tbuckley/cabot-search huggingface dataset:
Treatment patterns and outcomes of hepatocellular carcinoma (HCC) patients (pts) in the CancerLinQ Research Database (CLQ).
Authors: Shaum Kabadi, Linlin Luo, Andrew (Scott) Moren, Katherine Baria
Journal: Journal of Clinical Oncology (2021)

283 Background: Treatment and management of pts with HCC is complicated by the presence of underlying chronic liver disease. Clinical trials with unresectable HCC pts are generally limited to Child-Pugh A or pts with good performance status. Therefore there is limited data for less fit HCC pts, particularly those treated in the community practice setting. Methods: The study design was a retrospective cohort study using the US-based CancerLinQ Discovery Database (CLQ). CLQ was launched by the American Society of Clinical Oncology in 2016 and consists of longitudinal, demographically, and geographically diverse data aggregated from oncology practice Electronic Health Record databases. Eligible pts were ≥18 years at time of HCC diagnosis, had a diagnosis of stage IV HCC within the record, and had ≥2 clinical encounters on separate dates during follow-up after the date of diagnosis. The study period and patient identification period was Jan 1997–Aug 2019; follow up continued through May 2020. Patient demographics, clinical characteristics, and general treatment characteristics were summarized using descriptive statistics. Results: 460 pts were eligible for analysis. Of these, 141 pts (31%) had a Child-Pugh score as reported in medical charts or imputed based on structured and curated data. 76 (54%) pts were Child-Pugh class A, 59 (42%) Child-Pugh class B, and 6 (4%) Child-Pugh class C. The proportion of pts with chronic hepatitis C infection and liver cirrhosis was higher in pts with Child-Pugh classes B and C compared to A. Time from diagnosis to first systemic therapy decreased from a median of 126 days for pts with Child-Pugh class A, to 47 and 16 days for class B and C, respectively. Sorafenib was the most common regimen regardless of line of therapy, followed by PD-1 pathway inhibitors and chemotherapy. Median duration of sorafenib therapy decreased from Child-Pugh class A to C (table). There was a similar decrease in duration of therapy for pts receiving PD-1 pathway inhibitors and chemotherapy when moving from class A to class C. Conclusions: This is the first published retrospective study in HCC using the CLQ. Pts with Child-Pugh class B or C, who are typically excluded from clinical trials, represented 48% of the pts with a Child-Pugh score included in this analysis. Duration of therapy was numerically lower for pts with Child-Pugh class B or C compared to Child-Pugh class A. Further research is needed to describe real-world evidence outside the context of a clinical trial for HCC pts. Funding: AstraZeneca. [Table: see text] Avg, average; obs, observed; TKI, tyrosine kinase inhibitor
Prevalence and reclassification of BRCA1 and BRCA2 variants in a large, unselected Chinese Han breast cancer cohort
Authors: Yun Liu, Honglian Wang, Xin Wang, Jiaqi Liu, Junjian Li, Xiang Wang, Yun Zhang, Zhigang Bai, Qinghua Zhou, Ying Wu, Yi Shen, Xiaoling Weng, Fatao Liu, Jiancheng Guo, Lijun Di, Olivier Gires, Zhongtao Zhang, Yiding Chen, Hongxia Wang
Journal: Journal of Hematology & Oncology (2021)

Accurate interpretation of BRCA1/2 variants is critical for risk assessment and precise treatment of breast cancer (BC). Hence, the establishment of an ethnicity-based BRCA1/2 variant database of the Chinese population is of paramount importance. In this study, panel-based sequencing served to detect BRCA1/2 variants in a Chinese multicenter cohort of 21,216 BC patients and 6434 healthy controls. Overall, the percentage of subjects carrying pathogenic variants was 5.5% (1174/21,216) in BC patients and 1.1% (71/6434) in healthy controls. We identified 13 pathogenic variants as high-frequency variants that had a frequency of > 0.45‰ in BC patients (≥ 10 in 21,216 patients), none of which has been reported in Caucasians. Pathogenic BRCA1/2 variants correlated with younger onset age, higher frequencies of bilateral and triple-negative BC (TNBC), invasive carcinomas, high histological grades, and family history of BC and other cancers. Furthermore, the percentage of the subjects carrying VUS was 9.8% (2071/21,216) in BC patients and 6.9% (446/6434) in healthy controls. Based on our cohort study, we unambiguously reclassified 7 out of the 858 VUS resulting in lower VUS ratio in patients (from 9.8 to 7.9%) as well as in healthy control (from 6.9 to 5.3%). We also re-analyzed the 100 variants in 13 exons (2-5 and 15-23) of the BRCA1 genes using a functional assay (saturation genome editing; SGE). 55 of the 59 VUS had distinct status in the SGE study: 24 (43.6%) were pathogenic, and 31 (56.4%) were benign. Strong ethnicity-specific occurrences of pathogenic BRCA1/2 variants were identified in the Chinese population. Hence, the findings provide rationale and sequencing information for the implementation of BRCA1/2 variants tailored to the Chinese population into clinical risk assessment.
AAV-mediated AP-1 decoy oligonucleotide expression inhibits aortic elastolysis in a mouse model of Marfan syndrome
Authors: Anca Remes, Rawa Arif, Maximilian Franz, Andreas Jungmann, Marcin Zaradzki, Thomas Puehler, Markus B Heckmann, Norbert Frey, Matthias Karck, Klaus Kallenbach, Markus Hecker, Oliver J Müller, Andreas H Wagner
Journal: Cardiovascular Research (2021)

Marfan syndrome is one of the most common inherited disorders of connective tissue caused by fibrillin-1 mutations, characterized by enhanced transcription factor AP-1 DNA binding activity and subsequently abnormally increased expression and activity of matrix-metalloproteinases (MMPs). We aimed to establish a novel adeno-associated virus (AAV)-based strategy for long-term expression of an AP-1 neutralizing RNA hairpin (hp) decoy oligonucleotide (dON) in the aorta to prevent aortic elastolysis in a murine model of Marfan syndrome.Using fibrillin-1 hypomorphic mice (mgR/mgR), aortic grafts from young (9 weeks old) donor mgR/mgR mice were transduced ex vivo with AAV vectors and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Grafts were explanted after 30 days. For in vitro studies, isolated primary aortic smooth muscle cells (SMCs) from mgR/mgR mice were used. Elastica-van-Giesson staining visualized elastolysis, reactive oxygen species (ROS) production was assessed using dihydroethidine staining. RNA F.I.S.H. verified AP-1 hp dON generation in the ex vivo transduced aortic tissue. MMP expression and activity were assessed by western blotting and immunoprecipitation combined with zymography.Transduction resulted in stable therapeutic dON expression in endothelial and SMCs. MMP expression and activity, ROS formation as well as expression of monocyte chemoattractant protein-1 were significantly reduced. Monocyte graft infiltration declined and the integrity of the elastin architecture was maintained. RNAseq analysis confirmed the beneficial effect of AP-1 neutralization on the pro-inflammatory environment in SMCs.This novel approach protects from deterioration of aortic stability by sustained delivery of nucleic acids-based therapeutics and further elucidated how to interfere with the mechanism of elastolysis.
FRI0031 Cyclosporin-a plus methotrexate combination therapy is as safe as cyclosporin-a alone in patients with early rheumatoid arthritis
Authors: AH Gerards, RB Landewé, AP Prins, GA Bruijn, HS Goei The, BA Dijkmans
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Combination therapy with cyclosporin-A (CsA) and methotrexate (MTX) has shown to be advantageous in early RA. A major concern is still the possibility of synergistically increased toxicity. <h3>Objectives</h3> To assess whether long-term combination therapy wit CsA and MTX results in more renal and hepatic toxicity than CsA alone. <h3>Design</h3> A randomised double blind placebo controlled trial of 48 weeks duration. <h3>Methods</h3> 120 patients with active RA: mean age 52 yrs, mean disease duration 3 months. Patients received CsA and MTX or CsA and placebo. MTX was started at 7.5 mg/week, and was increased to 15 mg/wk after 16 weeks. CsA was started at 2.5 mg/kg/day, and was increased to a maximum of 5 mg/kg/day. Additionally, all patients used folic acid 1 mg/d. Patients who did not have an ACR 20 response at week 24 were withdrawn. <h3>Results</h3> The mean CsA dosage at 48 weeks was 2.8 mg/kg/day in the CsA and placebo group and 3.0 mg/kg/day in the CsA and MTX group. After 48 weeks of treatment mean creatinine rose significantly 19μmol/L (+25%) in the CsA and placebo group, and 21μmol/L (+28%) in the CsA and MTX group (p = 0.28 between groups). Changes in blood pressure and liver enzymes were not significant and clinically different between the two groups. Table 1: premature discontinuations due to: <h3>Conclusion</h3> Therapy with CsA and MTX in early RA does on average not result in more clinically relevant renal or hepatic toxicity than CsA alone, but a trend towards more discontinuations due to renal toxicity and hypertension was observed
The Shaping of a B Cell Pool Maximally Responsive to Infections
Authors: Nicole Baumgarth
Journal: Annual Review of Immunology (2021)

B cell subsets differ in development, tissue distribution, and mechanisms of activation. In response to infections, however, all can differentiate into extrafollicular plasmablasts that rapidly provide highly protective antibodies, indicating that these plasmablasts are the main humoral immune response effectors. Yet, the effectiveness of this response type depends on the presence of antigen-specific precursors in the circulating mature B cell pool, a pool that is generated initially through the stochastic processes of B cell receptor assembly. Importantly, germinal centers then mold the repertoire of this B cell pool to be increasingly responsive to pathogens by generating a broad array of antimicrobial memory B cells that act as highly effective precursors of extrafollicular plasmablasts. Such B cell repertoire molding occurs in two ways: continuously via the chronic germinal centers of mucosal lymphoid tissues, driven by the presence of the microbiome, and via de novo generated germinal centers following acute infections. For effectively evaluating humoral immunity as a correlate of immune protection, it might be critical to measure memory B cell pools in addition to antibody titers.
Genome-wide methylation profiling of glioblastoma cell-derived extracellular vesicle DNA allows tumor classification
Authors: Cecile L Maire, Marceline M Fuh, Kerstin Kaulich, Krystian D Fita, Ines Stevic, Dieter H Heiland, Joshua A Welsh, Jennifer C Jones, André Görgens, Tammo Ricklefs, Lasse Dührsen, Thomas Sauvigny, Simon A Joosse, Guido Reifenberger, Klaus Pantel, Markus Glatzel, Andras G Miklosi, James H Felce, Marco Caselli, Valerio Pereno, Rudolph Reimer, Hartmut Schlüter, Manfred Westphal, Ulrich Schüller, Katrin Lamszus, Franz L Ricklefs
Journal: Neuro-Oncology (2021)

Abstract Background Genome-wide DNA methylation profiling has recently been developed into a tool that allows tumor classification in central nervous system tumors. Extracellular vesicles (EVs) are released by tumor cells and contain high molecular weight DNA, rendering EVs a potential biomarker source to identify tumor subgroups, stratify patients and monitor therapy by liquid biopsy. We investigated whether the DNA in glioblastoma cell-derived EVs reflects genome-wide tumor methylation and mutational profiles and allows noninvasive tumor subtype classification. Methods DNA was isolated from EVs secreted by glioblastoma cells as well as from matching cultured cells and tumors. EV-DNA was localized and quantified by direct stochastic optical reconstruction microscopy. Methylation and copy number profiling was performed using 850k arrays. Mutations were identified by targeted gene panel sequencing. Proteins were differentially quantified by mass spectrometric proteomics. Results Genome-wide methylation profiling of glioblastoma-derived EVs correctly identified the methylation class of the parental cells and original tumors, including the MGMT promoter methylation status. Tumor-specific mutations and copy number variations (CNV) were detected in EV-DNA with high accuracy. Different EV isolation techniques did not affect the methylation profiling and CNV results. DNA was present inside EVs and on the EV surface. Proteome analysis did not allow specific tumor identification or classification but identified tumor-associated proteins that could potentially be useful for enriching tumor-derived circulating EVs from biofluids. Conclusions This study provides proof of principle that EV-DNA reflects the genome-wide methylation, CNV, and mutational status of glioblastoma cells and enables their molecular classification.
Understanding factors associated with hospital admission for colon cancer diagnosis and staging work up.
Authors: Jacob B Schriner, Vanessa Arientyl, Adam Kopp, Ali Kalam, Patricia Friedmann, Jiyue Qin, Haejin In
Journal: Journal of Clinical Oncology (2021)

17 Background: Cancer diagnosis, staging work up and treatment need to be done in a timely manner but are rarely emergencies. Cancer work up during a hospital admission is costly and can take away resources that are needed for more urgent patients. We aim to understand factors related to cancer work up in the hospital inpatient setting. Methods: Patients with a new diagnosis of colon cancer at a single academic institution in 2018 were identified using cancer registry. Patients were excluded if they had cancer other than carcinoma or if data on more than half of their work up was not available for review. A chart review was performed to obtain factors including their demographics, details on their cancer presentation, diagnostic and staging work up and treatment. Patients were considered to have had inpatient work up (Inpt_WU) if 50% or more of their cancer related diagnostic, staging and pre-treatment work up was conducted during a hospital admission, and included imaging, bloodwork, evaluation by consultants. Inpt_WU and non-Inpt_WU patients were compared. Logistic regression model was used calculate odds ratio (OR) and 95% confidence intervals (CI) to identify associations with Inpt_WU. Results: Data on 121 newly diagnosed colorectal cancer patients were analyzed. Inpt_WU occurred in 63 (52%) of the cohort. Inpt_WU and non-Inpt_WU patients required the same median number of work-up events [6, interquartile range (IQR) 5, 6]. Inpt_WU patients were more likely to initially present to the emergency department (ED: 91% vs 16%, p&lt;0.001), have Medicaid insurance (40% vs 17%, p=0.018), be functionally dependent (30% vs 16%, p=0.091), have more defined symptoms (75% vs 45% p=0.001), and have greater cancer severity (metastatic disease 33% vs 17%, p=0.004). The median time between presentation and treatment initiation was markedly less for Inpt_WU compared to non-Inpt_WU [11 days (IQR 5, 24) vs 48 (IQR 37, 81), p&lt;0.001]. The logistic model showed that ED presentation had over 40-fold higher odds of Inpt_WU (OR 41.2, 95% CI 12.1-177.4) after adjusting for comorbidities, insurance, functional status, symptoms, and cancer severity. Conclusions: The cancer diagnostic and pre-treatment work-up process was markedly expedited when done during hospital admission. Most cancers presenting to the ED as the initial location of presentation resulted in admission and cancer work up in the hospital. Further studies are needed to explore whether all of these patients necessitate inpatient admission, and whether healthcare systems can be modified to mimic the efficiency of in-hospital workup.
Targeting B7-H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes
Authors: Jie Liu, Shuo Yang, Bihui Cao, Guangyu Zhou, Fengjuan Zhang, Yuan Wang, Rixin Wang, Lipeng Zhu, Ya Meng, Cong Hu, Hui Liang, Xu Lin, Kangshun Zhu, Guokai Chen, Kathy Qian Luo, Lijun Di, Qi Zhao
Journal: Journal of Hematology & Oncology (2021)

Abstract Background B7-H3, an immune-checkpoint molecule and a transmembrane protein, is overexpressed in non-small cell lung cancer (NSCLC), making it an attractive therapeutic target. Here, we aimed to systematically evaluate the value of B7-H3 as a target in NSCLC via T cells expressing B7-H3-specific chimeric antigen receptors (CARs) and bispecific killer cell engager (BiKE)-redirected natural killer (NK) cells. Methods We generated B7-H3 CAR and B7-H3/CD16 BiKE derived from an anti-B7-H3 antibody omburtamab that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. Antitumor efficacy and induced-immune response of CAR and BiKE were evaluated in vitro and in vivo. The effects of B7-H3 on aerobic glycolysis in NSCLC cells were further investigated. Results B7-H3 CAR-T cells effectively inhibited NSCLC tumorigenesis in vitro and in vivo. B7-H3 redirection promoted highly specific T-cell infiltration into tumors. Additionally, NK cell activity could be specially triggered by B7-H3/CD16 BiKE through direct CD16 signaling, resulting in significant increase in NK cell activation and target cell death. BiKE improved antitumor efficacy mediated by NK cells in vitro and in vivo, regardless of the cell surface target antigen density on tumor tissues. Furthermore, we found that anti-B7-H3 blockade might alter tumor glucose metabolism via the reactive oxygen species-mediated pathway. Conclusions Together, our results suggest that B7-H3 may serve as a target for NSCLC therapy and support the further development of two therapeutic agents in the preclinical and clinical studies.
Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis
Authors: Benjamin Goeppert, Damian Stichel, Reka Toth, Sarah Fritzsche, Moritz Anton Loeffler, Anna Melissa Schlitter, Olaf Neumann, Yassen Assenov, Monika Nadja Vogel, Arianeb Mehrabi, Katrin Hoffmann, Bruno Köhler, Christoph Springfeld, Dieter Weichenhan, Christoph Plass, Irene Esposito, Peter Schirmacher, Andreas von Deimling, Stephanie Roessler
Journal: Gut (2021)

Objective A detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options. Design We analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling. Results Patients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but ROBO2 mutations occurred exclusively in invasive CCA and CTNNB1 mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin. Conclusion Integrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.
Compatibility of Evolutionary Responses to Constituent Antibiotics Drive Resistance Evolution to Drug Pairs
Authors: Leonie Johanna Jahn, Daniel Simon, Mia Jensen, Charles Bradshaw, Mostafa Mostafa Hashim Ellabaan, Morten Otto Alexander Sommer
Journal: Molecular Biology and Evolution (2021)

Antibiotic combinations are considered a relevant strategy to tackle the global antibiotic resistance crisis since they are believed to increase treatment efficacy and reduce resistance evolution (WHO treatment guidelines for drug-resistant tuberculosis: 2016 update.). However, studies of the evolution of bacterial resistance to combination therapy have focused on a limited number of drugs and have provided contradictory results (Lipsitch, Levin BR. 1997; Hegreness et al. 2008; Munck et al. 2014). To address this gap in our understanding, we performed a large-scale laboratory evolution experiment, adapting eight replicate lineages of Escherichia coli to a diverse set of 22 different antibiotics and 33 antibiotic pairs. We found that combination therapy significantly limits the evolution of de novode novo resistance in E. coli, yet different drug combinations vary substantially in their propensity to select for resistance. In contrast to current theories, the phenotypic features of drug pairs are weak predictors of resistance evolution. Instead, the resistance evolution is driven by the relationship between the evolutionary trajectories that lead to resistance to a drug combination and those that lead to resistance to the component drugs. Drug combinations requiring a novel genetic response from target bacteria compared with the individual component drugs significantly reduce resistance evolution. These data support combination therapy as a treatment option to decelerate resistance evolution and provide a novel framework for selecting optimized drug combinations based on bacterial evolutionary responses.