tbuckley/cabot-search huggingface dataset:
P14.17 Conventional MRI criteria differentiate true tumour progression from treatment-induced effects in irradiated WHO grade 3 and 4 gliomas
Authors: C M Flies, K H van Leuken, J J C Verhoeff, F Y F de Vos, T Seute, P A Robe, J Hendrikse, T D Witkamp, J W Dankbaar, T J Snijders
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Post-treatment radiological deterioration of patients with an irradiated high-grade (WHO grade 3 and 4) glioma (HGG) may be the result of true progressive disease (PD) or treatment-induced effects (TIE). Differentiation between these two entities is of great importance, but remains a diagnostic challenge. This study assesses the diagnostic value of conventional MRI characteristics to differentiate PD from TIE in treated HGGs. MATERIAL AND METHODS In this single-centre, retrospective cohort study, we included adult patients with a HGG, who were treated with radiotherapy and subsequently developed a new or increasing contrast-enhancing lesion on conventional follow-up MRI. TIE and PD were defined radiologically as stable/decreased for a minimum of six weeks or progressive according to the RANO criteria, and histologically as predominantly TIE without viable tumour or PD. Demographic and clinical data were retrieved. Twenty-one preselected MRI characteristics of the progressive lesions were assessed by two neuroradiologists. The statistical analysis included logistic regression to develop a) a full multivariable model b) a diagnostic model with model reduction, and a Cohen’s Kappa interrater reliability coefficient. RESULTS 210 patients (median age 61, IQR=54–68, 189 males) with 284 lesions were included, of which 141 (50%) had PD. Median time to PD was 2 (0.7–6.1) and to TIE 0.9 (0.7–3.5) months after RT. In multivariable modelling and after model reduction, the following determinants were significant diagnostic factors: Radiation dose (Odds ratio (OR)=0.68, p=0.017), longer time since radiotherapy (OR=3.56, p&amp;lt;0.0005), certain enhancement patterns (soap bubble enhancement: OR=2.63, p=0.003), isointense apparent diffusion coefficient-signal (OR=2.11, p=0.036), development of multiple new lesions (OR=1.68, p=0.088) and increased marginal enhancement (OR=2.04, p=0.027). ORs of &amp;gt;1 indicate higher odds of PD. The Hosmer &amp; Lemeshow test showed a good calibration (p=0.947) and the area under the ROC-curve was 0.722 (95%-CI=0.66–0.78). Interrater reliability analysis between neuroradiologists revealed moderate to near-perfect agreement for the significantly predictive items, but poor agreement for others. CONCLUSION In patients with irradiated high-grade gliomas, several characteristics from conventional MRI are significant predictors for the discrimination between true progression and treatment-induced effects. Interrater reliability for these characteristics was variable. Conventional MRI characteristics from this study should be incorporated into a multimodal diagnostic model that includes advanced imaging techniques. FUNDING INFORMATION Foundation Vrienden UMC Utrecht and The StophersenkankerNU Foundation.
Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell cancer
Authors: Stefanie D. Krens, Wim van Boxtel, Maike J. Uijen, Frank G. Jansman, Ingrid M. Desar, Sasja F. Mulder, Carla M. van Herpen, Nielka P. van Erp
Journal: Cancer Research (2021)
P-135 Pembrolizumab/quavonlimab coformulation in combination with lenvatinib in advanced hepatocellular carcinoma: Phase 2 trial in progress
Authors: D. Li, A. Cheng, H. Lim, J. Llovet, Y. Zhu, K. Hatogai, A. Siegel, M. Kudo
Journal: Annals of Oncology (2021)
M1 macrophage exosomes engineered to foster M1 polarization and target the IL-4 receptor inhibit tumor growth by reprogramming tumor-associated macrophages into M1-like macrophages
Authors: Gowri Rangaswamy Gunassekaran, Sri Murugan Poongkavithai Vadevoo, Moon-Chang Baek, Byungheon Lee
Journal: Biomaterials (2021)
Collateral effects of deletion of nlpD on rpoS and rpoS-dependent genes. Reply.
Authors: Inès Ambite, Ulrich Dobrindt, Catharina Svanborg
Journal: Journal of Clinical Investigation (2021)

In their Letter to the Editor, Tsunoi et al. (1) discuss a very interesting and relevant aspect of our published work (2) and suggest topics for further investigation.This published study identifies the E. coli NlpD protein as a potent regulator of gene expression in human cells.This effect is attributed to the inhibition of RNA polymerase II phosphorylation (Pol II), mediated, in part, by effects of NlpD on the Pol II RPB1 subunit and PAF1C (2, 3).The discovery of the NlpD effect was made possible by the isolation of a loss-of-function mutant (SN25) from a human carrier of the parent strain E. coli 83972, and a mutation strategy was devised to introduce the nlpD point mutation from SN25 into the parent strain and to complement SN25 with a fully functional nlpD gene cluster.To address whether NlpD exerts its effects on host cells independently or in synergy with sigma38 (σ 38 ), the 5′nlpD coding sequence was deleted in E. coli 83972, while leaving the rpoS promoter intact.The partial nlpD deletion mutant lost the ability to inhibit PAF1C and Pol II phosphorylation.In the E. coli genome, nlpD and rpoS form an operon.σ 38 expression is regulated, in part, from a promoter located within nlpD.Elegant studies addressing the role of σ 38 as a global regulator of bacterial gene expression are referenced in the letter by Tsunoi et al. (1).Global analyses of the rpoS regulon in E. coli K-12 have identified more than 1000 genes (4, 5).As pointed out by Dr. Iwase and colleagues, effects on σ 38 are therefore likely to affect bacterial phenotypes, under a variety of conditions.A loss of σ 38 expression changes metabolic activity or virulence in uropathogenic E. coli (6).Our preliminary comparison of E. coli 83972 and SN25 gene expression profiles indicates that typical σ 38 -dependent stress response genes are downregulated in SN25 relative to the 83972 wild-type strain.Importantly, the effects of NlpD on human cells were characterized using recombinant NlpD protein rather than whole bacteria.Therapeutic efficacy was demonstrated as inhibition of inflammation and accelerated bacterial clearance from infected tissues in a murine urinary tract infection model (Figure 1).In contrast to NlpD, recombinant σ 38 displayed no affinity for RPB1 or PAF1C in pull-down experiments.Instead, the data suggest that, by inhibiting TBP binding, σ 38 itself may act as an additional regulator of gene expression in infected hosts (2).Thanks to Drs.Tsunoi, Iyoda, and Iwase for initiating this interesting discussion.
Potential surrogates for performance status and survival in metastatic non-small cell lung cancer (NSCLC).
Authors: Wallace L. Akerley, Sonam Puri, Yeonjung Jo, Adriana M Coletta, Kathleen Claire Kerrigan, Shiven B. Patel, Kelly Moynahan, Laura Cannon, Matthew Gumbleton, Nicole Hillman, Kelsey Embrey, Benjamin Haaland
Journal: Journal of Clinical Oncology (2021)

170 Background: Performance status (PS), a physician-based, subjective assessment of a patient’s symptoms and ambulatory state, is an eligibility criterion for most clinical trials and a key clinical decision tool for treatment of NSCLC. Methods: Patients with metastatic NSCLC were asked to participate in a prospective, observational study of potential prognostic factors that includes demographics, laboratory, patient reported outcomes (PROs) by the patient reported outcomes measurement information system (PROMIS), PS reported by patient, PS assessed by physician, FitBit tracker (includes steps, distance, heart rate (HR), calories, METs), physical challenge and proteomics (Veristratâ). Correlation and regression analyses were performed for the initial 55 patients enrolled prior to COVID restrictions. Tracker data was collected and averaged over the first 7 days with wear &gt; 500 minutes/day. Other data were collected at baseline. Results: We enrolled 55 patients with metastatic NSCLC. There were 35 females and 20 males with a median age of 67 years. A majority of patients were never (38%, n = 21) or former smokers (40%, n = 22); adenocarcinoma (83%, n = 83%) was the most common histology. 30% (n = 17) patients were 2 nd or greater line of therapy. 52 were included for survival analysis and 21 expired with median survival 226 days (149, NA). There were minimal gender related differences in the study population except a higher incidence of adenocarcinoma in women (94% vs 65%, p = 0.012 and longer FiTBit assessed daily “very active minutes” (defined as METs &gt; = 6) in men compared to women (4.21 vs 0.43, p = 0.036). Patient- and physician assessed PS were not statistically different, although patients tended underestimated their PS relative to physicians. Physician assessed PS, patient assessed PS, two-minute walk distance, proteomics by Veristratâ, total daily steps, total daily distance covered, and heart rate/activity mismatch were independent predictors of survival. Age, gender, smoking, BMI, histology, and various CBC-based indices were not prognostic. Conclusions: Patient- and physician-assessment of PS do not always match, many alternate measures to PS are prognostic of survival and tracker-based methods are objective and feasible in clinical practice.
Poloxamer 188 vs Placebo for Painful Vaso-occlusive Episodes in Children and Adults With Sickle Cell Disease
Authors: Umut A. Gurkan
Journal: JAMA (2021)

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Fli1 Promotes Vascular Morphogenesis by Regulating Endothelial Potential of Multipotent Myogenic Progenitors
Authors: Anwarul Ferdous, Sarvjeet Singh, Yuxuan Luo, Md. J. Abedin, Nan Jiang, Cameron E. Perry, Bret M. Evers, Thomas G. Gillette, Michael Kyba, Maria Trojanowska, Joseph A. Hill
Journal: Circulation Research (2021)

[Figure: see text].
Screening and prevention of colorectal cancer
Authors: Priyanka Kanth, John M Inadomi
Journal: BMJ (2021)

Abstract Mortality from colorectal cancer is reduced through screening and early detection; moreover, removal of neoplastic lesions can reduce cancer incidence. While understanding of the risk factors, pathogenesis, and precursor lesions of colorectal cancer has advanced, the cause of the recent increase in cancer among young adults is largely unknown. Multiple invasive, semi- and non-invasive screening modalities have emerged over the past decade. The current emphasis on quality of colonoscopy has improved the effectiveness of screening and prevention, and the role of new technologies in detection of neoplasia, such as artificial intelligence, is rapidly emerging. The overall screening rates in the US, however, are suboptimal, and few interventions have been shown to increase screening uptake. This review provides an overview of colorectal cancer, the current status of screening efforts, and the tools available to reduce mortality from colorectal cancer.
Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events
Authors: Yiyi Zhang, Mark J. Pletcher, Eric Vittinghoff, Autumn M. Clemons, David R. Jacobs, Norrina B. Allen, Alvaro Alonso, Brandon K. Bellows, Elizabeth C. Oelsner, Adina Zeki Al Hazzouri, Dhruv S. Kazi, Sarah D. de Ferranti, Andrew E. Moran
Journal: JAMA Cardiology (2021)

Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Most observational studies on the association between LDL-C and CVD have focused on LDL-C level at a single time point (usually in middle or older age), and few studies have characterized long-term exposures to LDL-C and their role in CVD risk.To evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life.This cohort study analyzed pooled data from 4 prospective cohort studies in the US (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis). Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Data from 1971 to 2017 were collected and analyzed from September 25, 2020, to January 10, 2021.Cumulative exposure to LDL-C, TWA LDL-C, and LDL-C slope from age 18 to 60 years.Incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF).A total of 18 288 participants were included in this study. These participants had a mean (SD) age of 56.4 (3.7) years and consisted of 10 309 women (56.4%). During a median follow-up of 16 years, 1165 CHD, 599 ischemic stroke, and 1145 HF events occurred. In multivariable Cox proportional hazards regression models that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, the hazard ratios for CHD were as follows: 1.57 (95% CI, 1.10-2.23; P for trend = .01) for cumulative LDL-C level, 1.69 (95% CI, 1.23-2.31; P for trend <.001) for TWA LDL-C level, and 0.88 (95% CI, 0.69-1.12; P for trend = .28) for LDL-C slope. No association was found between any of the LDL-C variables and ischemic stroke or HF.This cohort study showed that cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with the risk of incident CHD, independent of midlife LDL-C level. These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.
Determining the cancer diagnostic interval using administrative data in a cohort of patients with pancreatic cancer.
Authors: Safiya Karim, Bailey Paterson, Shiying Kong, Alyson Mahar, Colleen Webber, Richard M. Lee-Ying, Winson Y. Cheung, Patti Groome
Journal: Journal of Clinical Oncology (2021)

336 Background: Pancreatic cancer is a leading cause of cancer death, largely due to vague presenting symptoms and late stage at diagnosis. Population-based administrative data can be a valuable resource for studying the diagnostic interval. The objective of this study was to determine the first encounter in the diagnostic interval and to calculate that interval in a cohort of patients with pancreatic cancer using an empirical approach. Methods: This is a retrospective, cohort study of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) from 2007 – 2015 in Alberta, Canada. We used the Alberta Cancer Registry (ACR), physician billing claims, hospital discharge and emergency room visits to identify health encounters that occurred more frequently in the 3 months prior to diagnosis compared to those in the 3-24 months prior to diagnosis. We used statistical control charts to define the lookback period for each encounter category and identify the earliest encounter that represented the start of the diagnostic interval (index contact date). The end of the interval was the diagnosis date. Quantile regression was used to determine factors associated with the diagnostic interval. Results: We identified 3142 patients with PDAC. Median age of diagnosis was 71 (IQR 61-80). We identified an index contact date in 96.5% of the patients. The median length of the diagnostic interval was 76 days (IQR 21-191; 90 th percentile 276 days). A higher Elixhauser comorbidity score (+18.57 days/ 1 point increase, 95% CI 16.07-21.07, p &lt; 0.001) and stage 3 disease (+22.55 days, 95% CI 5.02-40.08, p = 0.01) was associated with a longer diagnostic interval. Conclusions: In this cohort of patients with pancreatic cancer, there was a wide range in the diagnostic interval with 10% of patients having a diagnostic interval approaching one year. Diagnostic interval research using administrative databases can understand variations in diagnosis times, can inform early detection efforts and can improve quality of care.
De Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous Malformation
Authors: Hao Li, Yoonhee Nam, Ran Huo, Weilun Fu, Biaobin Jiang, Qiuxia Zhou, Dong Song, Yingxi Yang, Yuming Jiao, Jiancong Weng, Zihan Yan, Lin Di, Jie Li, Jie Wang, Hongyuan Xu, Shuo Wang, Jizong Zhao, Zilong Wen, Jiguang Wang, Yong Cao
Journal: Circulation Research (2021)

Rationale: Brain arteriovenous malformations (bAVMs) are abnormal entanglement of blood vessels in brain, with direct connections from arteries to veins, lacking functional capillary bed. Although several somatic mutations were reported, the molecular mechanism and genetic disposition of bAVM remain poorly understood. Objective: We aim to identify transcriptional anomalies and critical functional pathways in bAVM lesions and explore their association with key de novo germline and somatic variants in bAVM patients. Methods and Results: We established a comprehensive bAVM dataset from 269 patients, by performing single-cell sequencing of 17 bAVM lesions, whole-exome sequencing of germline DNA from 60 case-unaffected-parental trios, and genomic/transcriptomic sequencing of 231 bAVM lesions. We found abnormal expression of endothelial and mesenchymal markers in bAVM at both bulk and single-cell level, which was validated by flow cytometric analysis and immunofluorescence staining, suggesting an involvement of endothelial-to-mesenchymal transition (EndMT) process in AVM (arteriovenous-malformation). Using data from the 60 trios, we identified nonsynonymous de novo germline mutations affecting 46 genes, including EXPH5 (detected in 2 independent cases), and vessel-related genes, such as EPAS1 and ENG . Interestingly, knockdown of epas1 in zebrafish embryo showed AVM-like phenotype exclusively in brain. Subsequent computational and experimental analyses demonstrated that expression of genes affected by de novo germline mutations was enriched in vascular cell types and was involved in EndMT-relevant behaviors including cell migration, angiogenesis, and cell marker transition. Moreover, we detected somatic KRAS mutations in 129 of 179 (72%) cases and showed that KRAS mutations were associated with bleeding as the first symptom ( P =0.0072). Following experimental studies demonstrated that KRAS mutations independently regulated EndMT features, consolidating the involvement of EndMT in this disease. Lastly, we showed that lovastatin reversed EndMT features in vitro and ex vivo. Conclusions: Our results suggest the convergent role of de novo germline mutations and somatic mutations in regulating EndMT in bAVM and provided a potential therapeutic option.
How to Provide the Needed Protection from COVID-19 to Patients with Hematologic Malignancies
Authors: Antoni Ribas, Madhav V. Dhodapkar, Katie M. Campbell, Faith E. Davies, Steven D. Gore, Ronald Levy, Lee M. Greenberger
Journal: Blood Cancer Discovery (2021)

Patients with hematologic malignancies are particularly vulnerable to COVID-19 infections, and upon a pooled data analysis of 24 publications, there is evidence that they have suboptimal antibody responses to COVID-19 vaccination and boosters. To provide them the needed additional protection from COVID-19, it is imperative to achieve a 100% full immunization rate in health care workers and adult caretakers, and to foster research to test higher doses and repeated rounds of COVID-19 vaccines and the use of passive immune prophylaxis and therapy.
Persistent biliary hypoxia and lack of regeneration are key mechanisms in the pathogenesis of posttransplant nonanastomotic strictures
Authors: Iris E. M. de Jong, Diletta Overi, Guido Carpino, Annette S. H. Gouw, Marius C. van den Heuvel, Léon C. van Kempen, Carmine Mancone, Paolo Onori, Vincenzo Cardinale, Luca Casadei, Domenico Alvaro, Robert J. Porte, Eugenio Gaudio
Journal: Hepatology (2021)

Abstract Background and Aims Nonanastomotic biliary strictures (NAS) are a major cause of morbidity after orthotopic liver transplantation (OLT). Although ischemic injury of peribiliary glands (PBGs) and peribiliary vascular plexus during OLT has been associated with the later development of NAS, the exact underlying mechanisms remain unclear. We hypothesized that bile ducts of patients with NAS suffer from ongoing biliary hypoxia and lack of regeneration from PBG stem/progenitor cells. Approach and Results Forty‐two patients, requiring retransplantation for either NAS ( n = 18), hepatic artery thrombosis (HAT; n = 13), or nonbiliary graft failure (controls; n = 11), were included in this study. Histomorphological analysis of perihilar bile ducts was performed to assess differences in markers of cell proliferation and differentiation in PBGs, microvascular density (MVD), and hypoxia. In addition, isolated human biliary tree stem cells (hBTSCs) were used to examine exo‐metabolomics during in vitro differentiation toward mature cholangiocytes. Bile ducts of patients with NAS or HAT had significantly reduced indices of PBG mass, cellular proliferation and differentiation (mucus production, secretin receptor expression, and primary cilia), reduced MVD, and increased PBG apoptosis and hypoxia marker expression, compared to controls. Metabolomics of hBTSCs during in vitro differentiation toward cholangiocytes revealed a switch from a glycolytic to oxidative metabolism, indicating the need for oxygen. Conclusions NAS are characterized by a microscopic phenotype of chronic biliary hypoxia attributed to loss of microvasculature, resulting in reduced proliferation and differentiation of PBG stem/progenitor cells into mature cholangiocytes. These findings suggest that persistent biliary hypoxia is a key mechanism underlying the development of NAS after OLT.
Monoamine Oxidases Desensitize Intracellular β <sub>1</sub> AR Signaling in Heart Failure
Authors: Ying Wang, Meimi Zhao, Qian Shi, Bing Xu, Chaoqun Zhu, Minghui Li, Vaseem Mir, Donald M. Bers, Yang K. Xiang
Journal: Circulation Research (2021)
Increased Vulnerability and Distinct Layered Phenotype at Culprit and Nonculprit Lesions in STEMI Versus NSTEMI
Authors: Chao Fang, Yanwei Yin, Senqing Jiang, Shaotao Zhang, Jifei Wang, Yidan Wang, Lulu Li, Yini Wang, Junchen Guo, Huai Yu, Guo Wei, Fangmeng Lei, Tao Chen, Xuefeng Ren, Jinfeng Tan, Lei Xing, Jingbo Hou, Jiannan Dai, Bo Yu
Journal: JACC. Cardiovascular imaging (2021)