tbuckley/cabot-search huggingface dataset:
Abstract 2007: Investigating how RIPK1-mediated mitophagy induces cell death in ECM-detached cancer cells
Authors: Jordan Alexandria Cockfield, Ishan Antony, Samantha Ekanayake, Zachary T. Schafer
Journal: Cancer Research (2021)

Abstract Lead Contact Metastasis is responsible for 90% of deaths caused by cancer. For cancer cells to begin successful metastasis, they must detach from their extracellular matrix (ECM) and evade intrinsic cell death mechanisms. Detachment from the ECM is known to induce a caspase-dependent cell death program, termed anoikis, that cancer cells have been shown to circumvent. Nonetheless, overcoming caspase-dependent cell death alone is not sufficient to promote survival during ECM-detachment, but cancer cells must also address caspase-independent cell death programs. In our recent studies, we have identified RIPK1 as a critical mediator of ECM-detachment induced caspase-independent cell death via its capacity to promote mitophagy and subsequent accumulation of mitochondrial ROS. More recently, we have begun to examine how ROS levels are elevated as a consequence of mitophagy and how these ROS ultimately promote cell death. During mitophagy, autophagosomes containing mitochondria fuse with lysosomes containing a plethora of hydrolases that could facilitate cell death. As such, we sought to examine the relationship between RIPK1-mediated mitophagy and lysosomal membrane permeabilization (LMP) Using immunoblotting, we found that not only does ECM-detachment promote the expression of the lysosomal protease cathepsin B, but also that this induction is dependent upon RIPK1 activity. Given that mitochondrial ROS (mitoROS) was shown to be a consequence of RIPK1-mediated mitophagy during ECM-detachment, we investigated if mitoROS were required for the observed changes in cathepsin B expression. Indeed, when treated with a mitochondrial ROS (mitoROS) scavenger, cathepsin B protein levels noticeably reduce. Taken together, this data suggests that RIPK1-driven mitoROS production is playing a role in regulating cathepsin B expression during ECM-detachment. Future studies will be aimed at determining whether these RIPK1-mediated alterations in cathepsin B are linked to the induction of caspase-independent cell death. Citation Format: Jordan Alexandria Cockfield, Ishan Antony, Samantha Ekanayake, Zachary T. Schafer. Investigating how RIPK1-mediated mitophagy induces cell death in ECM-detached cancer cells [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 2007.
Variations in the mineral content of bottled still water across Europe: Comparison of 182 brands across 10 countries
Authors: S.J.M. Stoots, R. Geraghty, G.M. Kamphuis, E. Jamnadass, M.M.E.L. Henderickx, E. Ventimiglia, O. Traxer, E.X Keller, V. De Coninck, M. Talso, P. Kallidonis, E. Emiliani, E. Bres-Niewada, S. Karim, A. Picirilli, B.K Somani
Journal: European Urology (2021)
Abstract 1126: Solute carrier (SLC) transporter-mediated metabolic reprogramming during enzalutamide resistance in prostate cancer
Authors: Shiv Shankar Verma, Eswar Shankar, Ricky Chan, Sanjay Gupta
Journal: Cancer Research (2021)

Abstract Prostate cancer is the second-leading cause of cancer-related mortality among men in the United States. Androgen receptor (AR) signaling is dominant survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) through medical or surgical castration is the mainstay treatment for prostate cancer patients. Enzalutamide (Xtandi®), a second generation antiandrogen, is frequently prescribed for use in this clinical setting. Patient's response to this medication is usually temporary, and prolong treatment results in the emergence of drug resistance. A better understanding of molecular mechanism and its association with enzalutamide resistance will facilitate circumventing this problem. We employed next generation sequencing (NGS) and compared the transcriptomic profile of paired enzalutamide-sensitive and resistant human prostate cancer LNCaP and C4-2B cells for identification of genes involved in drug resistance along with in silico analysis. NGS data identified 9409 and 7757 genes differentially expressed in LNCaP and C4-2B cells compared to their parental counterparts. A subset of differentially expressed genes in both cell lines were validated at transcript level by qRT-PCR. Data analysis performed by IPA/i-pathway revealed metabolic signaling as predominantly overrepresented pathway and membrane transporters including solute carrier proteins, ATP-binding cassette transporters and other metabolizing enzymes as the most prominent genes dysregulated during metabolic reprogramming in both resistant cell lines. RNA-Seq data of resistant LNCaP cells demonstrate predominance of solute carrier genes, in particular, SLC12A5, SLC25A17 and SLC27A6, during metabolic reprogramming and in the development of drug resistance. Upregulation of these genes were associated with an increase in stemness; higher uptake of lactic/citric acid and lower glucose intake by the resistant cells. Our data suggest predominance of solute carrier genes (SLCs) during metabolic reprogramming of prostate cancer cells in an androgen-deprived environment. SLCs are important in cellular uptake of nutrients and drug absorption, thus could play a significant role in the emergence of drug-resistant phenotype, designating SLC genes as potentially attractive therapeutic targets. Citation Format: Shiv Shankar Verma, Eswar Shankar, Ricky Chan, Sanjay Gupta. Solute carrier (SLC) transporter-mediated metabolic reprogramming during enzalutamide resistance in prostate 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 1126.
Predictors of recurrence after metastasis-directed therapy in metachronous, castrate-sensitive oligometastatic prostate cancer
Authors: U. Milenkovic, J. Kuijk, G. Devos, T. Van Den Broeck, T. Duvillier, W. Van Haute, L. Verhamme, L. Goeman, S. Joniau
Journal: European Urology (2021)
Abstract 1009: Combination Niraparib and Metformin synergistically inhibits endometrial cancer cell growth and metastasis
Authors: Qiyu Gan, Jingxin Cheng, Rui Chen, Yachun Bie, Guozeng Wang, Linlin Chang
Journal: Cancer Research (2021)

Abstract Backgroud Endometrial Carcinoma (EC) is the most common gynecological malignancy among women. Even with a favorable prognosis, cure is still elusive with recurrence, chemotherapy resistance and poor outcome. Poly ADP-ribose polymerase inhibitors (PARPi) have been emerged as promising cancer therapeutics, especially for tumors with deficient homologous recombination (HR) repair. Niraparib for example is well established for ovarian cancer. Metformin, an antidiabetic drug, has been reported to be a new adjunctive strategy for different cancer types, including endometrial cancer. While the effect of Niraparib for EC as monotherapy or in combination with Metformin is still unknown. Method Here we used two types of endometrial cancer cell lines Ishikawa and HEC-1B to detect the effect of Niraparib as monotherapy or in combination with Metformin on cell proliferation, apoptosis, invasion and metastasis. The 50% Inhibitory concentration (IC50) was assessed, and transwell, Annexin V staining, clonogenic assay were applied. Also, western blotting was performed to determine the expression of proteins involved, such as Bax, Caspase-3, Bcl-2, p-AKT, RAD51, γ-H2AX and so on. Results Our study demonstrated that Niraparib inhibited endometrial cell growth in both Ishikawa and HEC-1B cell lines with IC50 0.024umol/L and 0.127umol/L separately. The invasion and metastasis were also suppressed. Annexin V staining showed that Niraparib could significantly promoted apoptosis, which was largely enhanced by Metformin combination therapy (p&amp;lt;0.01). Accordingly, the apoptosis-related proteins Bax, Caspase-3, and DNA damage-related protein RAD51, γ-H2AX were increased, while proliferation-related protein p-AKT, anti-apoptosis-related protein Bcl-2, invasion and metastasis-related protein E-cadherin were decreased, as confirmed by western blotting. Conclusion Niraparib shows the anticancer effect on endometrial cancer cell through inhibiting the cell viability, metastasis and inducing apoptosis, which is significantly enhanced by the combination with Metformin. Our results provide preclinical evidence that the combination of these well-establised drugs may warrant further clinical investigation for endometrial cancer treatment. Citation Format: Qiyu Gan, Jingxin Cheng, Rui Chen, Yachun Bie, Guozeng Wang, Linlin Chang. Combination Niraparib and Metformin synergistically inhibits endometrial cancer cell growth and metastasis [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 1009.
Abstract 295: Implementing fully automated kinase inhibitor characterization using a robotic system
Authors: Daniel A. Thomas, Tom A. Fleming, Martin-Immanuel Bittner
Journal: Cancer Research (2021)

Abstract About 50 kinase inhibitors have been approved by the FDA for different indications so far. On the way from target validation to approval, the biochemical characterisation of a novel kinase inhibitor is a challenging, yet absolutely critical task. High resolution, kinetic molecular profiling can enable better data-driven decision making early on in the drug discovery process, not only saving time and resources, but also leading to superior molecular design. Arctoris developed a robotics-enabled process for fully automated kinase inhibitor characterisation, providing an unparalleled depth of data capture, going beyond the current state-of-the-art of biochemical assay setup. We validated our technology platform establishing assays against four members of the Janus Kinase family (JAK1, JAK2, JAK3, TYK2), profiling a set of JAK inhibitors. Of note, several JAK inhibitors with prior FDA approval for other indications entered clinical trials for COVID-19 treatment, making this target class particularly relevant for an in-depth study. Reagent validation, assay development, calibration, and optimization were expedited through systematic multifactorial experimental design, high density assay plate formats and versatile automated liquid handling. The Arctoris Ulysses platform affords 9 orders of magnitude range in liquid volume handling, with picolitre precision and contact-free digital dispensing for true, non-serial, independent experimentation. Fully automated protocols were optimized, validated, versioned, and explicitly encoded. Robust potency measurements of all inhibitors were established against each of the JAK targets, revealing molecules with distinct isoform selectivity. Designing and selecting molecules with specific activity profiles enables the fine tuning of pharmacology and the avoidance of unwanted off-target toxicity. Our unique platform, assay design, and deep expertise enabled the identification of molecules within the JAK inhibitor set that exhibit a range of kinetic properties. Our mechanistic analyses can help to elucidate the mode of inhibition (competitive, allosteric, synergistic etc.) as well as provide information pertaining to the kinetic selectivity that may be present but missed by focusing solely on potency. Citation Format: Daniel A. Thomas, Tom A. Fleming, Martin-Immanuel Bittner. Implementing fully automated kinase inhibitor characterization using a robotic system [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 295.
Impaired respiratory burst contributes to infections in PKCδ-deficient patients
Authors: Anna-Lena Neehus, Kunihiko Moriya, Alejandro Nieto-Patlán, Tom Le Voyer, Romain Lévy, Ahmet Özen, Elif Karakoc-Aydiner, Safa Baris, Alisan Yildiran, Engin Altundag, Manon Roynard, Kathrin Haake, Mélanie Migaud, Karim Dorgham, Guy Gorochov, Laurent Abel, Nico Lachmann, Figen Dogu, Sule Haskologlu, Erdal İnce, Jamel El-Benna, Gulbu Uzel, Ayca Kiykim, Kaan Boztug, Marion R. Roderick, Mohammad Shahrooei, Paul A. Brogan, Hassan Abolhassani, Gonca Hancioglu, Nima Parvaneh, Alexandre Belot, Aydan Ikinciogullari, Jean-Laurent Casanova, Anne Puel, Jacinta Bustamante
Journal: The Journal of Experimental Medicine (2021)

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.
Abstract 2081: Transcriptional silencing of CDK18 in BRG1 mutant lung cancer
Authors: Loryn Michelle Phillips, Christopher A. Johnston, Steven A. Belinsky, Mathewos Tessema
Journal: Cancer Research (2021)

Abstract In ~10% of lung cancers, the BRG1 gene is mutated often causing a loss of function (LOF). BRG1 is a tumor suppressor that encodes a protein (SMARCA4), which is one of the mutually exclusive ATPase subunits of the Switch/Sucrose Non-fermentable (SWI/SNF) complex. The SWI/SNF complex functions to regulate transcription of many genes including tumor suppressor genes, through mediating chromatin remodeling and nucleosome repositioning by maintaining open chromatin and actively evicting polycomb repressive complexes (PRCs) from target genes and regions. Our previous research showed that BRG1 mutation occurs in approximately 9% of lung adenocarcinomas in smokers and 11% in smokers delineating BRG1 as a clinically relevant mutation. The goal of these studies is to elucidate the downstream effects of BRG1 LOF on gene expression. RNA sequencing of isogenic BRG1 wild type (WT) and knock out (KO) clones from malignant and transformed cell lines identified cell cycle control and chromosomal replication as the most significantly affected pathway. qRT-PCR was used to validate expression changes in 17 genes from this pathway in the WT and KO clones as well as wild type and mutant tumors lines. CDK18 was the most significantly affected target exhibiting a 78% reduction in expression (p&amp;lt;0.001) comparing wild type to mutant cell lines. Ongoing studies are investigating the epigenetic mechanisms leading to transcriptional repression of CDK18 that include cytosine DNA methylation and histone methylation of H3K27. In addition, functional assays (e.g., soft agar, cell migration) are evaluating the role of epigenetically repressed CDK18 in lung carcinogenesis and cell cycle control through siRNA knock down of CDK18 in wild type BRG1 cell lines and carcinogen transformed human bronchial epithelial cells. Together, these studies will provide new insight into the role of LOF of CDK18 in BRG1 mutant cancer. (Supported by P30 CA11800). Citation Format: Loryn Michelle Phillips, Christopher A. Johnston, Steven A. Belinsky, Mathewos Tessema. Transcriptional silencing of CDK18 in BRG1 mutant lung 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 2081.
<i>Braf</i>mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium
Authors: Lochlan Fennell, Alexandra Kane, Cheng Liu, Diane McKeone, Gunter Hartel, Chang Su, Catherine Bond, Mark Bettington, Barbara Leggett, Vicki Whitehall
Journal: Gut (2021)

Sessile serrated lesions (SSLs) are common across the age spectrum, but the BRAF mutant cancers arising occur predominantly in the elderly. Aberrant DNA methylation is uncommon in SSL from young patients. Here, we interrogate the role of ageing and DNA methylation in SSL initiation and progression.We used an inducible model of Braf mutation to direct recombination of the oncogenic Braf V637E allele to the murine intestine. BRAF mutation was activated after periods of ageing, and tissue was assessed for histological, DNA methylation and gene expression changes thereafter. We also investigated DNA methylation alterations in human SSLs.Inducing Braf mutation in aged mice was associated with a 10-fold relative risk of serrated lesions compared with young mice. There were extensive differences in age-associated DNA methylation between animals induced at 9 months versus wean, with relatively little differential Braf-specific methylation. DNA methylation at WNT pathway genes scales with age and Braf mutation accelerated age-associated DNA methylation. In human SSLs, increased epigenetic age was associated with high-risk serrated colorectal neoplasia.SSLs arising in the aged intestine are at a significantly higher risk of spontaneous neoplastic progression. These findings provide support for a new conceptual model for serrated colorectal carcinogenesis, whereby risk of Braf-induced neoplastic transformation is dependent on age and may be related to age-associated molecular alterations that accumulate in the ageing intestine, including DNA methylation. This may have implications for surveillance and chemopreventive strategies targeting the epigenome.
Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non–Small Cell Lung Cancer
Authors: Jia Luo, Victoria L. Martucci, Zoe Quandt, Stefan Groha, Megan H. Murray, Christine M. Lovly, Hira Rizvi, Jacklynn V. Egger, Andrew J. Plodkowski, Mohsen Abu-Akeel, Isabell Schulze, Taha Merghoub, Eduardo Cardenas, Scott Huntsman, Min Li, Donglei Hu, Matthew A. Gubens, Alexander Gusev, Melinda C. Aldrich, Matthew D. Hellmann, Elad Ziv
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE). Experimental Design: In patients with non–small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI. Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52–0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29–1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08–1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit. Conclusions: Thyroid irAEs were associated with response to anti–PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
Fear of cancer recurrence in bladder cancer patients undergoing radical cystectomy with urinary diversion - Preliminary results from a prospective study (NCT04535921)
Authors: Y. Volz, J. Troost, L. Eismann, P. Pfitzinger, F. Jokisch, G. Schulz, R. Waidelich, S. Böck, A. Buchner, B. Schlenker, C. Stief, S. Rodler
Journal: European Urology (2021)
Abstract 2891: Protein phosphatase 5 regulation of cell motility
Authors: n Li, Shile Huang
Journal: Cancer Research (2021)

Abstract Metastasis has been considered as one of the cancer hallmarks. Approximately 90% of cancer-related death is due to cancer metastasis. Tumor cell migration is a prerequisite for cancer metastasis. Protein phosphatase 5 (PP5) is a serine/threonine protein phosphatase that belongs to the phosphoprotein phosphatase (PPP) family including PP1 and PP2A. It is well known that PP5 regulates apoptosis, proliferation, and stress response. However, the role of PP5 in the regulation of cell motility is only beginning to be recognized, and the mechanism of PP5 regulation of cell motility is largely unknown. In this study, our tissue microarray (TMA) studies showed the expression of PP5 increased with the stages of prostate cancer, which is consistent with the previous findings that there is a positive correlation between PP5 overexpression and breast cancer metastases. Furthermore, by the single-cell motility assay, we found that overexpression of PP5 increased the motility of various tumor cells, whereas knockdown of PP5 decreased the cell motility, suggesting that PP5 positively regulates cell motility. As focal adhesion kinase (FAK) is a key regulator of cell motility, and a report has shown that PP5 forms a complex with ASK1, FAK, CXCR4 in wounded alveolar epithelial cancer cells, we examined whether PP5 activates FAK. The Western blotting results showed that overexpression of PP5 did not obviously affect the phosphorylation of FAK. The results suggest that PP5 regulates cell motility through a new mechanism. Further research is on the way to identify how PP5 positively regulates cell motility. (Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA.) Citation Format: n Li, Shile Huang. Protein phosphatase 5 regulation of cell motility [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 2891.
The evaluation of functional small intestinal submucosa for abdominal wall defect repair in a rat model: Potent effect of sequential release of VEGF and TGF-β1 on host integration
Authors: Zhengni Liu, Xuezhe Liu, Luhan Bao, Jiajie Liu, Xiaoqiang Zhu, Xiumei Mo, Rui Tang
Journal: Biomaterials (2021)
Identifying the optimal clinical setting for the use of multiparametric magnetic resonance imaging of the prostate as local staging tool in men candidate to radical prostatectomy. Results from a multi-institutional series
Authors: F. Barletta, A. Stabile, E. Mazzone, J.R. Karnes, U. Pinar, M. Roupret, T. Seisen, V. Cucchiara, C.A. Bravi, G. Rosiello, G. Sorce, F. Pellegrino, D. Robesti, A. Esposito, G. Brembilla, G. Gandaglia, N. Fossati, F. De Cobelli, F. Montorsi, A. Briganti
Journal: European Urology (2021)
Response and Survival in Newly Diagnosed Multiple Myeloma Patients Treated with Cybord Regimen Using Generic Bortezomib — Data from Two Centres from India
Authors: Neeraj Sidharthan, Akhila Sivadas, Anup Joseph Devasia, Uday Prakash Kulkarni, Remya Sudevan, Keechilat Pavithran, Raghuveer Prabhu, Rema Ganapathy, Arun Philip, Wesley Jose, Manoj Unni, Anu Korula, Nisham Pn, Aby Abraham, Alok Srivastava, Vikram Mathews, Biju George
Journal: Blood (2017)