost, requires relatively low DNA starting material, allows the simultaneous amplification and sequencing of hundreds of loci, and has shown to increase sample throughput. Using the SWARM® approach, we were able to analyze the methylation level of several hundreds of age-associated loci including the published Horvath Clock sites. Gender-specific age-predictive models were built using the elastic net regression of DNA methylation levels of the loci and chronological age of urine DNA samples of over 300 healthy subjects of 18 to 88 years old. Urine samples from bladder cancer patients exhibit significant age acceleration, with an average of &amp;gt;10 years. In brief, our gender-specific urine DNAge® analysis is a tool for the precise biological aging quantification and can be used to address questions in aging and urinary track cancers. Citation Format: Yap Ching Chew, Wei Guo, Xiaojing Yang, Paolo Piatti, Mingda Jin, Keith Booher, Benjamin Jara, Xi-Yu Jia. Accelerated epigenetic aging in bladder cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 828.
Kelch-like Protein 11 Antibodies in Seminoma-Associated Paraneoplastic Encephalitis
Authors: Caleigh Mandel-Brehm, Divyanshu Dubey, Thomas J. Kryzer, Brian D. O’Donovan, Baouyen Tran, Sara E. Vazquez, Hannah A. Sample, Kelsey C. Zorn, Lillian M. Khan, Ian O. Bledsoe, Andrew McKeon, Samuel J. Pleasure, Vanda A. Lennon, Joseph L. DeRisi, Michael R. Wilson, Sean J. Pittock
Journal: New England Journal of Medicine (2019)

A 37-year-old man with a history of seminoma presented with vertigo, ataxia, and diplopia.An autoantibody specific for kelch-like protein 11 (KLHL11) was identified with the use of programmable phage display.Immunoassays were used to identify KLHL11 IgG in 12 other men with similar neurologic features and testicular disease.Immunostaining of the patient's IgG on mouse brain tissue showed sparse but distinctive points of staining in multiple brain regions, with enrichment in perivascular and perimeningeal tissues.The onset of the neurologic syndrome preceded the diagnosis of seminoma in 9 of the 13 patients.An age-adjusted estimate of the prevalence of autoimmune KLHL11 encephalitis in Olmsted County, Minnesota, was 2.79 cases per 100,000 men.
Abstract LB-268: Assessment of flat dosing strategy for INCMGA00012 in patients with advanced tumors
Authors: Xuejun chen, Phil Wang, Sanjeev Kaul, Bradley Sumrow, Swamy Yeleswaram
Journal: Cancer Research (2019)

Abstract Background: INCMGA00012, a humanized, hinge-stabilized, IgG4κ monoclonal antibody that recognizes human PD-1, is being developed for the treatment of multiple solid tumor types, both as monotherapy and in combination with other potentially immunoactive agents. Flat dosing is preferred to weight-based dosing for multiple reasons, including convenience of preparation and administration, reduced errors in preparation calculation, and minimization of drug waste. A modeling and simulation approach was employed to support flat doses for later phase studies. Patients and Methods: INCMGA00012 has been administered to approximately 200 participants in a Phase 1 study (Study INCMGA 0012-101) at weight-based doses ranging from 1 to 10 mg/kg Q2W or Q4W and at flat doses of 500 mg Q4W and 750 mg Q4W. PK data from weight-based doses were used for population PK model development and data from flat doses were used for model validation. Simulations were performed to support the selection of RP2 flat dose. Results: The concentrations of INCMGA00012 were adequately described by a 2-compartment model with first-order elimination. Higher clearance was estimated for 1 mg/kg (23.5 mL/h) than the other dose groups (13.5 mL/h). Body weight dependence of clearance and volume of distribution for central compartment were characterized by power relationships with exponents of 0.911 and 0.493, respectively. The model was validated using PK data from participants who received INCMGA00012 500 mg Q4W and 750 mg Q4W, respectively, in the cohort expansion phase. Median steady state trough concentrations of 500 mg Q4W and 750 mg Q4W exceeded the target value. Conclusion: Modeling and simulation provide justification for 500 mg Q4W for further clinical development of INCMGA00012 based upon favorable safety, PK characteristics and presumed flat exposure-response relationships for efficacy. Citation Format: Xuejun chen, Phil Wang, Sanjeev Kaul, Bradley Sumrow, Swamy Yeleswaram. Assessment of flat dosing strategy for INCMGA00012 in patients with advanced tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-268.
Abstract 4328: Epigenetic modulation of SSTR2 expression provides the potential to broaden PEN-221 treatment population
Authors: Samantha Perino, James Quinn, Jessica Freda, Brian White, Scott Bailey, Viren Bhatia, Beata Sweryda-Krawiec, Mark Bilodeau, Jeffrey D. Bloss, Kerry Whalen, Richard Wooster
Journal: Cancer Research (2019)

Abstract The expression of somatostatin receptor subtype 2 (SSTR2) is increased in up to 80% of neuroendocrine tumors (NETs), 20-40% of small cell lung cancers (SCLC) and a number of other tumor types. As a cell surface receptor, SSTR2 is a logical target for a drug conjugate. However, marginal, or loss of, expression of SSTR2 in tumor tissues has potential to limit the benefit from such conjugates. Recent published preclinical studies have demonstrated that epigenetic modulators, such as HDAC inhibitors, can result in increased SSTR2 expression with treatment. Given that the expression of SSTR2 can be variable from patient to patient and in some cases low to absent, we hypothesized that the combination of epigenetic modulators with an SSTR2 target therapy may provide a benefit for patients who are not eligible for these targeted approaches on their own. PEN-221 is a miniature drug conjugate of an SSTR2 targeting peptide attached to the potent cytotoxic DM1 through a cleavable disulfide linker. PEN-221, currently in Phase 1/2a (NCT02936323), is designed as a potent and selective anticancer agent to treat patients whose tumors express SSTR2. The targeting peptide of PEN-221 selectively binds to SSTR2, triggers receptor internalization leading to the accumulation of the DM1 to provide antitumor activity by disrupting microtubule networks causing apoptosis and mitotic catastrophe. In preclinical studies, single agent PEN-221 treatment leads to complete and sustained tumor regression in xenograft models that over-express SSTR2. We hypothesize that increased expression of SSTR2 as a result of epigenetic modulation from HDAC or other epigenetic modulators, may allow for the broadening of PEN-221 treatable tumors. To evaluate these hypotheses, we have combined PEN-221 and epigenetic modulators in preclinical models of cancer. Efficacy studies were carried out in models expressing various degrees of SSTR2, and combinations resulted in greater efficacy than that of the single agent. In addition, a pharmacodynamic assessment of epigenetic modulator treatment on SSTR2 expression levels was performed. These data demonstrate that combination of PEN-221 and epigenetic modulators provide greater efficacy than single agent activity alone and support the evaluation of such combinations in the clinical setting. Citation Format: Samantha Perino, James Quinn, Jessica Freda, Brian White, Scott Bailey, Viren Bhatia, Beata Sweryda-Krawiec, Mark Bilodeau, Jeffrey D. Bloss, Kerry Whalen, Richard Wooster. Epigenetic modulation of SSTR2 expression provides the potential to broaden PEN-221 treatment population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4328.
Abstract 4830: ABX9xx: A bispecific centyrin that synergizes to attenuate intracellular signaling in Met/EGFR positive tumors
Authors: Russ Addis, Robert Kolakowski, Swapnil Kulkarni, Josh Gorsky, Rebecca Meyer, Karyn ONeil
Journal: Cancer Research (2019)

Abstract ABX9xx is a bispecific Centyrin targeting the Met-EGFR axis, an emerging cancer treatment paradigm. Centyrins are small, chemically simple proteins based on a human FN3 domain that can be engineered to have high affinity for a selected target and are easily linked to form multi-specific binders. The standard of care for patients with EGFR mutant non-small cell lung cancer (NSCLC) is treatment with small molecule tyrosine kinase inhibitors (TKI) including recently approved third generation molecules (ie. osimertinib). Despite initial promising responses with TKIs, most patients regress within 12-14 months due to resistance. A predominant resistance mechanism dependent on Met amplification and signaling has been described from both in vitro experiments and clinical data. Targeting Met and EGFR with a bispecific ligand blocking inhibitor that attenuates intracellular signaling may provide a significant efficacy advantage and reduced side effect profile compared to small molecule TKI combinations. Exploiting the potential for avidity on tumor tissue, a bispecific ligand blocking inhibitor of Met and EGFRis also anticipated to provide improved selectivity for tumor tissue that overexpress both receptors compared to normal tissue with lower receptor expression. To enable sustained exposure while maintaining small size for good tumor penetration, ABX9xx includes a domain comprising an albumin binding Centyrin. ABX9xx activity on Met, EGFR and downstream signaling proteins was confirmed on several lung cancer cell lines in vitro including those carrying clinically observed mutations in Met and EGFR. ABX9xx inhibited EGFR phosphorylation independent of EGFR mutational status with higher potency than osimertinib. In addition, ABX9xx inhibited Met phosphorylation with higher potency than Crizotinib, an ALK inhibitor with cross reactivity to Met, currently used to treat Met positive patients. The pharmacokinetic properties of ABX9xx in animal models suggest a suitable dosing paradigm in patients. Together the data provides a strong rationale for advancing ABX9xx into clinical development for NSCLC and other cancers where EGFR and MET are drivers of tumor progression. Citation Format: Russ Addis, Robert Kolakowski, Swapnil Kulkarni, Josh Gorsky, Rebecca Meyer, Karyn ONeil. ABX9xx: A bispecific centyrin that synergizes to attenuate intracellular signaling in Met/EGFR positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4830.
Abstract 1480: A novel mechanism of immunosuppression via nanotube mediated mitochondrial trafficking between cancer cell and immune cell
Authors: Tanmoy Saha, Chinmayee Dash, Sachin Khiste, Shiladitya Sengupta
Journal: Cancer Research (2019)

Abstract Cancer cells deploy multiple mechanisms for immune evasion. Here we report a novel mechanism of cancer cell-induced immune evasion via organelle trafficking between cancer cells and immune cells through physical nanotubes. Using high resolution scanning electron microscopy to analyze a co-culture assay of breast cancer cells and NKT cells revealed that the cancer cells and NKT cells form physical nanotube connections at early time points. Immunofluorescence imaging and quantification using flow cytometry revealed that the cancer cells rapidly hijack mitochondria from immune cells through these nanotubes. The transfer of mitochondria from immune cell to cancer cells imposes a metabolic impairment and results in a reduced population of immune cells. This is not observed in a control coculture using a Boyden chamber, where the two cell types are prevented from forming nanotubes. As the nanotubes are assembled via cytoskeletal rearrangement, we next tested whether the members of Rho-family of GTPases, Cdc42, Ral and Rac are involved in the actin polymerization. Indeed, an inhibitor for Cdc42/Rac1 GTPase inhibitor (ML141) and a geranylgeranyltransferase 1 inhibitor (L-778,123) significantly decreased mitochondrial transfer, and prevented the depletion of NKT cells in co-culture. Furthermore, treating 4T1 tumor-bearing animals with a combination of L-778,123 and a PD1 immune checkpoint inhibitor increased the anti-tumor efficacy compared to PD1 inhibition alone. Conclusion: Our study sheds insights on a novel mechanism of cancer immune suppression via nanotube-mediated intercellular organelle trafficking. The efficacy of GTPase- or geranylgeranyltransferase-inhibitors, in perturbing this process, and the increased efficacy of the combination with PD1 inhibitor, opens up the possibility of developing these as novel immunotherapy agents for cancer. Citation Format: Tanmoy Saha, Chinmayee Dash, Sachin Khiste, Shiladitya Sengupta. A novel mechanism of immunosuppression via nanotube mediated mitochondrial trafficking between cancer cell and immune cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1480.
Home versus outpatient pulmonary rehabilitation in COPD: a propensity-matched cohort study
Authors: Claire Marie Nolan, Djeya Kaliaraju, Sarah Elizabeth Jones, Suhani Patel, Ruth Barker, Jessica A Walsh, Stephanie Wynne, William Man
Journal: Thorax (2019)

Home-based exercise has been proposed as an equivalent treatment strategy to supervised outpatient pulmonary rehabilitation (PR), but it is not known whether its implementation into clinical practice produces similar benefits to those observed in trials. We compared the real-world responses of 154 patients with COPD undergoing home-based exercise with a matched group attending supervised PR. We observed smaller improvements in exercise capacity with home-based exercise compared with PR, but similar improvements in quality of life. We propose that supervised PR remains the standard of care, with home-based exercise a less effective alternative for those unable to attend PR.
Abstract 4380: LSR promotes cell proliferation and migration subsequent to uptake of fatty acid in epithelial ovarian cancer
Authors: Kosuke Hiramatsu, Satoshi Serada, Minoru Fujimoto, Yutaka Ueda, Tadashi Kimura, Tetsuji Naka
Journal: Cancer Research (2019)

Abstract Background Previously, we identified lipolysis-stimulated lipoprotein receptor (LSR) as a new therapeutic target of epithelial ovarian cancer (EOC), and we reported anti-cancer effect of our newly developed monoclonal antibody (mAb) against LSR-positive EOC in vitro and in vivo. We also demonstrated that LSR took in triglyceride-rich protein and contributed cell proliferation, however, lipid metabolic pathway via LSR is still unclear. Thus, we aimed to reveal the function of LSR on lipid metabolism in EOC cells. Methods We investigated the activation of beta-oxidation, ATP production, cell proliferation and cell migration via LSR after administration of fatty acid (FA) using LSR-positive EOC cells and LSR-knockout EOC cells. Moreover, we also investigated anti-cancer effect of our anti-LSR mAb against lipid metabolism via LSR. Results In LSR-positive EOC cells, FA administration increased intracellular lipid accumulation. In glucose restricted environment, LSR promoted FA uptake and promoted ATP production (p &amp;lt; 0.05). In addition, FA promoted cell proliferation and cell migration in LSR-positive EOC cells (p &amp;lt; 0.05). These results suggest that LSR promoted FA uptake in glucose restricted environment and also promoted lipid metabolism including beta-oxidation, TCA cycle and electron transport system leading to ATP production. Finally, our anti-LSR mAb inhibited these lipid metabolic pathways (p &amp;lt; 0.05). Conclusions Fatty acid uptake via LSR in glucose restricted environment contributed to cell proliferation and migration subsequent to activation of lipid metabolism, and anti-LSR mAb inhibited these processes. LSR might contribute to cancer spread and metastasis of EOC. Citation Format: Kosuke Hiramatsu, Satoshi Serada, Minoru Fujimoto, Yutaka Ueda, Tadashi Kimura, Tetsuji Naka. LSR promotes cell proliferation and migration subsequent to uptake of fatty acid in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4380.