tbuckley/cabot-search huggingface dataset:
Abstract 1307: Assessment of long IVT mRNA fragments with the Fragment Analyzer system
Authors: Kyle D. Luttgeharm, Solange Borg, Chava Pocernich
Journal: Cancer Research (2021)

Abstract Quality control analysis of long in vitro transcribed (IVT) RNAs is challenging due to the lack of commercially available kits for sizing RNA over 6,000 nt, thus, to analyze long IVT RNAs, an extended separation method was developed for the Agilent 5200 Fragment Analyzer using a commercially available RNA ladder. IVT mRNA was produced using the RiboMAX Large Scale RNA Production System (Promega). RNA transcripts 9,000 and 10,000 nt in length were diluted in nuclease-free water and separated on the Agilent 5200 Fragment Analyzer system with the Agilent RNA kit (15 nt) (p/n DNF-471) with the following modifications. The Lonza RNA marker (Lonza) (long RNA Ladder) replaced the Agilent RNA Ladder and was diluted in nuclease-free water to 96 ng/μL. The long RNA Ladder was added to the Agilent RNA Diluent Marker (15 nt) (p/n DNF-369-0004) according to the RNA kit protocol. The standard separation method (8 kV for 45 minutes) for the RNA kit (15 nt) was manually altered to the extended RNA method (4 kV for 90 minutes) in the Agilent 5200 Fragment Analyzer software for fragments greater than 6,000 nt. The extended RNA method with the long RNA Ladder was employed for all subsequent runs. The long RNA Ladder separated with the extended method displayed enhanced resolution compared to separation with the standard method as seen by the increased spacing between the ladder peaks and the increased sharpness of the 9,000 nt peak. The extended RNA method reported a lower average sizing percent error (-0.7 %) over the entire concentration range of the kit compared to the standard RNA method (8.4 %) for the 9,000 nt sample. The 10,000 nt IVT mRNA average percent sizing error was similar between the two separation methods throughout the dilution series. Using the extended method, the 9,000 and 10,000 nt IVT mRNA samples were successfully analyzed with good sizing precision and accuracy, demonstrating that a commercially available RNA ladder can be used with the Fragment Analyzer system to provide accurate sizing of large IVT mRNA samples. The extended RNA method is recommended when extremely accurate sizing or high resolution is needed for determining the presence of degradation or sizing differences from incomplete transcription in IVT mRNA samples longer than 6,000 nt. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Kyle D. Luttgeharm, Solange Borg, Chava Pocernich. Assessment of long IVT mRNA fragments with the Fragment Analyzer 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 1307.
Abstract 1251: Dithiocarb-copper complex, CuET, demonstrates anti-neoplastic activity in mouse model of prostate cancer and prevents recurrence of tumors
Authors: Daciana Catalina Dumut, Juan B. DeSanctis, Martin Mistrik, Zdenek Skrott, Petr Dzubak, Jiri Bartek, Marian Hajduch, Danuta Radzioch
Journal: Cancer Research (2021)

Abstract INTRODUCTION Prostate cancer (PCa) is the most common cancer in the North-American man. It was responsible for about 192,000 new cases and 33,000 deaths in the USA in 2020. Surgical resection and systemic androgen deprivation therapy are standard approaches to treat both localized and metastatic PCa (mPCa). The five-year survival from prostate cancer (PCa) without bone metastasis is 56% versus 3% with metastasis There is no cure for the metastatic prostate cancer (mPCa) which often spreads to the hip, spine, and pelvis bones. Therefore, new approaches and combination therapy need to be developed to improve patients's survival. Disulfiram's anti-cancer activity was previously explored and its metabolite ditiocarb-copper complex (CuET) was found to have high anti-cancer activity. The mechanism of action of CuET involves NPL4 aggregation and activation of ER stress, leading to preferential apoptosis of cancer cells. Since altered protein degradation is targeted by CuET, it might display high efficacy in highly mutated PCa. Consequently, we want to propose CuET for the treatment of mPCa. METHODS Survival curve and colony-formation assays in murine dKO cell line harboring PTEN and Rb driver mutations as well as in the human metastatic PC3 cell line, were performed. Anti-metastatic effect of CuET in vitro was assessed through Boyden chamber. In vivo efficacy of systemic treatment with CuET, was studied in dKO model of C57BL/6 mice. RESULTS Our results demonstrate that CuET displays cytotoxicity in dKO and PC3 cells at very low concentrations with respective IC50 of 46.2nM and 90.5nM. In vitro, CuET significantly reduced both the clonogenicity and migration ability of cells. In vivo, systemic treatment with CuET significantly reduced growth of dKO tumor and prevented recurrence of tumors. CONCLUSION Given these positive pre-clinical results, CuET should be investigated for its antineoplastic activity in clinical setting as an adjuvant therapy for mPCa. Citation Format: Daciana Catalina Dumut, Juan B. DeSanctis, Martin Mistrik, Zdenek Skrott, Petr Dzubak, Jiri Bartek, Marian Hajduch, Danuta Radzioch. Dithiocarb-copper complex, CuET, demonstrates anti-neoplastic activity in mouse model of prostate cancer and prevents recurrence of tumors [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 1251.
Robot-assisted laparoscopic living donor nephrectomy: The university of Florence technique
Authors: R. Campi, A. Pecoraro, F. Sessa, S. Morselli, L. Gemma, I. Greco, P. Barzaghi, A.A. Grosso, F. Corti, N. Mormile, P. Spatafora, S. Caroassai, A. Berni, C. Caneschi, M. Gacci, S. Giancane, A. Sebastianelli, V. Li Marzi, G. Vignolini, S. Serni
Journal: European Urology (2021)
Abstract 1215: Targeting TIP1 with a novel radiosensitizing antibody-drug conjugate (ADC) enhances the therapeutic efficacy of radiation for non-small cell lung carcinoma treatment
Authors: Calvin Lewis, Abhay K. Singh, Dinesh Thotala, Dennis E. Hallahan, Vaishali Kapoor
Journal: Cancer Research (2021)

Abstract Tax-interacting protein 1 (TIP1) is a multifunctional protein involved in cellular motility, cellular adhesion, migration, cancer cell protection from ionizing radiation, and metastasis. We found that TIP1 is a radiation inducible antigen that is translocated to the cancer cell surface. Antibody-drug-conjugates (ADCs) are emerging as promising anti-cancer immunoconjugates. ADCs carry antitumor payloads and allow site-specific targeting of cancer with increased cytotoxicity and decreased side effect profiles as compared to conventional chemotherapy. Monomethyl auristatin E (MMAE) is a potent radiosensitizing microtubule inhibitor with enhanced cancer cytotoxicity in combination with radiotherapy. We developed ADCs against radiation-inducible TIP1 for lung cancer treatment in combination with radiation. Out of the various anti-TIP1 antibodies, we prioritized the lead antibody that shows high affinity to TIP1 protein on the cancer cell surface and in vivo irradiated lung cancers. Our lead antibody, 7H5 undergoes endocytosis in cancer cells in vitro. We conjugated 7H5 to VcMMAE. Hydrophobic interaction chromatography (HIC) was performed to determine drug-to-antibody ratio (DAR). We obtained an average DAR of 3.7. Cytotoxic potential of 7H5-VcMMAE was evaluated in A549 and H1299 NSCLC cells. Cells were exposed to 7H5-VcMMAE or 7H5-antibody alone at various doses. At 10nM concentration, ~70% reduction in viable cells was observed following 7H5-VcMMAE treatment compared to 7H5 alone in both A549 (p=0.0032) and H1299 cells (p=0.0010). 7H5-VcMMAE sensitized A549 and H1299 cells to radiation as observed by significantly decreased (p&amp;lt;0.001) surviving fraction compared to 7H5 alone. In vivo therapeutic efficacy of the 7H5-VcMMAE was determined using mice bearing hind-limb human NSCLC tumors. The ADC showed a prolonged delay in tumor growth and improved tumor control was achieved with IR + 7H5-VcMMAE in A549 and H1299 hind-limb tumor models. Furthermore, mice in all groups displayed no toxicity associated with treatment. Our study suggests that targeting radiation-inducible TIP1 with a radiosensitizing ADC is a promising strategy to enhance therapeutic efficacy in lung cancer. This novel approach of targeting cancer using ADCs to radiation-inducible antigens will lead to clinical trials in lung cancer patients treated with radiotherapy. Citation Format: Calvin Lewis, Abhay K. Singh, Dinesh Thotala, Dennis E. Hallahan, Vaishali Kapoor. Targeting TIP1 with a novel radiosensitizing antibody-drug conjugate (ADC) enhances the therapeutic efficacy of radiation for non-small cell lung carcinoma treatment [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 1215.
Abstract 1279: Development of a selective CDK2-E inhibitor in CCNE driven cancers
Authors: Yoon J. Choi, Steve Wenglowsky, Victoria Brown, Neil Bifulco, Yeon S. Choi, Jian Guo, Megan Hatlen, Joseph Kim, Tim LaBranche, Riadh Lobbardi, Emanuele Perola, Emily Rozsahegyi, Michelle Maynard, Phil Ramsden, Grace Silva, Faith Stevison, Richard Vargas, Ruduan Wang, Doug Wilson, Rich Woessner, Dean Zhang, Rob Meissner, Klaus Hoeflich, Marion Dorsch
Journal: Cancer Research (2021)

Abstract Background: Cyclin dependent kinases (CDK) comprise a family of proteins which are activated upon cyclin binding to promote cell cycle progression. Historically, CDK family inhibitors have had limited utility in the clinic due to 1) toxicities associated with broad spectrum CDK inhibition; and 2) varied and unpredictable efficacy due to lack of a patient selection strategy. The recent approval of three selective CDK4/6 drugs (palbociclib, ribociclib and abemaciclib) has revived the pursuit of therapies against a related interphase kinase, CDK2. Cyclin E gene (CCNE) alterations are prevalent in cancers with high unmet medical need and are emerging as a potential mechanism of clinical resistance to targeted therapies (e.g. CDK4/6 therapies). Methods: Here we report preclinical validation leading to the development of a selective CDK2 inhibitor for the treatment of cancers harboring CCNE alterations. We highlight advanced, orally bioavailable compounds exhibiting single-digit low nanomolar biochemical and cellular potency (pRB), exquisite CDK family selectivity (CDK1, 4, 6, 7 and 9), and whole kinome selectivity. We have characterized the phenotypic and mechanistic consequences of targeting CDK2, employing both genetic and pharmacologic methods across cell lines and xenograft models (e.g. OVCAR-3, MKN-1, HCC1569). Results: In a panel of cell lines, CCNE1-amplified lines exhibited profound sensitivity to selective CDK2 inhibition by halting cells at the G1/S phase of the cell cycle. Upon further inspection, CDK2 inhibition induced multiple markers of senescence, e.g. SA-b-gal and IL-6, in CCNE1-amplified but not in CCNE non-amplified cell lines. Consistent with this, these compounds exhibit robust anti-tumor activity in multiple CCNE1-amplified xenograft models, which was sustained after removal of treatment with these compounds. Conclusions: These data provide a strong rationale for advancing this class of compounds toward clinical development in CCNE-altered cancers. Citation Format: Yoon J. Choi, Steve Wenglowsky, Victoria Brown, Neil Bifulco, Yeon S. Choi, Jian Guo, Megan Hatlen, Joseph Kim, Tim LaBranche, Riadh Lobbardi, Emanuele Perola, Emily Rozsahegyi, Michelle Maynard, Phil Ramsden, Grace Silva, Faith Stevison, Richard Vargas, Ruduan Wang, Doug Wilson, Rich Woessner, Dean Zhang, Rob Meissner, Klaus Hoeflich, Marion Dorsch. Development of a selective CDK2-E inhibitor in CCNE driven cancers [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 1279.
Viral populations of SARS-CoV-2 in upper respiratory tract, placenta, amniotic fluid and umbilical cord blood support viral replication in placenta
Authors: Maria Piñana, Josep F. Abril, Cristina Andrés, Aroa Silgado, Alexandra Navarro, Anna Suy, Elena Sulleiro, Tomàs Pumarola, Josep Quer, Andrés Antón
Journal: Clinical Microbiology and Infection (2021)
Abstract 2205: Molecular subtypes of head and neck cancer in patients with African ancestry
Authors: Nadia Mezghani, Alexandria G. Yao, Alison M. Taylor, Fatemeh Momen-Heravi
Journal: Cancer Research (2021)

Abstract Epidemiological data identifies disparities in black patients for head and neck squamous carcinoma (HNSCC) screening, detection, treatment, and survival. Although socioeconomic and environmental factors play a role in the existing racial disparities, HNSCC incidence and survival rates in the black population cannot be attributed to these factors alone. To investigate the role race plays in the genomics of head and neck cancer, we examined HNSCC samples from 49 black and 446 white patients in the Cancer Genome Atlas (TCGA). We used computationally-derived ancestry identifications to correlate race with HNSCC molecular features. We then characterized the extent to which genomic alterations in black patients impact their clinical outcomes. We found that black patients lived significantly fewer disease-free months and had a poorer overall survival than white patients. Black patients showed a higher frequency of human papillomavirus (HPV)-negative than HPV-positive tumors compared to white patients. Black patients were found to suffer higher rates of metastasis and more aggressive lymph node involvement. Differences in patient primary tumor site were also identified, with black patients having a higher prevalence of tumors in the larynx and lower prevalence of tumors in the tongue compared to white patients. We also found higher frequencies of RUNX1T1, KMT2D, and UNC13C mutations and lower frequency of PIK3CA mutations in black patients. We found a significant enrichment of MYC signaling and amplifications in the tumors of black patients compared to white patients. Novel data uncovered by this project brings us closer to understanding the racial disparities in HNSCC, and advances research aimed at eliminating those disparities. Unique tumor mutations and molecular signatures show promising clinical utility in providing more targeted, individualized screening diagnostic, and treatment modalities to reduce outcome disparities in the black population. Citation Format: Nadia Mezghani, Alexandria G. Yao, Alison M. Taylor, Fatemeh Momen-Heravi. Molecular subtypes of head and neck cancer in patients with African ancestry [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 2205.
Abstract 1118: Engineered cell line panel complemented with in vivo models to enable next-generation target therapy discovery in cancer
Authors: Zhixiang Zhang, Xiaohe Shi, Xiangyang Zuo, Qingyang Gu, Qunsheng Ji
Journal: Cancer Research (2021)

Abstract Many cancer types are driven by specific gene aberrances, like gene fusions, mutations and copy number changes. It has led to the successful application of a number of target therapeutics, of which kinase inhibitors represent a good example. However, acquired resistance is almost inevitable at the end of any target therapy treatment, which makes it urgent a need to discover new-generation therapeutics. There are strong evidences suggesting acquired resistance should be largely attributed to certain secondary mutations, such as EGFRT790M, RETV804L and BTKC481S. At discovery stage it is critical to generate preclinical cancer models harboring these specific gene aberrances both in vitro and in vivo. Biopsy from patient with clinical resistance could be an optional starting point. But it is much more straightforward and efficient if these well-studied gene aberrance could be constructed and engineered into host cell lines directly. The transformed cell line can further be inoculated into host mice to make in vivo test feasible. Here we are reporting the establishment of a panel of engineered BaF3 cell lines for a series of cancer driver gene aberrances against EGFR, RET, ROS1, BTK and FLT3. Taking RET as example, we constructed the activating gene fusion of KIF5B-RET, along with its mutated versions, KIF5B-RETV804L and KIF5B-RETV804M. These 3 constructs were transfected into BaF3 cell line, respectively. After rounds of in vitro selection, the stable BaF3 cell line harboring KIF5B-RETWT, KIF5B-RETV804L or KIF5B-RETV804M was subjected into in vitro test of three multiple kinase inhibitors with RET inhibitory activity, including Ponatinib, Sunitinib and Sorafenib. Consistent to other reports, Ponatinib was demonstrated superior to the other two RET inhibitors when suppressing the two V804 mutated cell line growths. The in vivo growth of these cell lines have also been confirmed in house. Beyond these five target genes, we have been working on other driver genes to expand the panel scope continuously. HER2 exon20 ins, PDGFRaT674I and KITT670I models are already under development, while many others are on our radar. In summary, our ever-expanding panel of engineered cell lines complemented with in vivo models represents valuable assets to empower the discovery of next-generation target therapeutics against cancer. Citation Format: Zhixiang Zhang, Xiaohe Shi, Xiangyang Zuo, Qingyang Gu, Qunsheng Ji. Engineered cell line panel complemented with in vivo models to enable next-generation target therapy discovery in 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 1118.
Abstract 3179: Deconvolving bulk gene expression to chart the immune activity and crosstalk in the tumor microenvironment
Authors: Kun Wang, Sushant Patkar, JooSang Lee, E. Michael Gertz, Welles Robinson, Fiorella Schischlik, Alejandro Schäffer, Eytan Ruppin
Journal: Cancer Research (2021)

Abstract The tumor microenvironment is a complex mixture of cell-types that interact with each other to affect tumor growth and clinical outcomes. To accelerate the discovery of such interactions, we develop CODEFACS (Confident Deconvolution For All Cell Subsets), a deconvolution tool that infers cell-type-specific gene expression in each sample from bulk expression measurements. We additionally developed LIRICS (Ligand Receptor Interactions between Cell Subsets), a pipeline that analyzes the deconvolved gene expression to further identify clinically relevant ligand-receptor interactions between cell-types. Using 15 benchmark datasets, we first demonstrate that CODEFACS substantially improves our ability to reconstruct cell-type-specific transcriptomes from individual bulk samples compared to the state-of-the-art method, CIBERSORTx. We next analyze the TCGA using CODEFACS and LIRICS to uncover tumor-immunological cell-type-specific interactions that are differentially activate in mismatch repair deficient tumors. This analysis shows that T-cell co-stimulating interactions are associated with higher survival rates in these tumors independent of their mutation burden levels. Finally, using machine learning, we identify key cell-type-specific ligand-receptor interactions that predict patient response to immune checkpoint blockade therapy in melanoma. Taken together, we present and validate a computational framework for analyzing large bulk gene expression datasets at a cell-type specific resolution that has many potential future applications, complementing single cell transcriptomics in a cost-effective manner. Citation Format: Kun Wang, Sushant Patkar, JooSang Lee, E. Michael Gertz, Welles Robinson, Fiorella Schischlik, Alejandro Schäffer, Eytan Ruppin. Deconvolving bulk gene expression to chart the immune activity and crosstalk in the tumor microenvironment [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 3179.
Effectiveness of interventions in patients who develop graft nephrolithiasis after kidney transplantation: A systematic review
Authors: R. Boissier, O. Rodriguez-Faba, V. Hevia, R. Hassan Zakri, K. Budde, A. Figueiredo, E. Lledo Garcia, J. Olsburgh, R. Heinz, C. Yuhong Yuan, A. Breda
Journal: European Urology (2021)
Covid-19: China’s CoronaVac vaccine offers 83.5% protection against symptomatic infection, interim analysis finds
Authors: Shaun Griffin
Journal: BMJ (2021)

Covid-19: China's CoronaVac vaccine offers 83.5% protection against symptomatic infection, interim analysis finds Shaun GriffinTwo doses of the new CoronaVac vaccine made in China have an efficacy of 83.5% against symptomatic covid-19, an interim analysis has shown. 1 The vaccine, developed by the Chinese company Sinovac Life Sciences and made from inactivated SARS-CoV-2 virus, shows promise for global distribution because of its relative stability.
Shear Wave Elastography, a New Tool for Diaphragmatic Qualitative Assessment: A Translational Study
Authors: Yassir Aarab, Aurelien Flatres, Fanny Garnier, Mathieu Capdevila, Fabrice Raynaud, Alain Lacampagne, David Chapeau, Kada Klouche, Pascal Etienne, Samir Jaber, Nicolas Molinari, Lucie Gamon, Stefan Matecki, Boris Jung
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Prolonged mechanical ventilation is often associated with either a decrease (known atrophy) or an increase (supposed injury) in diaphragmatic thickness. Shear wave elastography is a noninvasive technique that measures shear modulus, a surrogate of tissue stiffness and mechanical properties. Objectives: To describe changes in shear modulus (SM) during the ICU stay and the relationship with alterations in muscle thickness. To perform a comprehensive ultrasound-based characterization of histological and force production changes occurring in the diaphragm. Methods: Translational study using critically ill patients and mechanically ventilated piglets. Serial ultrasound examination of the diaphragm collecting thickness and SM was performed in both patients and piglets. Transdiaphragmatic pressure and diaphragmatic biopsies were collected in piglets. Measurements and Main Results: We enrolled 102 patients, 88 of whom were invasively mechanically ventilated. At baseline, SM was 14.3 ± 4.3 kPa and diaphragm end-expiratory thickness was 2.0 ± 0.5 mm. Decrease or increase by more than 10% from baseline was reported in 86% of the patients for thickness and in 92% of the patients for SM. An increase in diaphragmatic thickness during the stay was associated with a decrease in SM (β = -9.34 ± 4.41; P = 0.03) after multivariable analysis. In the piglet sample, a decrease in SM over 3 days of mechanical ventilation was associated with loss of force production, slow and fast fiber atrophy, and increased lipid droplets accumulation. Conclusions: Increases in diaphragm thickness during critical illness is associated with decreased tissue stiffness as demonstrated by shear wave ultrasound elastography, consistent with the development of muscle injury and weakness. Clinical trial registered with www.clinicaltrials.gov (NCT03550222).
The efficacy and tolerability of pollen extract in combination with hyaluronic acid and vitamins in the management of patients affected by CP/CPPS: A 26 weeks, randomized, controlled, single-blinded, phase III study
Authors: T. Cai, L. Gallelli, P. Verze, A. Palmieri, G. Bonkat, V. Mirone, F. Wagenlehner, T.E. Bjerklund Johansen
Journal: European Urology (2021)