tbuckley/cabot-search huggingface dataset:
Abstract PR18: Comparative screening of skin-derived NCSCs, melanocytes, and melanoma developmental programs reveals LPAR1 in MAPKi resistance
Authors: Vito W. Rebecca, Jianglan Liu, Thomas Connelly, Keith Flaherty, Ze’ev Ronai, Meenhard Herlyn
Journal: Cancer Research (2020)

Abstract Despite the high efficacy of BRAFi/MEKi in BRAF-MT melanomas, resistance arises in the majority of cases. Melanoma hijacks developmental pathways that drive aggressiveness; however, gene signatures shared by melanocyte progenitor cells and melanoma cells remain poorly understood. Here, we define common dependencies in neural crest stem cells (NCSCs) and melanoma cells not present in melanocytes through computational transcriptome analyses and targeted siRNA screens against shared developmental genes. Secondary validation coupled with Ingenuity Pathway Analysis identified the LPAR1-RAPGEF5-RAP1A axis as the top pathway critical for stem cell maintenance and melanoma aggressiveness. Genome-wide gene expression data in the CCLE demonstrates LPAR1 correlates with the MITFlo/AXLhi intrinsic MAPKi resistance signature. In agreement, LPAR1 is elevated in MAPKi-resistant PDX models, and in a subset of post-treatment tumor biopsies from patients who relapsed on MAPKi, relative to respective paired pretreatment biopsies. Melanocytes and fibroblasts express low levels of LPAR1 and are not sensitive to LPAR1i. In contrast, genetic silencing of LPAR1 and pharmacologic inhibition of LPAR1 with HA130, an upstream LPAR1 inhibitor, triggers cell cycle arrest and antitumor activity in MAPKi-resistant cells in vivo. Mechanistically, genetic and pharmacologic targeting of LPAR1 downregulates genes involved in the PI3K/mTOR and Hippo/YAP. Concurrent depletion of YAP and S6K cells significantly impairs melanoma viability relative to knockdown of YAP or S6K alone, suggesting that Hippo/YAP and mTOR/S6K pathways are main downstream effectors of LPAR1 signaling in melanoma. Our data identify novel pathways responsible for the escape of BRAF mutant melanoma from MAPKi therapy, and our hypothesis is that concurrent BRAFi/MEKi/LPAR1i may have therapeutic efficacy. This abstract is also being presented as Poster B02. Citation Format: Vito W. Rebecca, Jianglan Liu, Thomas Connelly, Keith Flaherty, Ze’ev Ronai, Meenhard Herlyn. Comparative screening of skin-derived NCSCs, melanocytes, and melanoma developmental programs reveals LPAR1 in MAPKi resistance [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR18.
Nonsuppressible HIV-1 viremia: a reflection of how the reservoir persists
Authors: Janet D. Siliciano, Robert F. Siliciano
Journal: Journal of Clinical Investigation (2020)

Antiretroviral therapy (ART) generally reduces plasma HIV to undetectable levels, although virus persists in latently infected CD4+ T cells. In some individuals, viremia remains detectable despite adherence to ART and the absence of drug resistance mutations. In this issue of the JCI, Halvas et al. describe HIV RNA sequences from plasma of 8 donors with persistent viremia. Residual viremia was dominated by identical HIV-1 RNA sequences that remained relatively constant over 4 years. Plasma virus matched replication-competent virus cultured from CD4+ T cells. Integration site analysis confirmed the presence of large clones of infected cells. These results indicate that nonsuppressible viremia can be due to expanded clones of infected CD4+ T cells carrying replication-competent virus. The individuals described here represent extreme examples of a phenomenon that is seen in all infected individuals and that is a major barrier to curing HIV infection, the in vivo proliferation of latently infected cells.
Significant difference between sirolimus and paclitaxel nanoparticles in anti-proliferation effect in normoxia and hypoxia: The basis of better selection of atherosclerosis treatment
Authors: Youlu Chen, Yong Zeng, Xiaowei Zhu, Lifu Miao, Xiaoyu Liang, Jianwei Duan, Huiyang Li, Xinxin Tian, Liyun Pang, Yongxiang Wei, Jing Yang
Journal: Bioactive Materials (2020)

Compared with paclitaxel, sirolimus has been more used in the treatment of vascular restenosis gradually as an anti-proliferative drug, but few basic studies have elucidated its mechanism. The anti-proliferative effects of sirolimus or paclitaxel have been demonstrated by numerous studies under normoxia, but few studies have been achieved focusing hypoxia. In this study, porcine carotid artery injury model and classical cobalt chloride hypoxia cell model were established. Sirolimus nanoparticles (SRM-NPs), paclitaxel nanoparticles (PTX-NPs) and blank nanoparticles (Blank-NPs) were prepared respectively. The effect of RPM-NPs on the degree of stenosis, proliferative index and the expression of PCNA after 28 days of porcine carotid artery injury model was evaluated. Compared with saline group and SRM groups, SRM-NPs group suppressed vascular stenosis, proliferative index and the expression of PCNA (P < 0.01 and P < 0.05). Endothelial cell (EC) and smooth muscle cell (SMC) were pre-treated with cobaltous chloride, followed by SRM-NPs, PTX-NPs, Blank-NPs or PBS control treating, the effects on cell proliferation, HIF-1 expression and glycolysis were detected. SRM-NPs could inhibit EC and SMC proliferation under hypoxia, while PTX-NPs couldn't (P < 0.001). Significant differences between sirolimus and paclitaxel NPs in anti-proliferation effect under normoxia and hypoxia may due to the different inhibitory effects on HIF-1α expression and glycolysis. In conclusion, these results suggest that sirolimus can inhibit the proliferation of hypoxic cells more effectively than paclitaxel. These observations may provide a basis for understanding clinical vascular stenosis therapeutic differences between rapamycin and paclitaxel.
Abstract 15688: Percutaneous Left Atrial Appendage Occlusion With Intracardiac Echocardiogram Guidance: A Meta-Analysis
Authors: Bhavi P Pandya, Bhrugesh Shah, David Biglari, Nickalaus Gramze, Todd Hurst, Ligita Centorino, Radha Gopalan, Franciso Arabia, Kenith Fang, Kalya Anantharam, Wilber Su, Firas Abbas, Nachiket Patel, George Gellert, Samuel Butman, Frank Tamburrino, Kandov Ruben, James Lafferty, Martha Gulati, Divya Ratan Verma
Journal: Circulation (2019)

Background: Transesophageal echocardiography (TEE) is standard imaging modality for guiding percutaneous left atrial appendage occlusion. Intracardiac echocardiography may be a suitable alternative...
Abstract B28: A novel intestinal microbiome-derived peptide modulates immune cell activity and the tumor microenvironment
Authors: Helena Kiefel, Dhwani Haria, Yuliya Katlinskaya, Divya Ravichandar, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham
Journal: Cancer Research (2020)

Abstract The composition of the gut microbiota affects cancer development, progression, and response to therapy. A number of commensal bacteria, including Bifidobacterium, have been associated with increased response to immune checkpoint inhibitors in mouse tumor models, as well as in melanoma patients. We hypothesized that secreted peptides or proteins contribute to the effects mediated by Bifidobacterium strains in vivo. We used our unique bioinformatics-driven discovery platform to nominate putatively secreted Bifidobacterium-derived peptides for evaluation in immune cell effector assays. We have previously described bacterial peptides that induce secretion of proinflammatory cytokines (e.g., IL-6, TNF) by in vitro-generated mouse and human dendritic cells, as well as effector cytokine secretion (e.g., IFNγ, IL-2) by mouse splenic T lymphocytes in vitro. To investigate the function of Bifidobacterium-derived peptides in the context of the tumor microenvironment, we injected a candidate peptide, termed SG-A, directly into the tumors of tumor-bearing mice. We then performed immune phenotyping via the Nanostring PanCancer Immune Profiling panel, as well as by flow cytometry. Both Nanostring and flow cytometry analysis demonstrated an increase in CD45+ lymphocytes within the tumors of mice treated with SG-A. Peptide SG-A also induced upregulation of dendritic cell function genes (CD40, CD83, and CD86) and multiple effector cytokines and chemokines. Restimulation of tumor-draining lymph node cells with a tumor-derived peptide antigen also increased induction of IFNγ in SG-A treated animals (vs. vehicle-treated controls). Collectively, our results demonstrate the utility of the Second Genome discovery platform for leveraging microbiome science to identify novel immunomodulatory factors. This platform offers the potential to identify agents that may complement or enhance efficacy of existing approaches to immunotherapy for melanoma and other cancers. Citation Format: Helena Kiefel, Dhwani Haria, Yuliya Katlinskaya, Divya Ravichandar, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham. A novel intestinal microbiome-derived peptide modulates immune cell activity and the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B28.
Analysis of wild tomato introgression lines elucidates the genetic basis of transcriptome and metabolome variation underlying fruit traits and pathogen response
Authors: Jędrzej Szymański, Samuel Bocobza, Sayantan Panda, Prashant Sonawane, Pablo D. Cárdenas, Justin Lashbrooke, Avinash Kamble, Nir Shahaf, Sagit Meir, Arnaud Bovy, Jules Beekwilder, Yury Tikunov, Irene Romero de la Fuente, Dani Zamir, Ilana Rogachev, Asaph Aharoni
Journal: Nature Genetics (2020)
Low rate of conversion to positive tuberculosis status among patients with psoriasis on biologic therapies: A retrospective study from a US academic medical center
Authors: Vijaya T. Daniel, Kaitlin C. Blankenship, Robert F. Daly, Elizabeth Tkachenko, Peyton C. Morss-Walton, Nikki A. Levin
Journal: Journal of the American Academy of Dermatology (2020)
Hypertension in Pregnancy in the US—One Step Closer to Better Ascertainment and Management
Authors: Elena V. Kuklina
Journal: JAMA Network Open (2020)

The study by Butwick et al 1 examined the prevalence of prepregnancy (chronic) and pregnancyassociated hypertension using 2017 US birth certificate data.The 2003 version of the birth certificate that was in use in all states in 2017 provides checkboxes for prepregnancy (chronic) hypertension, gestational hypertension, and eclampsia. 2Gestational hypertension includes transient hypertension, preeclampsia, and hemolysis, elevated liver enzyme levels, and low platelet levels syndrome. 2Thus, while Butwick et al 1 use the term hypertensive disorders of pregnancy, gestational
Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn’s disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource
Authors: Evangelos Stournaras, Wendi Qian, Apostolos Pappas, You Yi Hong, Rasha Shawky, Tim Raine, Miles Parkes
Journal: Gut (2020)

Objective Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn’s disease (CD), including their impact on need for surgery. Design Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. Results Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p&lt;0.0001). This difference was corroborated in a multivariable analysis: after adjusting for variables including treatment era, thiopurine monotherapy was less effective in CD than UC (OR 0.47, 95% CI 0.43 to 0.51, p&lt;0.0001). Thiopurine intolerance was associated with increased risk of surgery in UC (HR 2.44, p&lt;0.0001); with a more modest impact on need for surgery in CD (HR=1.23, p=0.0015). Conclusion Thiopurine monotherapy is an effective long-term treatment for UC but significantly less effective in CD.
BHQ880, a novel anti-DKK1 neutralizing antibody, inhibits tumor-induced osteolytic bone disease
Authors: Seth Ettenberg, Feng Cong, Janine Shulok, Stefanie Urlinger, Michael Bardroff, Olga Charlat, Yuji Mishina, Shanming Liu, Michael Daley, Sharon Li, Renee Walsh, Georges Rawadi, Philippe Clement-Lacroix, Patrick Mollat, Youzhen Wang, Yung-Mae Yao, David Stover
Journal: Cancer Research (2008)

3987  Several cancers have a pathology which includes lytic bone disease. In particular, Multiple Myeloma (MM) patients often develop debilitating bone pain and fractures from osteolytic lesions. Recent publications have demonstrated elevated levels of DKK1 in the serum of MM patients, and this is correlated with an increase in osteolytic lesions. DKK1 is also elevated in patients with other tumor types that give rise to osteolytic metastases, such as breast and prostate cancers. DKK1 is a negative regulator of the canonical Wnt signaling pathway, which is a critical mediator of osteoblast differentiation and survival. We have identified a fully human IgG1λ monoclonal antibody (BHQ880) that potently and selectively neutralizes DKK1 suppression of Wnt signaling.  BHQ880 was selected based on its high affinity for human, mouse, rat, and monkey DKK1 using MorphoSyś HuCAL GOLD® phage display library. BHQ880 neutralizes DKK1 suppression of Wnt signaling in a TCF luciferase reporter assay. Furthermore, BHQ880 reactivates the production of Alkaline Phosphatase from DKK1-suppressed, osteoblast-like, mouse embryonic fibroblast cells (C3H10T1/2). BHQ880 binds within the Cys-2 domain of DKK1 and inhibits the interaction between DKK1 and both LRP5 and LRP6.  BHQ880 has demonstrated potent efficacy in several models of tumor-induced osteolytic disease. These include two models of osteolytic metastasis that express high levels of DKK1, an intratibial prostate (PC3M-2AC6) tumor model in mice and an osteolytic breast tumor (MDA-MB-231) model using both intratibial and systemic delivery. Additionally, BHQ880 significantly inhibited bone loss in a systemic MM model (MMIS). In all three models, BHQ880 protected mice from tumor induced bone loss.  These data highlight the potential for anti-DKK1 therapy in tumor induced osteolytic bone disease.
T cell immunity to hepatitis C virus: Lessons for a prophylactic vaccine
Authors: Robert Thimme
Journal: Journal of Hepatology (2020)

There is consensus that HCV-specific T cells play a central role in the outcome (clearance vs. persistence) of acute infection and that they contribute to protection against the establishment of persistence after reinfection. However, these T cells often fail and the virus can persist, largely as a result of T cell exhaustion and the emergence of viral escape mutations. Importantly, HCV cure by direct-acting antivirals does not lead to a complete reversion of T cell exhaustion and thus HCV reinfections can occur. The current lack of detailed knowledge about the immunological determinants of viral clearance, persistence and protective immunity is a major roadblock to the development of a prophylactic T cell vaccine. This minireview highlights the basic concepts of successful T cell immunity, major mechanisms of T cell failure and how our understanding of these concepts can be translated into a prophylactic vaccine.
Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer
Authors: Ming-Jun Shi, Xiang-Yu Meng, Jacqueline Fontugne, Chun-Long Chen, François Radvanyi, Isabelle Bernard-Pierrot
Journal: Genome Medicine (2020)

Abstract Background APOBEC-driven mutagenesis and functional positive selection of mutated genes may synergistically drive the higher frequency of some hotspot driver mutations compared to other mutations within the same gene, as we reported for FGFR3 S249C. Only a few APOBEC-associated driver hotspot mutations have been identified in bladder cancer (BCa). Here, we systematically looked for and characterised APOBEC-associated hotspots in BCa. Methods We analysed 602 published exome-sequenced BCas, for part of which gene expression data were also available. APOBEC-associated hotspots were identified by motif-mapping, mutation signature fitting and APOBEC-mediated mutagenesis comparison. Joint analysis of DNA hairpin stability and gene expression was performed to predict driver or passenger hotspots. Aryl hydrocarbon receptor (AhR) activity was calculated based on its target genes expression. Effects of AhR knockout/inhibition on BCa cell viability were analysed. Results We established a panel of 44 APOBEC-associated hotspot mutations in BCa, which accounted for about half of the hotspot mutations. Fourteen of them overlapped with the hotspots found in other cancer types with high APOBEC activity. They mostly occurred in the DNA lagging-strand templates and the loop of DNA hairpins. APOBEC-associated hotspots presented systematically a higher prevalence than the other mutations within each APOBEC-target gene, independently of their functional impact. A combined analysis of DNA loop stability and gene expression allowed to distinguish known passenger from known driver hotspot mutations in BCa, including loss-of-function mutations affecting tumour suppressor genes, and to predict new candidate drivers, such as AHR Q383H. We further characterised AHR Q383H as an activating driver mutation associated with high AhR activity in luminal tumours. High AhR activity was also found in tumours presenting amplifications of AHR and its co-receptor ARNT . We finally showed that BCa cells presenting those different genetic alterations were sensitive to AhR inhibition. Conclusions Our study identified novel potential drivers within APOBEC-associated hotspot mutations in BCa reinforcing the importance of APOBEC mutagenesis in BCa. It could allow a better understanding of BCa biology and aetiology and have clinical implications such as AhR as a potential therapeutic target. Our results also challenge the dogma that all hotspot mutations are drivers and mostly gain-of-function mutations affecting oncogenes.
Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors
Authors: N. Shaverdian, J. Beattie, M. Thor, M. Offin, A.F. Shepherd, D.Y. Gelblum, A.J. Wu, C.B. Simone, M.D. Hellmann, J.E. Chaft, A. Rimner, D.R. Gomez
Journal: Annals of Oncology (2020)
Screening for COVID-19 in Symptomatic Cancer Patients in a Cancer Hospital
Authors: Yu Fujiwara, Yasuyoshi Sato, Xiaofei Wang, Katsunori Oikado, Yoshinao Sato, Naoki Fukuda, Taisuke Enokida, Koichi Takeda, Daisuke Ohkushi, Brian Hayama, Yoko Egi, Yoshitaka Tokai, Yumi Yamada, Yuki Nakajima, Motoko Kubota, Satomi Haruki, Takako Shimizu, Yasuko Uchida, Kuniko Utsugi, Yoshinori Ito, Shinji Ohno, Shunji Takahashi, Tomohiro Tsuchida
Journal: Cancer Cell (2020)
Endoscopic direct visualization of gallbladder polypoid lesion using peroral digital single-operator cholangioscopy
Authors: Hideki Kamada, Hideki Kobara, Hiroki Yamana, Keiichi Okano, Yasuyuki Suzuki, Naoki Fujita, Tsutomu Masaki
Journal: Endoscopy (2020)

Corrected by: Correction: Endoscopic direct visualization of gallbladder polypoid lesion using peroral digital single-operator cholangioscopyEndoscopy 2021; 53(07): C8-C8DOI: 10.1055/a-1491-3849
Comparison of Colorectal and Endometrial Microsatellite Instability Tumor Analysis and Premm<sub>5</sub> Risk Assessment for Predicting Pathogenic Germline Variants on Multigene Panel Testing
Authors: Alessandro Mannucci, C. Sloane Furniss, Chinedu Ukaegbu, Miki Horiguchi, Tara Fehlmann, Hajime Uno, Matthew B. Yurgelun, Sapna Syngal
Journal: Journal of Clinical Oncology (2020)

Tumor testing for microsatellite instability and/or mismatch repair-deficiency (MSI/IHC) and clinical prediction models effectively screen for Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been assessed for their ability to identify non-LS forms of inherited risk. The aim of this study was to compare MSI/IHC and the PREMM
Dual Delivery of Gemcitabine and Paclitaxel by Wet‐Spun Coaxial Fibers Induces Pancreatic Ductal Adenocarcinoma Cell Death, Reduces Tumor Volume, and Sensitizes Cells to Radiation
Authors: Samantha J. Wade, Zeliha Sahin, Ann‐Katrin Piper, Sepehr Talebian, Morteza Aghmesheh, Javad Foroughi, Gordon G. Wallace, Simon E. Moulton, Kara L. Vine
Journal: Advanced Healthcare Materials (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with surgical resection of the tumor in conjunction with systemic chemotherapy the only potential curative therapy. Up to 80% of diagnosed cases are deemed unresectable, prompting the need for alternative treatment approaches. Herein, coaxial polymeric fibers loaded with two chemotherapeutic agents, gemcitabine (Gem) and paclitaxel (Ptx), are fabricated to investigate the effect of local drug delivery on PDAC cell growth in vitro and in vivo. A wet‐spinning fabrication method to form a coaxial fiber with a polycaprolactone shell and alginate core loaded with Ptx and Gem, respectively, is used. In vitro, Gem+Ptx fibers display significant cytotoxicity as well as radiosensitizing properties toward PDAC cell lines greater than the equivalent free drugs, which may be attributed to a radiosensitizing effect of the polymers. In vivo studies assessing Gem+Ptx fiber efficacy found that Gem+Ptx fibers reduce tumor volume in a xenograft mouse model of PDAC. Importantly, no difference in mouse weight, circulating cytokines, or liver function is observed in mice treated with Gem+Ptx fibers compared to the empty fiber controls confirming the safety of the implant approach. With further development, Gem+Ptx fibers can improve the treatment of unresectable PDAC in the future.
Aβ-accelerated neurodegeneration caused by Alzheimer’s-associated <i>ACE</i> variant R1279Q is rescued by angiotensin system inhibition in mice
Authors: Leah K. Cuddy, Dmitry Prokopenko, Eric P. Cunningham, Ross Brimberry, Peter Song, Rory Kirchner, Brad A. Chapman, Oliver Hofmann, Winston Hide, Daniele Procissi, Taleen Hanania, Steven C. Leiser, Rudolph E Tanzi, Robert Vassar
Journal: Science Translational Medicine (2020)

Ace1 knockin mice have increased neuronal ACE1 and hippocampal neuron loss that is accelerated by Aβ and blocked by approved angiotensin pathway drugs.