tbuckley/cabot-search huggingface dataset:
Cabazitaxel multiple rechallenge in metastatic castration-resistant prostate cancer: A therapeutic option to increase overall survival?
Authors: Cedric Pobel, Edouard Auclin, Diego Teyssonneau, Brigitte Laguerre, Mathilde Cancel, Elouen Boughalem, Johanna Noel, Pierre Emmanuel Brachet, Denis Maillet, Philippe Barthelemy, Carole Helissey, Constance Thibault, Stephane Oudard
Journal: Journal of Clinical Oncology (2021)

97 Background: Cabazitaxel rechallenge could be a more efficient therapy with an acceptable toxicity than docetaxel in the treatment of patients with a metastatic castration resistant prostate cancer (mCRPC). The aim of this study was to assess the feasibility and efficacy of cabazitaxel multiple rechallenge. Methods: This is a multicenter, retrospective cohort study including patients from 9 centers in France who received 3 lines or more of cabazitaxel from February 2012 to July 2020. Cabazitaxel schedule differed between patients: 25 mg/m 2 q3w, 20 mg/m 2 q3w, 16 mg/m 2 q2w or 10 mg/m 2 weekly. Efficacy was assessed by overall survival (OS) and progression-free survival (PFS) from each cabazitaxel line start. Only toxicities grade ≥ 3 were reported. Results: Twenty-two patients were included. The median follow-up from mCRPC was 94.7 months, median age at initial diagnosis was 59.5 years old, median ISUP score at diagnosis was 4 and median PSA at diagnosis was 55 ng/ml. Median number of cabazitaxel cycles was 7 at first-line, 6 at first rechallenge, and 5 for subsequent rechallenges. Median OS from mCRPC diagnosis was 105 months. Median PFS from cabazitaxel line start was 11.8 months at first use, 9.6 for first rechallenge and 5.6 in second rechallenge (table). Only one case of febrile neutropenia and 6 events of grade ≥ 3 toxicity were reported. Conclusions: Cabazitaxel multiple rechallenge could efficiently extend OS with manageable toxicities for patients. Even if anti-PARP therapy and immunotherapy are promising treatments, cabazitaxel rechallenge could be also a relevant therapeutic option for long responder patients. Specific biomarkers should be explored to predict the efficacy of cabazitaxel rechallenge. [Table: see text]
Biomarker analysis from a randomized phase II study of olaparib with or without cediranib in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rana R. McKay, Marc R Radke, Yu Shyr, Shilin Zhao, Mary-Ellen Taplin, Nancy B. Davis, Paul Monk, Leonard Joseph Appleman, Primo "Lucky" N. Lara, Ulka N. Vaishampayan, Jingsong Zhang, Asit K. Paul, Glenn Bubley, Ying Huang, Geoffrey Shapiro, Patricia LoRusso, S. Percy Ivy, Daniel Peter Petrylak, Elizabeth M. Swisher, Joseph W. Kim
Journal: Journal of Clinical Oncology (2021)

7 Background: We previously reported that cediranib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, combined with olaparib, a poly (ADP-ribose) polymerase inhibitor, prolonged radiographic progression-free survival (rPFS) compared with olaparib alone in patients with mCRPC. Herein, we present updated clinical data in the overall population and in subgroups by homologous recombination (HR) gene status. Methods: Men with a minimum of one prior line of systemic therapy for mCRPC were randomized 1:1 to receive olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily (C+O) or olaparib 300 mg by mouth twice daily (O). Patients were required to undergo a baseline metastasis biopsy. Next generation sequencing of HR genes was performed on available samples using BROCA-HR assay. HR deficiency (HRD) was defined by presence of homozygous deletions or deleterious mutations in HR genes including BRCA1, BRCA2, ATM, and others. The primary endpoint was rPFS and secondary endpoint was overall survival (OS). Results: Eighty-four patients were included in the analysis of whom 26 patients (31.0%) had HRD mCRPC. The most common HR gene alterations included BRCA2 (n=17, 20%), CDK12 (n=9, 11%), and ATM (n=7, 8%). Consistent with our prior report, in the overall cohort, C+O compared to O resulted in a significant improvement in rPFS (Table). The benefit in rPFS was most pronounced in patients with HRD mCRPC; however, there was no difference between arms in HR proficient (HRP) cancers. Independent of arm allocation, rPFS and OS were numerically longer in patients with HRD mCRPC compared to HRP mCRPC (rPFS: 8.8 versus 4.3 months, p=0.14; OS: 18.6 vs. 12.3 months, p=0.24). Conclusions: C+O improved rPFS in patients with mCPRC compared with O alone. The biomarker analyses revealed that the rPFS benefit of C+O over O is likely driven by patients with HRD mCRPC. Our data warrant validation and support further investigation of the combination of C+O in patients with HRD mCRPC. Clinical trial information: NCT02893917. [Table: see text]
Exosome-functionalized polyetheretherketone-based implant with immunomodulatory property for enhancing osseointegration
Authors: Lei Fan, Pengfei Guan, Cairong Xiao, Huiquan Wen, Qiyou Wang, Can Liu, Yian Luo, Limin Ma, Guoxin Tan, Peng Yu, Lei Zhou, Chengyun Ning
Journal: Bioactive Materials (2021)

The host immune response effecting on biomaterials is critical to determine implant fates and bone regeneration property. Bone marrow stem cells (BMSCs) derived exosomes (Exos) contain multiple biosignal molecules and have been demonstrated to exhibit immunomodulatory functions. Herein, we develop a BMSC-derived Exos-functionalized implant to accelerate bone integration by immunoregulation. BMSC-derived Exos were reversibly incorporated on tannic acid (TA) modified sulfonated polyetheretherketone (SPEEK) via the strong interaction of TA with biomacromolecules. The slowly released Exos from SPEEK can be phagocytosed by co-cultured cells, which could efficiently improve the biocompatibilities of SPEEK. In vitro results showed the Exos loaded SPEEK promoted macrophage M2 polarization via the NF-κB pathway to enhance BMSCs osteogenic differentiation. Further in vivo rat air-pouch model and rat femoral drilling model assessment of Exos loaded SPEEK revealed efficient macrophage M2 polarization, desirable new bone formation, and satisfactory osseointegration. Thus, BMSC-derived Exos-functionalized implant exerted osteoimmunomodulation effect to promote osteogenesis.
Association of Eviction With Adverse Birth Outcomes Among Women in Georgia, 2000 to 2016
Authors: Gracie Himmelstein, Matthew Desmond
Journal: JAMA Pediatrics (2021)

More than 2 million families face eviction annually, a number likely to increase due to the coronavirus disease 2019 pandemic. The association of eviction with newborns' health remains to be examined.To determine the association of eviction actions during pregnancy with birth outcomes.This case-control study compared birth outcomes of infants whose mothers were evicted during gestation with those whose mothers were evicted at other times. Participants included infants born to mothers who were evicted in Georgia from January 1, 2000, to December 31, 2016. Data were analyzed from March 1 to October 4, 2020.Eviction actions occurring during gestation.Five metrics of neonatal health included birth weight (in grams), gestational age (in weeks), and dichotomized outcomes for low birth weight (LBW) (<2500 g), prematurity (gestational age <37.0 weeks), and infant death.A total of 88 862 births to 45 122 mothers (mean [SD] age, 26.26 [5.76] years) who experienced 99 517 evictions were identified during the study period, including 10 135 births to women who had an eviction action during pregnancy and 78 727 births to mothers who had experienced an eviction action when not pregnant. Compared with mothers who experienced eviction actions at other times, eviction during pregnancy was associated with lower infant birth weight (difference, -26.88 [95% CI, -39.53 to 14.24] g) and gestational age (difference, -0.09 [95% CI, -0.16 to -0.03] weeks), increased rates of LBW (0.88 [95% CI, 0.23-1.54] percentage points) and prematurity (1.14 [95% CI, 0.21-2.06] percentage points), and a nonsignificant increase in mortality (1.85 [95% CI, -0.19 to 3.89] per 1000 births). The association of eviction with birth weight was strongest in the second and third trimesters of pregnancy, with birth weight reductions of 34.74 (95% CI, -57.51 to -11.97) and 35.80 (95% CI, -52.91 to -18.69) g, respectively.These findings suggest that eviction actions during pregnancy are associated with adverse birth outcomes, which have been shown to have lifelong and multigenerational consequences. Ensuring housing, social, and medical assistance to pregnant women at risk for eviction may improve infant health.
Differential Splicing of Skipped Exons Predicts Drug Response in Cancer Cell Lines
Authors: Edward Simpson, Steven Chen, Jill L. Reiter, Yunlong Liu
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Alternative splicing of pre-mRNA transcripts is an important regulatory mechanism that increases the diversity of gene products in eukaryotes. Various studies have linked specific transcript isoforms to altered drug response in cancer; however, few algorithms have incorporated splicing information into drug response prediction. In this study, we evaluated whether basal-level splicing information could be used to predict drug sensitivity by constructing doxorubicin-sensitivity classification models with splicing and expression data. We detailed splicing differences between sensitive and resistant cell lines by implementing quasi-binomial generalized linear modeling (QBGLM) and found altered inclusion of 277 skipped exons. We additionally conducted RNA-binding protein (RBP) binding motif enrichment and differential expression analysis to characterize cis- and trans-acting elements that potentially influence doxorubicin response-mediating splicing alterations. Our results showed that a classification model built with skipped exon data exhibited strong predictive power. We discovered an association between differentially spliced events and epithelial-mesenchymal transition (EMT) and observed motif enrichment, as well as differential expression of RBFOX and ELAVL RBP family members. Our work demonstrates the potential of incorporating splicing data into drug response algorithms and the utility of a QBGLM approach for fast, scalable identification of relevant splicing differences between large groups of samples.
Abstract 16826: Reversal of TSPO Upregulation in the Diabetic Heart by Chronic TSPO Gene Silencing Causes Metabolic Sink via an Increase in ROMK Expression
Authors: Zeki Ilkan, Benjamin Strauss, Fadi G Akar
Journal: Circulation (2018)

Introduction: The mitochondrial translocator protein (TSPO) is an integral component of a macromolecular complex that regulates cell death &amp; survival pathways. Myocardial TSPO levels are markedly increased in diabetes. Objectives: We sought to investigate the electrophysiological effects of TSPO in diabetes using a cardiotropic TSPO gene silencing approach that avoids off-target effects of TSPO ligands. Methods: In a standard model of diabetes mellitus consisting of Zucker Obese rats, AAV9.shTSPO (5E11 gc/mL) was delivered by tail vein injection (N=5). Non-diabetic lean (N=4) and spontaneously hypertensive (N=16) rats served as treatment controls. Untreated diabetic (N=6) and non-diabetic (N=6) hearts were also studied. The TSPO ligand DZP (64μμ) was perfused in additional diabetic hearts to contrast its effects with those of chronic TSPO knockdown. Optical action potential (AP) mapping was performed 2 wks following gene transfer. Hearts were challenged with 12 min ischemia followed by reperfusion. Results: Myocardial TSPO knockdown by AAV9.shTSPO promoted metabolic sink in diabetic hearts. This manifested as rapid and spatially heterogeneous loss of AP amplitude and upstroke velocity in response to ischemia (Figure). Areas of early loss of excitability remained inexcitable upon reperfusion resulting in wide regions of conduction block that supported VT. These findings were specific to diabetes as AAV9.shTSPO did not alter the response of non-diabetic hearts to ischemia. Loss of excitability was not related to irreversible cell death by TUNEL staining. Analysis of the expression of ATP-sensitive channel subunits revealed marked upregulation of ROMK in response to TSPO knockdown exclusively in the diabetic heart. Unlike TSPO knockdown, DZP did not promote metabolic sink but rather prevented post-ischemic VT. Conclusions: Chronic gene silencing of TSPO promotes VT via a metabolic sink mechanism likely arising from compensatory upregulation of ROMK.
Explaining decisions of graph convolutional neural networks: patient-specific molecular subnetworks responsible for metastasis prediction in breast cancer
Authors: Hryhorii Chereda, Annalen Bleckmann, Kerstin Menck, Júlia Perera-Bel, Philip Stegmaier, Florian Auer, Frank Kramer, Andreas Leha, Tim Beißbarth
Journal: Genome Medicine (2021)

Abstract Background Contemporary deep learning approaches show cutting-edge performance in a variety of complex prediction tasks. Nonetheless, the application of deep learning in healthcare remains limited since deep learning methods are often considered as non-interpretable black-box models. However, the machine learning community made recent elaborations on interpretability methods explaining data point-specific decisions of deep learning techniques. We believe that such explanations can assist the need in personalized precision medicine decisions via explaining patient-specific predictions. Methods Layer-wise Relevance Propagation (LRP) is a technique to explain decisions of deep learning methods. It is widely used to interpret Convolutional Neural Networks (CNNs) applied on image data. Recently, CNNs started to extend towards non-Euclidean domains like graphs. Molecular networks are commonly represented as graphs detailing interactions between molecules. Gene expression data can be assigned to the vertices of these graphs. In other words, gene expression data can be structured by utilizing molecular network information as prior knowledge. Graph-CNNs can be applied to structured gene expression data, for example, to predict metastatic events in breast cancer. Therefore, there is a need for explanations showing which part of a molecular network is relevant for predicting an event, e.g., distant metastasis in cancer, for each individual patient. Results We extended the procedure of LRP to make it available for Graph-CNN and tested its applicability on a large breast cancer dataset. We present Graph Layer-wise Relevance Propagation (GLRP) as a new method to explain the decisions made by Graph-CNNs. We demonstrate a sanity check of the developed GLRP on a hand-written digits dataset and then apply the method on gene expression data. We show that GLRP provides patient-specific molecular subnetworks that largely agree with clinical knowledge and identify common as well as novel, and potentially druggable, drivers of tumor progression. Conclusions The developed method could be potentially highly useful on interpreting classification results in the context of different omics data and prior knowledge molecular networks on the individual patient level, as for example in precision medicine approaches or a molecular tumor board.
Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China
Authors: Zhiqiang Wang, Zhibo Zhang, Yong Li, Li Sun, Dezhen Peng, Danyu Du, Xian Zhang, Luwei Han, Liwen Zhao, Ligong Lu, Hongzhi Du, Shengtao Yuan, Meixiao Zhan
Journal: Acta Pharmaceutica Sinica B (2021)

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.
Sacral Insufficiency Fracture on 68Ga-DOTATATE PET/CT
Authors: Nuh Filizoglu, Onur Bugdayci, Salih Ozguven
Journal: Clinical Nuclear Medicine (2021)

68Ga-DOTATATE PET/CT is an important tool for imaging neuroendocrine tumors, including skeletal metastases. However, false-positive results can occur in inflammatory pathologies such as sacral insufficiency fracture. We report the case of a 47-year-old man who was diagnosed with a neuroendocrine tumor of the pancreas. 68Ga-DOTATATE PET/CT showed 68Ga-DOTATATE uptake at the right side of the sacrum. Afterward, MRI made the diagnosis of sacral insufficiency fracture.
Oral anticancer agent (OAA) adherence and survival in elderly patients with metastatic renal cell carcinoma (mRCC).
Authors: Michaela Ann Dinan, Lauren E Wilson, Melissa A. Greiner, Lisa Spees, Jessica Pritchard, Tian Zhang, Deborah Kaye, Daniel J. George, Charles D. Scales, Stephanie B. Wheeler
Journal: Journal of Clinical Oncology (2021)

280 Background: Multiple effective oral anticancer agents (OAAs) are now approved for the treatment of patients with advanced or metastatic renal cell carcinoma (mRCC) based on improvement in overall and progression-free survival in randomized clinical trials. However, real-world adherence and outcomes associated with OAA use in the general mRCC patient population have not been previously investigated. Methods: Retrospective analysis of SEER-Medicare patients with mRCC who received treatment with an OAA between 2007 and 2015. Adherence was assessed as proportion of days covered (PDC) within 3 months of OAA initiation with PDC &gt; 50% categorized as adherent. The impact of initial OAA adherence on overall and disease-specific survival was analyzed landmarked at 3 months after OAA initiation. Results: A total of 905 patients met study criteria, of which 577 (63.8%) were categorized as adherent to initial OAA treatment. Multivariable analysis adjusting for clinical and demographic factors revealed that living within an impoverished neighborhood was associated with a 20% lower likelihood of adherence (OR 0.80, CI 0.68 – 0.93). No association was observed between adherence and race, ethnicity, marital status, or number of comorbidities. In survival analyses OAA adherence was associated with a significant reduction in both overall (HR 0.71, CI 0.58 – 0.87) and RCC-specific mortality (HR 0.68, CI 0.57 – 0.86). Receipt of sunitinib was associated with a significant reduction in overall and disease specific mortality compared with sorafenib. Post-hoc analysis of patients taking pazopanib as their initial OAA (N = 252) demonstrated reduced all-cause mortality if they received the minimum effective dose of 800 mg daily (HR 0.50, CI 0.35 – 0.72) and decreased adherence associated with initial higher out-of-pocket payments (χ 2 test, p = 0.003). Conclusions: Socioeconomic factors predict poor adherence to OAA therapy in Medicare beneficiaries with metastatic RCC, which is in turn associated with poor overall and disease-specific survival. Efforts to improve outcomes and mitigate disparities in the general mRCC population should incorporate considerations of OAA adherence and economic factors. Sunitinib and pazopanib appear associated with favorable survival and remain the most commonly used OAAs in this over 65 year old patient population.
The adenosinergic pathway in mesenchymal stem cell fate and functions
Authors: Bruna C. Galgaro, Liziane R. Beckenkamp, Martha van den M. Nunnenkamp, Vitória G. Korb, Liliana I. S. Naasani, Katarzyna Roszek, Márcia R. Wink
Journal: Medicinal Research Reviews (2021)

Abstract Mesenchymal stem cells (MSCs) play an important role in tissue homeostasis and damage repair through their ability to differentiate into cells of different tissues, trophic support, and immunomodulation. These properties made them attractive for clinical applications in regenerative medicine, immune disorders, and cell transplantation. However, despite multiple preclinical and clinical studies demonstrating beneficial effects of MSCs, their native identity and mechanisms of action remain inconclusive. Since its discovery, the CD73/ecto‐5′‐nucleotidase is known as a classic marker for MSCs, but its role goes far beyond a phenotypic characterization antigen. CD73 contributes to adenosine production, therefore, is an essential component of purinergic signaling, a pathway composed of different nucleotides and nucleosides, which concentrations are finely regulated by the ectoenzymes and receptors. Thus, purinergic signaling controls pathophysiological functions such as proliferation, migration, cell fate, and immune responses. Despite the remarkable progress already achieved in considering adenosinergic pathway as a therapeutic target in different pathologies, its role is not fully explored in the context of the therapeutic functions of MSCs. Therefore, in this review, we provide an overview of the role of CD73 and adenosine‐mediated signaling in the functions ascribed to MSCs, such as homing and proliferation, cell differentiation, and immunomodulation. Additionally, we will discuss the pathophysiological role of MSCs, via CD73 and adenosine, in different diseases, as well as in tumor development and progression. A better understanding of the adenosinergic pathway in the regulation of MSCs functions will help to provide improved therapeutic strategies applicable in regenerative medicine.