tbuckley/cabot-search huggingface dataset:
Abstract 1059: Combination of gemcitabine and cytidine deaminase inhibitor: A breakthrough cocktail for the treatment of pancreatic ductal adenocarcinoma
Authors: Manali Patki, Aishwarya Saraswat, Shraddha Bhutkar, Vikas Dukhande, Ketankumar Patel
Journal: Cancer Research (2021)

Abstract Pancreatic ductal adenocarcinoma is a very common type of pancreatic cancer and is one of the deadliest cancers. Gemcitabine (Gem), is still the mainstay drug for the treatment of PDAC. Gem is a hydrophilic drug which requires nucleoside transporters for its efficient uptake. Once inside the cell, Gem is converted to an active triphosphate form which inhibits DNA synthesis and causes apoptosis. However, Gem gets inactivated by cytidine deaminase (CDA). Long term treatment with Gem leads to increased CDA production thereby developing resistance. We hypothesize that combination of Gem with CDA inhibitor like Zebularine (Zeb), could prevent the intracellular degradation of Gem. Combination can potentially result in enhancing the anti-cancer activity of Gem, reduced dose and dosing frequency and minimizing side effects. The objectives of our study were; (a) to investigate the cytotoxic interaction of Gem and Zeb alone and in combination (b) Evaluating effect of various apoptosis and proliferation markers using flow cytometry and western blot assay. Initially we explored the anti-proliferative effects of Gem and Zeb as a single drug and in combination on MiaPaca-2 cells using MTT assay. Combination index was calculated using chou talalay method and Combenefit software. Effect of Gem, Zeb, and combination treatment on the cell viability of 3D tumor spheroids and its area was carried out using fluorescence microscopy and ImageJ software respectively. Apoptosis study was carried out using Annexin V apoptosis kit.Gem and Zeb exhibited dose-dependent inhibition in viability of MiaPaca-2 cells with an IC50 of 0.48 and 67.82 µM, respectively. The combination index of 0.09 suggest “very strong synergism” (Table 1). 3D spheroid treated with combination exhibited a highly distorted surface with significantly higher number of dead cells. Our research confirms that this synergistic combination can be a breakthrough approach for the treatment of PDAC. Table 1.IC50 of Gem, Zeb and combination of Gem+Zeb in Miapaca2 cellsDrugMolar RatioIC50 of GemIC50 of ZebCombination IndexSingle-0.4867.82Gem1:100.0440.40.09 Citation Format: Manali Patki, Aishwarya Saraswat, Shraddha Bhutkar, Vikas Dukhande, Ketankumar Patel. Combination of gemcitabine and cytidine deaminase inhibitor: A breakthrough cocktail for the treatment of pancreatic ductal adenocarcinoma [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 1059.
Impact of non-pharmaceutical interventions against COVID-19 in Europe in 2020: a quasi-experimental non-equivalent group and time series design study
Authors: Paul R Hunter, Felipe J Colón-González, Julii Brainard, Steven Rushton
Journal: Eurosurveillance (2021)

Introduction The current pandemic of coronavirus disease (COVID-19) is unparalleled in recent history as are the social distancing interventions that have led to a considerable halt on the economic and social life of so many countries. Aim We aimed to generate empirical evidence about which social distancing measures had the most impact in reducing case counts and mortality. Methods We report a quasi-experimental (observational) study of the impact of various interventions for control of the outbreak through 24 April 2020. Chronological data on case numbers and deaths were taken from the daily published figures by the European Centre for Disease Prevention and Control and dates of initiation of various control strategies from the Institute of Health Metrics and Evaluation website and published sources. Our complementary analyses were modelled in R using Bayesian generalised additive mixed models and in STATA using multilevel mixed-effects regression models. Results From both sets of modelling, we found that closure of education facilities, prohibiting mass gatherings and closure of some non-essential businesses were associated with reduced incidence whereas stay-at-home orders and closure of additional non-essential businesses was not associated with any independent additional impact. Conclusions Our findings are that schools and some non-essential businesses operating ‘as normal’ as well as allowing mass gatherings were incompatible with suppressing disease spread. Closure of all businesses and stay at home orders are less likely to be required to keep disease incidence low. Our results help identify what were the most effective non-pharmaceutical interventions in this period.
Abstract 2623: Investigation into factors influencing probability of success in oncology clinical trials and trends over time
Authors: Mary Jane Hinrichs, Shomesh E. Chaudhuri, Robert Bowden, Andrew W. Lo, David W. Jenkins
Journal: Cancer Research (2021)

Abstract The regulatory approval process for new therapies in oncology involves costly clinical trials that can span multiple years and historically have had a low probability of success. To derive estimates of the probability of success and other related risk characteristics in oncology clinical trials, we searched Informa Pharma Intelligence's Trialtrove and Pharmaprojects databases for oncology-specific drug-indication programs between 2001 and 2020. In total, we identified 10,083 oncology-specific drug-indication programs, which included 2,800 therapeutic agents (excluding biosimilars) tested across 98 indications. The features we considered included indication and indication group, clinical phase, follow-on indication status, presence and type of patient selection biomarker, drug modality, and accelerated approval status. In several cases, clinical success rates were higher than the benchmark oncology historical average of the phase 1 to approval success rate of 4.1% found in our sample set. For example, the use of pre-selection biomarkers in early clinical development was associated with a greater than two-fold increase in probability of approval from phase 1. Moreover, drugs with prior approvals in another indication were more than three times more likely to be successful from phase 1 than a candidate targeting a novel mechanism. In addition, we found that monoclonal antibodies were numerically more successful than other modalities in the historical data, while oncolytic viruses, vaccines, and bispecific antibodies have been less successful. In all cases, concomitant with the emergence of genomic technologies, an improved scientific understanding of cancer biology, and an evolving regulatory environment that includes a higher number of accelerated approvals, success rates in oncology have improved during the time period of this analysis and particularly in the past 5 years. Citation Format: Mary Jane Hinrichs, Shomesh E. Chaudhuri, Robert Bowden, Andrew W. Lo, David W. Jenkins. Investigation into factors influencing probability of success in oncology clinical trials and trends over time [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 2623.
Modification of the Association Between Severe Hypoglycemia and Ischemic Heart Disease by Surrogates of Vascular Damage Severity in Type 1 Diabetes During ∼30 Years of Follow-up in the DCCT/EDIC Study
Authors: Elke R. Fahrmann, Laura Adkins, Henry K. Driscoll
Journal: Diabetes Care (2021)

OBJECTIVE Literature suggests that severe hypoglycemia (SH) may be linked to cardiovascular events only in older individuals with high cardiovascular risk score (CV-score). Whether a potential relationship between any-SH and cardiovascular disease exists and whether it is conditional on vascular damage severity in a young cohort with type 1 diabetes (T1D) without apparent macrovascular and no or mild-to-moderate microvascular complications at baseline is unknown. RESEARCH DESIGN AND METHODS We evaluated data of 1,441 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study volunteers (diabetes duration 1–15 years) followed for ∼30 years. Time-dependent associations between any-SH and ischemic heart disease (IHD: death, silent/nonfatal myocardial infarct, revascularization, or confirmed angina) and associations between interactions of any-SH with surrogates of baseline micro-/macrovascular damage severity and IHD were analyzed. Diabetes duration, steps on DCCT Early Treatment Diabetic Retinopathy Study severity scale (DCCT-ETDRS), Diabetes Complications Severity Index (DCSI), and CV-scores were considered as surrogates of baseline micro-/macrovascular damage severity. RESULTS Without interactions, in the minimally adjusted model controlling for confounding bias by age and HbA1c, SH was a significant IHD factor (P = 0.003). SH remained a significant factor for IHD in fully adjusted models (P &amp;lt; 0.05). In models with interactions, interactions between SH and surrogates of microvascular complications severity, but not between SH and CV-score, were significant. Hazard ratios for IHD based on SH increased 1.19-fold, 1.32-fold, and 2.21-fold for each additional year of diabetes duration, DCCT-ETDRS unit, and DCSI unit, respectively. At time of IHD event, ∼15% of 110 participants with SH had high CV-scores. CONCLUSIONS In a young cohort with T1D with no baseline macrovascular complications, surrogates of baseline microvascular damage severity impact the effect of SH on IHD. Older age with high CV-score per se is not mandatory for an association of SH with IHD. However, the association is multifactorial.
Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines
Authors: Peng Cao, Changmao Chen, An Liu, Qinghong Shan, Xia Zhu, Chunhui Jia, Xiaoqi Peng, Mingjun Zhang, Zahra Farzinpour, Wenjie Zhou, Haitao Wang, Jiang-Ning Zhou, Xiaoyuan Song, Liecheng Wang, Wenjuan Tao, Changjian Zheng, Yan Zhang, Yu-Qiang Ding, Yan Jin, Lin Xu, Zhi Zhang
Journal: Neuron (2021)
Untargeted metabolomics of prostate cancer zwitterionic and positively charged compound in urine
Authors: M. Maggi, A. Cerrato, C. Bedia, A.L. Capriotti, C. Cavaliere, V. Gentile, C.M. Montone, S. Piovesana, A. Sciarra, R. Tauler, A. Laganà
Journal: European Urology (2021)
Impact of abdominal aortic atherosclerotic burden in patients submitted to partial nephrectomy: A pilot study on 142 cases
Authors: A. Tafuri, E. Serafin, K. Odorizzi, A. Gozzo, G. Di Filippo, A. Bianchi, M. Borzi, G. Zamboni, G. Mansueto, A.B. Porcaro, M. Brunelli, M.A. Cerruto, G. Zaza, P. Fiorini, B. Maris, A. Antonelli
Journal: European Urology (2021)
Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit in Patients With Refractory Gastrointestinal Stromal Tumors
Authors: Andrew J. Wagner, Paul L. Severson, Anthony F. Shields, Amita Patnaik, Rashmi Chugh, Gabriel Tinoco, Guoxian Wu, Marika Nespi, Jack Lin, Ying Zhang, Todd Ewing, Gaston Habets, Elizabeth A. Burton, Bernice Matusow, James Tsai, Garson Tsang, Rafe Shellooe, Heidi Carias, Katrina Chan, Hamid Rezaei, Laura Sanftner, Adhirai Marimuthu, Wayne Spevak, Prabha N. Ibrahim, Kerry Inokuchi, Oscar Alcantar, Glenn Michelson, Athanasios C. Tsiatis, Chao Zhang, Gideon Bollag, Jonathan C. Trent, William D. Tap
Journal: JAMA Oncology (2021)

Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors.
Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia
Authors: Xueliang Gao, Shenghui Qin, Yongxia Wu, Chen Chu, Baishan Jiang, Roger H. Johnson, Dong Kuang, Jie Zhang, Xi Wang, Anand Mehta, Kenneth D. Tew, Gustavo W. Leone, Xue-Zhong Yu, Haizhen Wang
Journal: Journal of Clinical Investigation (2021)

PFKP (phosphofructokinase, platelet), the major isoform of PFK1 expressed in T cell acute lymphoblastic leukemia (T-ALL), is predominantly expressed in the cytoplasm to carry out its glycolytic function. Our study showed that PFKP is a nucleocytoplasmic shuttling protein with functional nuclear export and nuclear localization sequences (NLSs). Cyclin D3/CDK6 facilitated PFKP nuclear translocation by dimerization and by exposing the NLS of PFKP to induce the interaction between PFKP and importin 9. Nuclear PFKP stimulated the expression of C-X-C chemokine receptor type 4 (CXCR4), a chemokine receptor regulating leukemia homing/infiltration, to promote T-ALL cell invasion, which depended on the activity of c-Myc. In vivo experiments showed that nuclear PFKP promoted leukemia homing/infiltration into the bone marrow, spleen, and liver, which could be blocked with CXCR4 antagonists. Immunohistochemical staining of tissues from a clinically well-annotated cohort of T cell lymphoma/leukemia patients showed nuclear PFKP localization in invasive cancers, but not in nonmalignant T lymph node or reactive hyperplasia. The presence of nuclear PFKP in these specimens correlated with poor survival in patients with T cell malignancy, suggesting the potential utility of nuclear PFKP as a diagnostic marker.
Abstract 1282: IND-enabling characterization of the selective GPER agonist, LNS8801
Authors: Chris Natale, Tina Garyantes
Journal: Cancer Research (2021)

Abstract LNS8801 is the first-in-class, small molecule, orally bioavailable, agonist of GPER being developed for the treatment of patients with advanced cancer. LNS8801 is highly selective for GPER over the classical nuclear hormone estrogen receptors α and β, and it was also highly selective for GPER in Eurofins' Safety47 panel. LNS8801 has very low aqueous solubility and is highly protein bound. Pharmacokinetic studies demonstrate that LNS8801 has high clearance and moderate, solubility-dependent, oral bioavailability. The rank ordering of metabolic liability in hepatocytes is dog&amp;lt;human&amp;lt;mouse&amp;lt;rat, which is consistent with the observed clearance rates in these species. LNS8801 metabolism, and thus clearance, is slower in dogs. Oral bioavailability is ~80% and dose proportional in human formulations tested in dogs. LNS8801 is primarily metabolized by oxidation followed by phase II conjugation. In vitro metabolism studies indicate that LNS8801 is a potential substrate for several cytochrome P450 enzymes and thus has a low potential for participating in drug-drug interactions (DDIs). Given that maximal efficacy is expected at low exposures (Cmax of ≤5 nM) and that LNS8801 is highly protein bound, it is unlikely that these effects will cause adverse DDIs in humans. In the pivotal 28-day toxicity studies, the no-observed-adverse-effect level (NOAEL) was &amp;gt;1000 mg/kg/day (the maximum feasible dose) in the rat and 30 mg/kg/day in the dog. Exposure was higher in dogs than in rats due to considerable accumulation. In the dog, mortality at doses that gave very high exposures was attributed to myelopoietic hypocellularity of the bone marrow and subsequent lymphoid depletion in associated organs. The primary target organs were identified as bone marrow, lymphoid tissues, and reproductive organs. Exposure at the canine NOAEL was more than 24,000 times the predicted maximally efficacious exposure in humans, and thus LNS8801 is anticipated to be very safe. Citation Format: Chris Natale, Tina Garyantes. IND-enabling characterization of the selective GPER agonist, LNS8801 [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 1282.
Abstract 2413: POLE gene mutations in African Americans colorectal cancer
Authors: Hassan Brim, Babak Shokrani, Hamed Azimi, Sudhir Varma, Edward Lee, Hassan Ashktorab
Journal: Cancer Research (2021)

Abstract Background: Most focus in genetic instability in colon carcinogenic transformation was on DNA Mismatch Repair (MMR) genes alterations as they relate to the microsatellite instability phenotype. However, POLE gene mutations can also be instrumental in triggering genetic instability, at even higher magnitude of genome mutation rate. Aim: To assess POLE gene mutations in African Americans with colorectal cancer (CRC). Methods: Data from Whole exome sequencing of 12 CRC African American tumors was searched to scan POLE gene mutations. All detected mutations were checked in tumors and matched normal. The detected mutations were validated in a second set of samples that were sequenced using POLE gene targeted sequencing. Detected and validated mutations were checked in available databases such as COSMIC and dbSNP to determine novel mutations in our population that is at high risk of aggressive CRC. Results: Six out of 12 patients (50%) displayed mutations in POLE gene. There were 41 detected mutations, 11 are novel mutations and 15 are amino-acid changing. Nine of these were non-synonymous and predicted to have deleterious effects. All these mutations were validated using targeted sequencing. In comparison to DNA MMR, POLE gene has four folds more mutations than MSH2gne (10 mutations and MSH6 (11 mutations and two fold more than MSH3 gene (20 mutations) in the same set of 12 cancer/matched normals. The POLE mutations heterozygous/homozygous status was overall similar in normal and matched normal. However, most of the mutations were homozygous. Conclusion: POLE gene mutations are increasingly recognized as another important element in genetic instability. Our data shows that mutations affecting this gene are likely more significant than those affecting DNA MMR genes. Moreover, POLE mutations might be more consequential, especially those affecting its exonuclease domain of polymerase epsilon, proofreading catalytic subunit. Microsatellite-stable, hypermutated CRCs might need to be explored for POLE gene mutations to track the origin of high mutation rates. Citation Format: Hassan Brim, Babak Shokrani, Hamed Azimi, Sudhir Varma, Edward Lee, Hassan Ashktorab. POLE gene mutations in African Americans colorectal 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 2413.
Abstract 632: Growth hormone deficiency in childhood germ cell tumor survivors
Authors: Diana W. Lone, Karim T. Sadak, Bradley S. Miller, Aubrey K. Hubbard, Jeannette Sample, Michelle Roesler, Jenny N. Poynter
Journal: Cancer Research (2021)

Abstract Introduction: Germ cell tumors (GCTs) are a rare heterogenous group of cancers accounting for 3% of childhood cancers and 15% of cancers in adolescents. Cure rates for GCTs exceed 90% and GCTs currently comprise the 3rd largest group of childhood cancer survivors in the United States. Little systematic evidence exists on late effects of cancer treatment in this group. Treatment for GCTs includes some combination of chemotherapy, radiation, and gonadectomy; interventions that place survivors at high risk for developing endocrinopathies. One of the most common endocrinopathies experienced by childhood cancer survivors is growth hormone deficiency (GHD). In this analysis, we evaluated the prevalence of growth hormone deficiency among GCT survivors. Methods: Participants were previously enrolled in the Germ Cell Tumor Epidemiology Study (GaMETES), which is a case parent triad study conducted using the Children's Oncology Group registry protocols. Data on late effects and outcomes are currently available for a subset of the participants who have provided additional consent for a follow-up study including a self-administered questionnaire and medical record retrieval. GHD was identified via self-report and validated through medical records. Treatment information was abstracted from the medical records. Results: In this interim analysis, 230 participants completed the self-administered questionnaire, including 61 with ovarian tumors, 40 with testicular tumors, 38 extragonadal tumors, and 92 intracranial tumors. Thirty-six of the participants reported having growth hormone deficiency (GHD), all of whom had intracranial germ cell tumors (iGCTs). Thus, the prevalence of GHD among iGCT survivors was 39.1%. We validated 45 questionnaire responses against chart review of iGCT patients. Among these 45, 24 (53.33%) iGCT survivors had GHD. Participants who were treated with high doses of cranial radiation (&amp;gt;30 Gy) were more likely to have GHD (OR = 2.3, 95% CI 0.4-13.1). Conclusions: Growth hormone deficiency is highly prevalent in survivors of childhood intracranial germ cell tumors. The increased prevalence is likely related to the propensity for germ cell tumor involvement of the pituitary stalk, chemotherapy and cranial radiation. Exposure to higher cumulative doses of cranial radiation is associated with higher risk for developing growth hormone deficiency. Citation Format: Diana W. Lone, Karim T. Sadak, Bradley S. Miller, Aubrey K. Hubbard, Jeannette Sample, Michelle Roesler, Jenny N. Poynter. Growth hormone deficiency in childhood germ cell tumor survivors [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 632.
Comparison of the surgical outcomes and couples’ satisfaction with the type of penile prosthesis; Malleable versus Inflatable penile prosthesis: From 157 patients with erectile dysfunction who underwent penile prosthesis implantation in single center
Authors: Y.U. Kim, J.Y. Choi, Y.H. Ko, P.H. Song, K.H. Moon, H.C. Jung
Journal: European Urology (2021)
Transrectal ultrasound guided prostate needle biopsy is still a standard of care for prostate cancer diagnosis – A multicentre Australian analysis of infection rates
Authors: C.J. Parkin, M.W. Louie-Johnsun, S. Chapman, A. Shepherd, S. Mccredie, J. Kam, N. Joshi, N. Gikenye, R. Grills, T. Smilovic, A. Manivasagam, S. Weinstein
Journal: European Urology (2021)
Overexpression of KMT2E Is Associated with Higher Granulocytic Differentiation Rate in Response to ATRA-Based Treatment in Acute Promyelocytic Leukemia Cell Lines
Authors: Diego Antonio Pereira-Martins, Isabel Weinhäuser, Luciana Yamamoto Almeida, Virginia Mara De Deus Wagatsuma, Priscila S Scheucher, Antonio R. Lucena-Araujo, Eduardo Magalhães Rego
Journal: Blood (2017)