tbuckley/cabot-search huggingface dataset:
Abstract LB050: Modulation of innate and adaptive immunity in blood and tumor of patients receiving the SHP2 inhibitor RMC-4630
Authors: Ariel Yung-Chia Chen, Eric Haura, Jose Pacheco, Marianna Koczywas, Michael Gordon, Susanna Ulahannan, Howard A. Burris, Sai-Hong Ignatius Ou, Judy S. Wang, Jonathan W. Riess, Caroline McCoach, Anna Capasso, Elsa Quintana, Josie Hayes, Richa Dua, Bojena Bitman, Martha Guerra, Hongfang Wang, Xiaolin Wang, Pasi A. Janne
Journal: Cancer Research (2021)

Abstract RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node in the RAS signaling pathway. In preclinical models, SHP2 inhibition not only directly inhibited tumor growth through suppression of tumor-intrinsic RAS signaling, but also resulted in transformation of the tumor immune microenvironment, characterized by an increase in CD8+T cell infiltrates and selective depletion of pro-tumorigenic M2 macrophages. In this study, we evaluated pharmacodynamic biomarkers in blood and tumors from patients in the RMC-4630 phase I monotherapy clinical trial (NCT 03634982) by using flow cytometry and immunohistochemistry (IHC). Safety, PK and efficacy data are reported in a separate abstract. Longitudinal analysis of immune cell phenotyping in blood was conducted in 35 patients. There was a trend for lower pre-study monocytic myeloid-derived suppressor cell (mMDSC) to be associated with a better clinical outcome on RMC-4630 therapy. While the proportion of circulating T cell and B cell populations did not change, both blood mMDSC and total monocytes were significantly reduced during RMC-4630 administration. Furthermore, tumor volumes changes, and the proportion of patients with SD versus PD, positively correlated with the ratio of mMDSCs to total monocytes on RMC-4630 treatment. Inhibition of pERK was observed in a subset of patients. Three paired tumor biopsies from efficacy-evaluable patients, including 1 PR, 1 SD and 1 PD, were available for tumor microenvironment analysis by multiplexed-IHC assays. Increase in tumor infiltrating T cells in the tumors of one patient with a PR and another with SD was observed on RMC-4630 therapy. Inhibition of tumor PD-L1 expression and a decrease in M2 macrophages was also observed on treatment in the tumor biopsy of the PR patient. Collectively, the preliminary clinical biomarker data supports the preclinical observations that SHP2 inhibition with RMC-4630 modulates both innate and adaptive anti-tumor immunity. Citation Format: Ariel Yung-Chia Chen, Eric Haura, Jose Pacheco, Marianna Koczywas, Michael Gordon, Susanna Ulahannan, Howard A. Burris, Sai-Hong Ignatius Ou, Judy S. Wang, Jonathan W. Riess, Caroline McCoach, Anna Capasso, Elsa Quintana, Josie Hayes, Richa Dua, Bojena Bitman, Martha Guerra, Hongfang Wang, Xiaolin Wang, Pasi A. Janne. Modulation of innate and adaptive immunity in blood and tumor of patients receiving the SHP2 inhibitor RMC-4630 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB050.
Abstract 2202: Genetic characterization of metastasis and prognosis in high-grade serous ovarian cancer
Authors: Emilee N. Kotnik, Nicholas C. Spies, Tiandao Li, Matthew Inkman, Jin Zhang, Fernanda Martins-Rodrigues, Ian S. Hagemann, Carolyn K. McCourt, Premal H. Thaker, Andrea R. Hagemann, Matthew A. Powell, David G. Mutch, Christopher A. Maher, Christopher A. Miller, Katherine C. Fuh
Journal: Cancer Research (2021)

Abstract High-grade serous ovarian cancer (HGSC) is the most lethal histotype of ovarian cancer and is highly prone to metastasis, with the majority of patients presenting at advanced stages of disease. There are few targeted treatment options for HGSC patients, especially for women with high metastatic tumor burdens. In order to identify potential genetic targets in metastatic disease, we characterized the genomic and transcriptomic alterations of metastatic tumors in HGSC patients. In this study, matched normal tissue, primary, and metastatic tumors from 23 HGSC short-term (ST) survivors (overall survival [OS] &amp;lt;3.5 years) and 14 long-term (LT) survivors (OS &amp;gt;5 years) underwent whole exome and RNA sequencing. We compared somatic mutations, copy number alternations, mutational burdens, differential expression, immune cell fractions, and gene fusion predictions between the primary and metastatic tumors of the ST and LT survival groups. We confirmed that tumors of LT survivors were more likely to have BRCA1 alterations and more copy-altered segments when compared to tumors of ST survivors. There was a higher percentage of shared variants between the primary and metastatic tumors for ST survivors compared to LT survivors. ST survivors also had a greater mutational burden and more predicted gene fusions than LT. We observed few differentially expressed genes between primary and metastatic tumors, but we did observe significant differences between the transcriptomes of LT and ST survivors' tumors. Overall, we observed that HGSC primary and metastatic tumors had similar genomic and transcriptomic landscapes, but we identified genetic characteristics specific to metastatic tumors that correlate with survival. Citation Format: Emilee N. Kotnik, Nicholas C. Spies, Tiandao Li, Matthew Inkman, Jin Zhang, Fernanda Martins-Rodrigues, Ian S. Hagemann, Carolyn K. McCourt, Premal H. Thaker, Andrea R. Hagemann, Matthew A. Powell, David G. Mutch, Christopher A. Maher, Christopher A. Miller, Katherine C. Fuh. Genetic characterization of metastasis and prognosis in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2202.
DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a smoking-associated malignancy index
Authors: Sheng-Fang Su, Hao Ho, Jia-Hua Li, Ming-Fang Wu, Hsu-Chieh Wang, Hsiang-Yuan Yeh, Shuenn-Wen Kuo, Huei-Wen Chen, Chao-Chi Ho, Ker-Chau Li
Journal: Journal of Clinical Investigation (2021)

Unlike the better-studied aberrant epigenome in the tumor, the clinicopathologic impact of DNA methylation in the tumor microenvironment (TME), especially the contribution from cancer-associated fibroblasts (CAFs), remains elusive. CAFs exhibit profound patient-to-patient tumorigenic heterogeneity. We asked whether such heterogeneity may be exploited to quantify the level of TME malignancy. We developed a robust and efficient methylome/transcriptome co-analytical system for CAFs and paired normal fibroblasts (NFs) from non-small-cell lung cancer patients. We found 14,781 CpG sites of CAF/NF differential methylation, of which 3,707 sites showed higher methylation changes in ever-smokers than in nonsmokers. Concomitant CAF/NF differential gene expression analysis pointed to a subset of 54 smoking-associated CpG sites with strong methylation-regulated gene expression. A methylation index that summarizes the β values of these CpGs was built for NF/CAF discrimination (MIND) with high sensitivity and specificity. The potential of MIND in detecting premalignancy across individual patients was shown. MIND succeeded in predicting tumor recurrence in multiple lung cancer cohorts without reliance on patient survival data, suggesting that the malignancy level of TME may be effectively graded by this index. Precision TME grading may provide additional pathological information to guide cancer prognosis and open up more options in personalized medicine.
Reporting of Percutaneous Coronary Interventions Site-Specific Mortality
Authors: Edward L. Hannan, Kimberly Cozzens
Journal: JAMA Cardiology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Sexual and functional outcomes after prolapse surgery: Trocarless Transvaginal Mesh (TTMs) versus Pelvic Organ Prolapse Suspension (POPS)
Authors: A. Martoccia, A. Fuschi, Y. Al Salhi, M. Maggi, L. Capone, P.P. Suraci, S. Scalzo, M. Cervigni, A. Carbone, A.L. Pastore
Journal: European Urology (2021)
Abstract 15972: Cholesterol Efflux Capacity of HDL is Impaired in Patients With Persistent Atrial Fibrillation
Authors: Asuka Takano, Hiroshi Iwata, Katsutoshi Miyosawa, Tomoyuki Shiozawa, Hidemori Hayashi, Takehiro Funamizu, Shinichiro Doi, Haruna Tabuchi, Gaku Sekita, Hiroyuki Daida
Journal: Circulation (2018)

Background: Numerous lines of evidence have suggested that function of high-density lipoprotein (HDL), rather than serum HDL cholesterol (HDL-C) levels, is more important in the pathogenesis and pr...
Global mapping of Salmonella enterica-host protein-protein interactions during infection
Authors: Philipp Walch, Joel Selkrig, Leigh A. Knodler, Mandy Rettel, Frank Stein, Keith Fernandez, Cristina Viéitez, Clément M. Potel, Karoline Scholzen, Matthias Geyer, Klemens Rottner, Olivia Steele-Mortimer, Mikhail M. Savitski, David W. Holden, Athanasios Typas
Journal: Cell Host & Microbe (2021)

Intracellular bacterial pathogens inject effector proteins to hijack host cellular processes and promote their survival and proliferation. To systematically map effector-host protein-protein interactions (PPIs) during infection, we generated a library of 32 Salmonella enterica serovar Typhimurium (STm) strains expressing chromosomally encoded affinity-tagged effectors and quantified PPIs in macrophages and epithelial cells. We identified 446 effector-host PPIs, 25 of which were previously described, and validated 13 by reciprocal co-immunoprecipitation. While effectors converged on the same host cellular processes, most had multiple targets, which often differed between cell types. We demonstrate that SseJ, SseL, and SifA modulate cholesterol accumulation at the Salmonella-containing vacuole (SCV) partially via the cholesterol transporter Niemann-Pick C1 protein. PipB recruits the organelle contact site protein PDZD8 to the SCV, and SteC promotes actin bundling by phosphorylating formin-like proteins. This study provides a method for probing host-pathogen PPIs during infection and a resource for interrogating STm effector mechanisms.
Abstract 640: Precision cancer medicine in pediatric tumors for improved survival in African children
Authors: Kasimu Umar Adoke, Yawale Iliyasu
Journal: Cancer Research (2021)

Abstract Introduction: Childhood cancers as a growing public health challenge and is increasingly being recognized worldwide, including the developing nations. Each year, the number of pediatric cancers recorded in Africa shows an increase trend with the small round blue cells of childhood been the most common. About 90 percent of children with pediatric solid tumors die either of the complications of the tumor, chemotherapy or financial burden. Since mutation rate in pediatric cancer is lower than adult cancers, with targetable mutations identified in less than 50% of cases, we believe that using precision cancer medicine and to some extent implementational science can help reduce this burden in Africa. Methods: Forty-six cases of pediatric cancer were reviewed over a five-year period (2016- 2020). Their case notes were retrieved and data on site, tumor type, mode of diagnosis, drugs given, complications, follow-up visits and financial implications were accessed. Data was analyzed using spss version 21. Results: Patients age ranges from 3months to 12 years with a male female ratio of 4:3. The commonest site of pediatric tumor was the jaw 12(26%), eye 7(15.2%) and upper extremities 5(10.9%). The commonest tumor type was Burkitt lymphoma, retinoblastoma, alveolar rhabdomyosarcoma, follicular lymphoma and nephroblastoma with rare types like synovial sarcoma and Ewing sarcoma also seen. Majority (70%) were diagnosed with routine H&amp;E only with few diagnosed using immunohistochemistry. No FISH, CISH or NGS done on any of the tumors. Most patients (85%) received chemotherapy with the most common complication been tumor lysis syndrome. About 75% mortality was seen mainly due to complication of treatment. Conclusion: Childhood cancer is a big burden and has a dismal prognosis in our setting due to several factors. Incorporation of precision cancer medicine and implementation science can go a long way in improving pediatric cancer outcomes. Citation Format: Kasimu Umar Adoke, Yawale Iliyasu. Precision cancer medicine in pediatric tumors for improved survival in African children [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 640.
Abstract 1498: Nanobody-based CAR T cells targeting B7-H3 in pancreatic cancer
Authors: Dan Li, RuiXue Wang, Tianyuzhou Liang, Brad St. Croix, Mitchell Ho
Journal: Cancer Research (2021)

Abstract Pancreatic cancer is a common cause of cancer-related mortality worldwide with a poor 5-year survival rate. Adoptive transfer of T cells engineered with chimeric antigen receptors (CAR T cells) have shown promising potency in hematological malignancies, but it is more challenging to apply CAR T cells in the treatment of solid tumors. One of the major barriers is the lack of appropriate therapeutic targets. B7-H3 (CD276) is an emerging and promising pan-cancer target that is overexpressed in multiple solid tumors including pancreatic ductal adenocarcinoma (PDAC) and neuroblastoma (NB) but limited in normal tissues. Interestingly, it is highly expressed in not only tumor cells but also tumor-associated myeloid cells in the tumor microenvironment. In this study, we isolated a panel of novel B7-H3 specific nanobodies from our camel VHH single domain phage libraries. These nanobodies bind to human B7-H3-expressing tumor cell lines and cross-react with B7-H3 of different species. Notably, three nanobody-based CAR T cells (B12, C4 and G8) demonstrate potent cytolytic effects on B7-H3 positive PDAC and NB cell lines in vitro. In particular, CAR T cells have been tested in a metastatic PDAC model and a NB model in mice, showing that C4 and B12 nanobody-based CAR T cells have potent antitumor efficacy without evident side effects. Therefore, we conclude that our new B7-H3 targeted nanobody-based CAR T cells, in particular C4 and B12 derived CAR T cells, are promising for treating solid tumors such as pancreatic cancer and other deadly solid tumors. Citation Format: Dan Li, RuiXue Wang, Tianyuzhou Liang, Brad St. Croix, Mitchell Ho. Nanobody-based CAR T cells targeting B7-H3 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1498.
Abstract 46: A new class of precision therapeutics that inhibit prostate cancer mediated bone destruction
Authors: Ryan R. Gordon, Abhinandan Pattanayak, Wenqi Li, Raymond Bergan
Journal: Cancer Research (2021)

Abstract The destructive nature of bone metastases dominates the clinical management of advanced prostate cancer (PCa) and is a common cause of morbidity and mortality. Our current ability to therapeutically target this process is limited. Here we describe the synthesis and functional characterization of the first-in-class Dual Acting Bone Defending agents (DABDs), which couple a small molecule therapeutic that inhibits cell movement to bone trophic bisphosphonates. Upfront in-vitro screens assessed DABD efficacy at inhibiting PCa cell migration and invasion and osteoclast mediated bone destruction. Systemic models of PCa metastasis, inclusive of intracardiac (IC) and intratibial (IT) injection models, were deployed to characterize tolerance and efficacy in-vivo. Finally, in-vitro characterization of DABD molecular mechanism of action was performed, as guided by the existing knowledge base related to the parental compounds. Results demonstrated that DABDs inhibit PCa cell migration and invasion, chemically bind hydroxyappetite, and inhibit osteoclast mediated bone destruction in vitro. Following IC injection of PCa cells, a model where cells are placed into circulation, metastasize to bone, grow and induce bone destruction, emulating the clinical scenario in humans, DABD treatment inhibited circulating PCa cells from forming new bone metastasis and prolonged life in a dose-dependent fashion. In the IT mouse models of established metastatic lesions, DABDs induce reversion of PCa cell growth and disrupt further bone destruction. DABDs at doses 1000 fold higher than those associated with efficacy are well tolerated. At the molecular level, DABDs retain the molecular mechanisms of action of their constituent chemicals. They inhibit farnesyl diphosphate synthase (FDPS), in the mevalonate pathway, leading to decreased prenylation of small GTPases, including the Ras related protein, Rap-1A, as well as inhibit Raf1 activation, inducing apoptosis and impaired cell movement, respectively. DABDs are a new class of agents that inhibit formation of new bone metastasis, revert growth of established metastasis, prolong life, and have a high potential for improving clinical outcome in humans. Citation Format: Ryan R. Gordon, Abhinandan Pattanayak, Wenqi Li, Raymond Bergan. A new class of precision therapeutics that inhibit prostate cancer mediated bone destruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 46.
Covid-19: Judge gives permission for NHS trust to remove life support from patient
Authors: Clare Dyer
Journal: BMJ (2021)

A High Court judge has given permission for an NHS trust to remove a 52 year old man with covid-19 from life support and allow him to die. 1 The man, named only as KM, had deep vein thrombosis as a result of a long haul flight and was admitted to hospital with chest pains.He had previously been fit and well, with no significant medical history.
Abstract 219: Identifying genetic interactions resulting form diverse biological mechanisms to inform cancer drug development
Authors: Manuel Garcia-Quismondo, Olivier Elemento, Neel Madhukar, Coryandar Gilvary
Journal: Cancer Research (2021)

Abstract Identifying gene interactions, such as synthetic lethal relationships, has led to actionable, clinical insights, enabling targeted oncology therapies. However, identifying these interactions has proven difficult, in large part due to the multiple mechanisms by which two genes can interact, such as occurring in the same pathways or conversely occurring in parallel pathways, but involved in the same biological functions. Therefore, experimentally testing all possible sources of gene interactions is costly and time consuming, however a robust computational approach would allow researchers to investigate these interactions efficiently. Here, we describe a machine learning approach that integrates multiple metrics, such as gene-gene pairwise expression correlations, similarity metrics for genetic biological functions, and pathway co-occurrence, to derive a global interaction score. Our model can simultaneously achieve significant predictive performance (Area under the receiver operator curve = 0.8), while also elucidating the underlying mechanism of predicted gene interactions, informing future experimental validation protocols. Additionally, we leveraged transcriptomic and genomic profiles of cancer patients to identify clinically actionable genetic interactions. Our tool provides a novel multi-faceted approach for the detection of gene interactions and can be used to identify biomarkers, novel oncology targets and overall enhance our understanding of biological mechanisms. Citation Format: Manuel Garcia-Quismondo, Olivier Elemento, Neel Madhukar, Coryandar Gilvary. Identifying genetic interactions resulting form diverse biological mechanisms to inform cancer drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 219.
Abstract 2941: Development and characterization of the ultra-immunodeficient NOD.CB17-<i>Prkdcscid IL2rgtm1</i>/Bcgen (B-NDG) mouse model
Authors: Sheryl June Wildt, Jamie Naden, Jie Xiang, Yuelei Shen, Meiling Zhang
Journal: Cancer Research (2021)

Abstract The “B-NDG” (NOD.CB17-Prkdcscid IL2rgtm1/Bcgen) mouse was designed and generated by Biocytogen. IL2rg (common gamma) gene was deleted in NOD-scid mice resulting in a mouse that lacks mature B cells, T cells, NK cells and has a deficiency in cytokine signaling. This level of immunodeficiency makes this model ideal for engraftment with human immune cells and human tumor cells or tissues. Herein we describe the development and characterization of the B-NDG model, which includes growth curve, complete blood count, serum chemistry, flow cytometry, tumor growth and humanization. A cohort of B-NDG mice (N=50 males and 50 females) were weighed weekly from 3 to 9 weeks of age. A cohort of six male B-NDG mice were analyzed to determine baseline levels for complete blood cell count and serum chemistry. Splenocytes of C57BL/6, NOD-scid and B-NDG mice were isolated and examined for total T cells, B cells, NK cells, CD4+ T cells, CD8+ T cells and regulatory T cells using flow cytometry. Data showed complete lack of all T cells, B cells and NK cells in the B-NDG modelTwo different methods of humanization were examined in the B-NDG model. Human peripheral blood mononuclear cells (hPBMCs) were injected at 5x106 into the caudal vein of three B-NDG mice. After 24 days, the hCD45+ and mCD45+ cells were examined and mice had 30-80% hCD45+ cells. Of those hCD45+ cells, over 99% were identified as T cells. The second humanization method used was injection of 1x105 human CD34+ hematopoietic stem cells after irradiation. The percentage of human CD45+ cell in the peripheral blood was over 20% by eight weeks post injection in over 70% engrafted mice. At 16 weeks post injection, of the total number of human lymphocytes in the humanized mice, 60% were B cells, 2% were NK cells and over 10% were T cells. The percentage of human T cells increases steadily with the extended observation window. We have demonstrated that B-NDG mice have several features that translate many benefits as compared to other immunodeficient models. This model has demonstrated better tumor growth than the NOD-scid and C.B17 scid mice for cell lines as well as PDX lines. We have also shown that this model is extremely useful for studies that require humanization of an immunodeficient mouse model. Citation Format: Sheryl June Wildt, Jamie Naden, Jie Xiang, Yuelei Shen, Meiling Zhang. Development and characterization of the ultra-immunodeficient NOD.CB17-Prkdcscid IL2rgtm1/Bcgen (B-NDG) mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2941.