tbuckley/cabot-search huggingface dataset:
Real-time CGM Is Superior to Flash Glucose Monitoring for Glucose Control in Type 1 Diabetes: The CORRIDA Randomized Controlled Trial
Authors: Aneta Hásková, Lucie Radovnická, Lenka Petruželková, Christopher G. Parkin, George Grunberger, Eva Horová, Vendula Navrátilová, Ondřej Kádě, Martin Matoulek, Martin Prázný, Jan Šoupal
Journal: Diabetes Care (2020)

OBJECTIVE The aim of this trial was to compare the efficacy of real-time and intermittently scanned continuous glucose monitoring (rtCGM and isCGM, respectively) in maintaining optimal glycemic control. RESEARCH DESIGN AND METHODS In this randomized study, adults with type 1 diabetes (T1D) and normal hypoglycemia awareness (Gold score &amp;lt;4) used rtCGM (Guardian Connect Mobile) or isCGM (FreeStyle Libre) during 4 days of physical activity (exercise phase) and in the subsequent 4 weeks at home (home phase). Primary end points were time in hypoglycemia (&amp;lt;3.9 mmol/L [&amp;lt;70 mg/dL]) and time in range (3.9–10.0 mmol/L [70–180 mg/dL]). The isCGM group wore an additional masked Enlite sensor (iPro2) for 6 days to check for bias between the different sensors used by the rtCGM and isCGM systems. RESULTS Sixty adults with T1D (mean age 38 ± 13 years; A1C 62 ± 12 mmol/mol [7.8 ± 1.1%]) were randomized to rtCGM (n = 30) or isCGM (n = 30). All participants completed the study. Percentage of time in hypoglycemia (&amp;lt;3.9 mmol/L [&amp;lt;70 mg/dL]) was lower among rtCGM versus isCGM participants in the exercise phase (6.8 ± 5.5% vs. 11.4 ± 8.6%, respectively; P = 0.018) and during the home phase (5.3 ± 2.5% vs. 7.3 ± 4.4%, respectively; P = 0.035). Hypoglycemia differences were significant and most notable during the night. rtCGM participants spent more time in range (3.9–10 mmol/L [70–180 mg/dL]) than isCGM participants throughout both the exercise (78.5 ± 10.2% vs. 69.7 ± 16%, respectively; P = 0.0149) and home (75.6 ± 9.7% vs. 67.4 ± 17.8%, respectively; P = 0.0339) phases. The results were robust to the insignificant bias between rtCGM and isCGM sensors that masked CGM found in the isCGM arm. CONCLUSIONS rtCGM was superior to isCGM in reducing hypoglycemia and improving time in range in adults with T1D with normal hypoglycemia awareness, demonstrating the value of rtCGM alarms during exercise and in daily diabetes self-management.
Abstract 124: Recycling endosomes in mature epithelia restrain tumorigenic signaling
Authors: Sayantani Goswami
Journal: Cancer Research (2020)

Abstract The effects of polarized membrane trafficking in mature epithelial tissue on cell growth and cancer progression have not been fully explored in vivo. A majority of colorectal cancers have reduced and mislocalized Rab11, a small GTPase dedicated to trafficking of recycling endosomes. Patients with low Rab11 protein expression have poor survival rates. Using genetic models across species, we show that intact recycling endosome function restrains aberrant epithelial growth elicited by APC or RAS mutations. Loss of Rab11 protein led to epithelial dysplasia in early animal development and synergized with oncogenic pathways to accelerate tumor progression initiated by carcinogen, genetic mutation, or aging. Transcriptomic analysis uncovered an immediate expansion of the intestinal stem cell pool along with cell-autonomous Yki/Yap activation following disruption of Rab11a-mediated recycling endosomes. Intestinal tumors lacking Rab11a traffic exhibited marked elevation of nuclear Yap, upd3/IL6-Stat3, and amphiregulin-MAPK signaling, while suppression of Yki/Yap or upd3/IL6 reduced gut epithelial dysplasia and hyperplasia. Examination of Rab11a function in enteroids or cultured cell lines suggested that this endosome unit is required for suppression of the Yap pathway by Hippo kinases. Thus, recycling endosomes in mature epithelia constitute key tumor suppressors, loss of which accelerates carcinogenesis. Statement of significance: Recycling endosome traffic in mature epithelia constitutes a novel tumor suppressing mechanism. Citation Format: Sayantani Goswami. Recycling endosomes in mature epithelia restrain tumorigenic signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 124.
Abstract 1335: Analytical evaluation of a targeted solid tumor next-generation sequencing assay
Authors: Jeff H. Tsai, Valerie Montel, Nathalie Mouttham
Journal: Cancer Research (2020)

Abstract With the growing interest in personalized medicine for cancer patients, next generation sequencing (NGS) variant screening assays are becoming a powerful clinical tool for tumor classification. The AmpliSeqTM for Illumina Focus Panel is a targeted sequencing approach that interrogate 52 of the most common solid tumor genes for single nucleotide variants (SNVs), insertion/deletions (indels), and copy number variants (CNVs) in DNA and gene fusions in RNA concurrently. To evaluate the performance of the Focus assay, an analytical performance study was conducted. Using an automated workflow with high quality DNA reference samples, both intra-assay and inter-assay experiments resulted in high reproducibility (R2 &amp;gt;0.95) for detecting expected variants at various frequencies. Similarly, using high quality RNA reference samples, 100% of all expected fusions were detected in all experiments, demonstrating accuracy and precision of the Focus panel assay with high quality samples. To evaluate assay sensitivity, limit of detection (LOD) studies were carried out by titrating the nucleic acid input into the assay. Using a 5% variant allele frequency threshold (empirically established in the analysis pipeline), the assay detected all expected SNVs and indels across sample across sample input amounts. Using extracted DNA from a human cell line model (HL-60) with a confirmed MYC gene gain, results showed reliable MYC gain detection down to 4 copies in a diploid background. Similarly, extracted RNA from a confirmed EML4-ALK fusion positive cell line (H2228) diluted into background RNA showed 100% positive fusion calling down to 250pg or 133 copies. Finally, to understand the assay performance on clinically-relevant FFPE samples, somatic variant detection in 8 human cell lines and 68 total FFPE samples was evaluated. For FFPE DNA samples, the libraries averaged &amp;gt;90% on-target alignment and coverage uniformity with &amp;gt;3000x mean coverage across all samples. While FFPE RNA showed lower alignment for poor quality samples, the assay showed overall high positive and negative predictive value for variant and fusion calling. In summary, the AmpliSeqTM for Illumina Focus panel is an automation-compatible small panel NGS assay with robust performance to assess somatic variants in solid tumors. Citation Format: Jeff H. Tsai, Valerie Montel, Nathalie Mouttham. Analytical evaluation of a targeted solid tumor next-generation sequencing assay [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1335.
Abstract 4849: YPN-005, an oral CDK7 inhibitor, shows a significant antitumor activity in Myc amplified solid tumors and MCL-1 overexpressed blood cancer
Authors: Jakyung Yoo, Jun Hee Lee, Mi Jung Lee, Kang Woo Lee, Ji Eun Min, Jinhwan Kim, Ki-Nam Min, Da-Hye Jeon, Dae Seong Lim, Kwang-Ok Lee
Journal: Cancer Research (2020)

Abstract Background: Cyclin dependent kinase 7 (CDK7) has been recognized as one of potential therapeutic targets in Myc-driven cancers. Previously, we synthesized selective irreversible CDK7 inhibitor and we demonstrated a significant inhibition of the proliferation of TNBC and HCC cells by down-regulation of c-Myc and MCL-1. We further report YPN-005 of the preclinical data with biological characterization. Methods: Antiproliferative activity of YPN-005 was measured in solid tumor cell lines with Myc amplification and in hematologic cancer cells with MCL-1overexpression. To investigate the mechanism of action of YPN-005, the expression levels of phospho-RNA polymerase II, phospho-CDK2 and -CDK4, BClXL, cleaved-PARP, c-Myc and MCL-1 were analyzed by Western Blot analyses. CDK7 occupancy was determined by using a biotinylated small molecule probe following incubating of TNBC, HCC, AML cells and hPBMC with YPN-005. The therapeutic efficacy of YPN005 was evaluated in TNBC and HCC xenograft mouse model. Results: YPN-005 treatment induced apoptosis and cell cycle arrest. Selectivity of YPN-005 on CDK7 was confirmed in the 468 kinases panel assay. YPN-005 significantly inhibited the proliferation of TNBC, ER+ breast cancer, HCC, ovarian cancer, small cell lung cancer (SCLC), pancreas, prostate and various types of blood cancer cells and IC50's were determined in 1-20 nM range. Inhibition of cell proliferation was accompanied by down-regulation of RNA PolII phosphorylation, c-Myc and MCL-1 expression. Washout assay by Western Blot demonstrated that YPN-005 irreversibly blocked RNA PolII phosphorylation. In addition, YPN-005 downregulated the adaptive immune checkpoint PD-L1 by the depletion of c-Myc in TNBCs. CDK7 occupancy over 90% was observed in TNBC, HCC, and AML cells with 100nM of YPN-005. In vivo xenograft models of TNBC and HCC showed that daily oral administration of YPN-005 for 21 days (once, and 10~20mg/kg) efficiently inhibited the growth of tumor. All the mice survived and there was no significant changes in their hematologic profiles. Conclusion: Our findings suggest that YPN-005 is an orally available, potent, and selective CDK7 inhibitor which can be used for the treatment of Myc and MCL-1 overexpressing cancer patients. These data support the rationale for advancing YPN-005 towards IND-enabling studies. Citation Format: Jakyung Yoo, Jun Hee Lee, Mi Jung Lee, Kang Woo Lee, Ji Eun Min, Jinhwan Kim, Ki-Nam Min, Da-Hye Jeon, Dae Seong Lim, Kwang-Ok Lee. YPN-005, an oral CDK7 inhibitor, shows a significant antitumor activity in Myc amplified solid tumors and MCL-1 overexpressed blood cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4849.
Abstract 1308: <i>CDK12</i> alterations define a distinct molecular subtype of prostate cancers with unique genomic and clinical characteristics
Authors: Bastien Nguyen, Jose Mauricio Mota, Subhiksha Nandakumar, Konrad H. Stopsack, Emily Weg, Dana Rathkopf, Michael J. Morris, Howard Scher, Philip W. Kantoff, Anuradha Gopalan, Dmitriy Zamarin, David B. Solit, Nikolaus Schultz, Wassim Abida
Journal: Cancer Research (2020)

Abstract Background: CDK12 alterations are present in several tumor types but little is known regarding their oncogenic role and their clinical significance. Here we sought to describe the landscape of CDK12 alterations across solid cancers and the clinical features of CDK12-altered prostate cancer. Methods: A total of 26,743 patients across 25 solid tumor types with available targeted sequencing data from MSK-IMPACT as part of their clinical care were included. Clinicopathological features and outcomes were assessed in prostate cancer. CDK12 alterations and association with genomic characteristics are described. For prostate cancer patients, overall survival from the date of metastasis and time to castration-resistance from the start of androgen deprivation therapy were assessed using univariable and multivariable Cox regression analysis. Results: CDK12 alterations were identified in 404/26,743 (1.5%) patients overall, but were most frequent in prostate (100/1875, 5.3%) and ovarian cancer (43/1034, 4.2%) where they were associated with a high prevalence of truncating variants and biallelic inactivation. CDK12 alterations defined a distinct subtype of prostate cancer with more aggressive clinical features, a unique copy number alteration profile and involvement of distinct oncogenic pathway alterations, including cell cycle pathway genes. Independent of standard clinical factors and genomic instability, CDK12-altered prostate cancer patients were associated with shorter overall survival (median 64.4 vs 74.9 months, adjusted hazard ratio [aHR] 1.65, 95% CI 1.07-2.53, p = 0.03) and shorter time to the development of castration-resistant disease (median 10.8 months vs 13.1, aHR 1.43, 95%CI 1.07-1.8, p = 0.02). Conclusions: CDK12 loss of function is a rare event across solid cancers but defines a distinct molecular subtype of prostate cancer that is associated with more aggressive clinical features and unique genomic alterations. Citation Format: Bastien Nguyen, Jose Mauricio Mota, Subhiksha Nandakumar, Konrad H. Stopsack, Emily Weg, Dana Rathkopf, Michael J. Morris, Howard Scher, Philip W. Kantoff, Anuradha Gopalan, Dmitriy Zamarin, David B. Solit, Nikolaus Schultz, Wassim Abida. CDK12 alterations define a distinct molecular subtype of prostate cancers with unique genomic and clinical characteristics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1308.
Abstract 3098: Urine-based molecular biomarker signatures for bladder cancer
Authors: Zhixin Zhao, Amy Chang, Binggang Xiang, Feng Xie, Xiaohong Wang, Kemin Zhou, Jianjun Yu, Pan Du, Shidong Jia
Journal: Cancer Research (2020)

Abstract Introduction: By 2020 the estimated incidence of genitourinary (GU) cancers (prostate, bladder, and kidney) will be over 2 million worldwide and responsible for ∼800 000 deaths. Current diagnosis and monitoring methods of GU cancer patients are often invasive and/or lack sensitivity and specificity. The tremendous success in cell-free DNA (cfDNA) blood test provides a strong rationale for using body fluids such as blood and urine as minimally invasive “liquid biopsies” to identify DNA-based molecular biomarkers in urologic malignancies. Urinary cfDNA as a liquid biopsy holds greater potential for a more sensitive alternative to blood biopsies-based tests for clinical use in GU cancers. Urinary biomarker test offers advantages including the potential for more convenient testing, monitoring, and home use. Methods: Analytic validation was conducted using urine cfDNA samples containing different SNPs with different titrations. Urine samples were collected from two different groups, including treatment-naïve patients with pathology-confirmed bladder cancer (BLCA) and healthy donors. Both tumor and germline tissues were collected from the BLCA patients. Results: We report the development, validation, and clinical application of the urine-based next-generation sequencing for integrated genomic cfDNA profiling of bladder cancers, including genomic alterations, tumor mutation burden (TMB) and microsatellite instability (MSI). The analytic sensitivity goes down to 0.5% with 100% analytical specificity. High concordance for mutations between tumor tissue and urinary cfDNA suggests a higher sensitivity alternative for the non-invasive early detection of BLCA. In addition to the NGS-based test, we also developed a Bio-Rad digital PCR assay for orthogonal confirmation of the detected biomarkers such as FGFR3 hotspot mutations. Conclusions: Our work has demonstrated the promise of using urinary cfDNA for detecting genomic alterations at the early stage of BLCA for biomarker detections. Citation Format: Zhixin Zhao, Amy Chang, Binggang Xiang, Feng Xie, Xiaohong Wang, Kemin Zhou, Jianjun Yu, Pan Du, Shidong Jia. Urine-based molecular biomarker signatures for bladder cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3098.
Health economic evaluation of a clinical pharmacist's intervention on the appropriate use of devices and cost savings: A pilot study
Authors: Virginie Chasseigne, Sophie Bouvet, Sihame Chkair, Marlène Buisson, Marie Richard, Renaud de Tayrac, Martin Marie Bertrand, Christel Castelli, Jean-Marie Kinowski, Géraldine Leguelinel-Blache
Journal: International Journal of Surgery (2020)

Good management of disposable and reusable supplies may improve surgical efficiency in the operating room (OR) and also corresponds to the best eco-responsible approach. The purpose of this study was to assess the impact of a clinical pharmacist's intervention in the OR on the non-compliant use of medical devices. We also assessed the economic impact of the pharmaceutical intervention. We conducted a monocentric prospective study in the OR of a University hospital over one year. Three surgical specialties: urologic, digestive and gynecologic were audited after a preparatory phase to optimize usage of medical devices used for surgeries. The supply costs concerning the three specialties were compared before and after the pharmacist intervention. One hundred and fifty surgical procedures were audited in digestive (33.3%, n = 50), gynecologic (32%, n = 48) and urologic (34.7%, n = 52) surgeries. With the pharmacist in OR, 51 procedures (34% CI95%[26.4%; 41.6%]) with a non-compliance concerning at least one medical device were found compared to the 50% rate without the pharmacist reported previously (P < .0001). Eighteen percent of surgical procedures had at least one circulator retrieval for the reason "incomplete case cart despite device listed on the case cart list" versus 29.1% before pharmacist intervention (P = .0028). A €33 014 saving associated with the presence of the pharmacist in OR was observed. This prospective interventional study showed that the intervention of a pharmacist specialized in the medical device field could significantly reduce non-compliances in medical device use and reduce costs in OR.
Abstract 5591: Differential profiles of pro-inflammatory chemokines identified in patients with prostate cancer and benign prostatic hyperplasia
Authors: Niradiz Reyes, Raj Tiwari, Jan Geliebter
Journal: Cancer Research (2020)

Abstract Background: Prostate cancer (PCa) is the most frequently diagnosed malignant disease and the second leading cause of cancer-related deaths of men in the United States. The development of PCa has been linked to inflammation; thus, systemic inflammatory biomarkers may be useful to differentiate PCa from other prostatic disorders, such as benign prostatic hyperplasia (BPH). Proinflammatory chemokines are among the factors that regulate inflammatory processes through the recruitment of leukocytes to the sites of infection or injury. The aim of the present study was to compare the serum profiles of pro-inflammatory chemokines of patients newly diagnosed either with PCa or BPH. Methods: Serum was prepared from blood samples collected at the time of diagnosis from a cohort of patients newly diagnosed with PCa or BPH. Protein concentrations of chemokines were measured in each group of samples with a multiplex ELISA kit specific for the quantification of 12 proinflammatory chemokines: CCL2, CCL3, CCL4, CCL5, CCL11, CCL17, CCL22, CXCL1, CXCL8, CXCL9, CXCL10 and CXCL11. Results were further validated for selected chemokines using single analyte ELISA kits. This work was approved by the Institutional Review Board of the University of Cartagena. Results: Our study showed that PCa patients had a significantly different proinflammatory chemokine profile compared to BPH patients. Serum samples in the PCa group had significant higher levels of CXCL8, CCL2, CCL3, CCL4, CXCL11 and CXCL1 compared with the BPH group. Conclusion: Our study showed that PCa patients had a high proinflammatory chemokine profile. Additional studies are required to determine whether proinflammatory chemokine profiles can serve as a diagnostic signature to differentiate between PCa and BPH, and whether proinflammatory chemokine profiles are correlated with clinical outcomes of PCa patients. Keywords: Prostate cancer, chemokine, inflammation, Benign Prostatic Hyperplasia Citation Format: Niradiz Reyes, Raj Tiwari, Jan Geliebter. Differential profiles of pro-inflammatory chemokines identified in patients with prostate cancer and benign prostatic hyperplasia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5591.
PARK2 promotes mitochondrial pathway of apoptosis and antimicrotubule drugs chemosensitivity <i>via</i> degradation of phospho-BCL-2
Authors: Hengxing Chen, Yun Li, Yu Li, Zhen Chen, Limin Xie, Wenjia Li, Yuanxin Zhu, Hong Xue, H. Phillip Koeffler, Wenjing Wu, Kaishun Hu, Dong Yin
Journal: Theranostics (2020)

Rationale: Neoadjuvant chemotherapy has become the standard treatment of locally advanced breast cancer. Antimicrotubule drugs and DNA-damaging drugs are the most popular medicines used for neoadjuvant chemotherapy. However, we are unable to predict which chemotherapeutic drug will benefit to an individual patient. PARK2 as a tumor suppressor in breast cancer has been reported. While the role of PARK2 in chemotherapy response remains unknown. In this study, we explore the impact of PARK2 on chemosensitivity in breast cancer. Methods: PARK2 expression in breast cancer patients with different neoadjuvant chemotherapeutic regimens was studied using immunohistochemistry. Data was correlated to disease-free survival (DFS), overall survival and pathologic complete response (pCR). The functional roles of PARK2 were demonstrated by a series of in vitro and in vivo experiments. Including mass spectrometry, Co-immunoprecipitation, isolation of subcellular fractionation, fluorescence microscopy, in vivo ubiquitination assay and luciferase analyses. Results: Highly expressed PARK2 predicted better response to antimicrotubule drugs-containing regimen associated with higher rate of pathologic complete response (pCR). In contrast, PARK2 expression did not predict response to the DNA-damaging drugs regimen. Following antimicrotubule drugs treatment, levels of PARK2 was upregulated due to the repression of STAT3-mediated transcriptional inhibition of PARK2. Moreover, overexpression of PARK2 specifically rendered cells more sensitive to antimicrotubule drugs, but not to DNA-damaging drugs. Depletion of PARK2 enhanced resistance to antimicrotubule drugs. Mechanistically, PARK2 markedly activated the mitochondrial pathway of apoptosis after exposure to antimicrotubule drugs. This occurred through downregulating the antiapoptotic protein, phospho-BCL-2. BCL-2 phosphorylation can be specifically induced by antimicrotubule drugs, whereas DNA-damaging drugs do not. Notably, PARK2 interacted with phospho-BCL-2 (Ser70) and promoted ubiquitination of BCL-2 in an E3 ligase-dependent manner. Hence, PARK2 significantly enhanced the chemosensitivity of antimicrotubule drugs both in vitro and in vivo, while loss-of-function PARK2 mutants did not. Conclusions: Our findings explained why PARK2 selectively confers chemosensitivity to antimicrotubule drugs, but not to DNA-damaging drugs. In addition, we identified PARK2 as a novel mediator of antimicrotubule drugs sensitivity, which can predict response of breast cancer patients to antimicrotubule drugs-containing regime.