tbuckley/cabot-search huggingface dataset:
The Serum Proteome and Ursodeoxycholic Acid Response in Primary Biliary Cholangitis
Authors: Ben Barron‐Millar, Laura Ogle, George Mells, Steven Flack, Jonathan Badrock, Richard Sandford, John Kirby, Jeremy Palmer, Laura Jopson, John Brain, Graham R. Smith, Steve Rushton, Vinod S. Hegade, Rebecca Jones, Simon Rushbrook, Douglas Thorburn, Steve Ryder, Gideon Hirschfield, Jessica K. Dyson, David E.J. Jones
Journal: Hepatology (2021)

Background and Aims Stratified therapy has entered clinical practice in primary biliary cholangitis (PBC), with routine use of second-line therapy in nonresponders to first-line therapy with ursodeoxycholic acid (UDCA). The mechanism for nonresponse to UDCA remains, however, unclear and we lack mechanistic serum markers. The UK-PBC study was established to explore the biological basis of UDCA nonresponse in PBC and identify markers to enhance treatment. Approach and Results Discovery serum proteomics (Olink) with targeted multiplex validation were carried out in 526 subjects from the UK-PBC cohort and 97 healthy controls. In the discovery phase, untreated PBC patients (n = 68) exhibited an inflammatory proteome that is typically reduced in scale, but not resolved, with UDCA therapy (n = 416 treated patients). Nineteen proteins remained at a significant expression level (defined using stringent criteria) in UDCA-treated patients, six of them representing a tightly linked profile of chemokines (including CCL20, known to be released by biliary epithelial cells (BECs) undergoing senescence in PBC). All showed significant differential expression between UDCA responders and nonresponders in both the discovery and validation cohorts. A linear discriminant analysis, using serum levels of C-X-C motif chemokine ligand 11 and C-C motif chemokine ligand 20 as markers of responder status, indicated a high level of discrimination with an AUC of 0.91 (CI, 0.83-0.91). Conclusions UDCA under-response in PBC is characterized by elevation of serum chemokines potentially related to cellular senescence and was previously shown to be released by BECs in PBC, suggesting a potential role in the pathogenesis of high-risk disease. These also have potential for development as biomarkers for identification of high-risk disease, and their clinical utility as biomarkers should be evaluated further in prospective studies.
Reducing psychological distress and depression in humanitarian emergencies: An essential role for nonspecialists
Authors: John A. Naslund, Eirini Karyotaki
Journal: PLoS Medicine (2021)

Humanitarian emergencies such as war, natural disasters, or pandemics profoundly disrupt the daily lives of those impacted and result in psychological distress and high risk of mental disorders.With increasing frequency of humanitarian emergencies over the past decade, including the most recent Coronavirus Disease 2019 (COVID-19AU : PleasenotethatCOVID À 19hasbe) pandemic, there is immediate need for brief scalable interventions that can be readily delivered to at-risk population groups [1].With the dearth of available mental health specialists, especially in low-resource settings susceptible to crises, natural disasters, or displacement, combined with fragmented or poor functioning health systems during emergencies, nonspecialists may be ideally positioned to deliver such programs [2].Nonspecialists, such as community health workers or lay persons, do not have specialty training in mental healthcare; yet, these frontline providers often play an essential role in delivering primary care services in many low-and middle-income countries [3,4], and they are increasingly being recognized as critical for scaling up access to psychological treatments for mental disorders [5,6].Further, in a humanitarian crisis, use of nonspecialists from the affected population offers key benefits, such as empowering community members and drawing upon the experience of facilitators [7].In an accompanying study in PLOS Medicine, Mark Jordans and colleagues demonstrate that community members with no prior mental health training could effectively deliver the WHO Group Problem Management Plus (Group PM+) program in a humanitarian setting in Nepal [8].The research team conducted a cluster randomized controlled trial enrolling 72 wards and found that the 5-session Group PM+ delivered by nonspecialists contributed to reduction in psychological distress and depressive symptoms when compared to usual care.There may be opportunities to expand on these findings and further advance task sharing efforts in humanitarian settings.
EPCT-15. RAPID EPIGENOMIC CLASSIFICATION OF BRAIN TUMORS ENABLES INTRAOPERATIVE NEUROSURGICAL RISK MODULATION
Authors: Luna Djirackor, Skarphedinn Halldorsson, Pitt Niehusmann, Henning Leske, Luis P Kuschel, Jens Pahnke, Bernt J Due-Tønnessen, Iver A Langmoen, Cecilie J Sandberg, Philipp Euskirchen, Einar O Vik-Mo
Journal: Neuro-Oncology (2021)

Abstract Background Clear identification of tumor subtype is the main predictor of patient outcome and ultimately what is considered an adequate level of surgical risk. At brain tumor resection, imaging modalities and intraoperative histology often give an ambigious diagnosis, complicating intraoperative surgical decision-making. Here, we report a nanopore DNA methylation analysis (NDMA) sequencing approach combined with machine learning for classification of tumor entities that could be used intraoperatively. Methods We analyzed 50 biopsies obtained from biobanked tissue (43, prospective) or sampled at surgery (7, intraoperative) from 20 female and 30 male patients with a median age of 8 years. DNA was extracted using spin columns, quantified on a Qubit fluorometer and assessed for purity using NanoDrop spectrophotometer. DNA was then barcoded with the Rapid Barcoding kit from Oxford Nanopore technologies and loaded onto a MinION flow cell. Sequencing was performed for 3 hours (intraoperative) and 24 hours (prospective). Raw reads were basecalled using the Guppy algorithm, then fed into a snakemake workflow (nanoDx pipeline). This generated a report showing the copy number profile, genome-wide methylation status and subclassification of the tumor according to the Heidelberg reference cohort. Results Twelve different tumor classes were discovered within our cohort spanning from WHO Grade I to Grade IV. The results generated by NDMA were concordant with standard neuropathological diagnosis in 43 out of 50 cases (86%). Of the discordant cases, six were due to the biological complexity of the tumor and one case was misclassified by the pipeline. NDMA enabled correct subclassification of 6/7 intraop cases within a mean of 129 minutes. Conclusion NDMA can accurately subclassify tumor entities intraoperatively and guide surgical procedures when preoperative imaging and frozen section evaluation are unclear.
NCI Awardee Skills Development Consortium (NASDC): Applicant profiles.
Authors: Claire F. Verschraegen, Mia Hashibe, Ann O'Connell, Ushma Neill, Romina Rodriguez, William F. Pirl, Tamryn Gray, Miryam Yusufov, Elizabeth Hexner, David A. Mankoff, Cauleen Noel, Madeline Romney, Jeannette Korczak, Lindsay Matthews, Iness Jedidi, Rebecca Jackson
Journal: Journal of Clinical Oncology (2021)

11030 Background: In 2020, the NCI funded a new educational consortium, NASDC (NCI Awardee Skills Development Consortium, RFA-CA-19-010 and -011), through four institutionally granted UE5 awards to deliver a specific course each and a U24 award as a Coordinating Center. The goal is to teach current early-career faculty NCI grantees skills in areas critical for successful independent academic cancer research careers. Courses focus on leadership and socioemotional skills, health disparities, immuno-oncology, and cell and gene therapy. Teaching will initially be virtual, given the COVID pandemic. Methods: A steering committee and four working groups were established to build the consortium infrastructure, including the NASDC (osu.edu) website. Clientele are early-career faculty PD/PI of a current NCI-funded grant (K01, K07, K08, K22, K23, K25, R00, R21, DP1, DP2, DP5, R01, R23, R29, R37, R56, RF1, RL1, U01), of whom 454 were directly contacted. Blast emails and social media were also used. We are reporting the characteristics of 154 applicants, who completed the RedCap application online. Results: 85% of the applicants are within the first 5 years of a faculty appointment, 87% at the assistant professor rank, and 65% on tenure track. 40% hold an M.D. degree and 72% a Ph.D. 81% are US citizens, 52% females, and 45/33/16/2/4%-11% are White/Asian/Black/Native Americans/Other–Hispanics/Latino. 76% work at NCI-designated comprehensive cancer centers. Mean protected research time is 80%. Non-mutually exclusive fields of research interest are therapeutics (46%), basic science (37%), disparities (34%) prevention (32%), public health (28%), and pediatrics (10%). 66% have received a K-award grant, 13% each an R21 or R00, and 3% an R01. Additionally, 35% had a second NCI grant as PI, 10% a third grant, and 60% had non-NCI grants. Reasons for applying included (1) not quite ready to lead a research team (42%), (2) need for stronger career mentoring (37%), and (3) not being fully confident in research skills (21%). Conclusions: Applicants to the new NCI educational consortium (NASDC) have a successful start to their academic career with a third having obtained more than one NCI award. Most applicants work at NCI-designated comprehensive cancer centers. As cancer research continues to evolve and has the potential to address critical health care needs of the nation, NASDC will strive to equip scientists to be leaders, teach advances in technology, and impart confidence in research skills.
Activated microglia mitigate Aβ-associated tau seeding and spreading
Authors: Maud Gratuze, Yun Chen, Samira Parhizkar, Nimansha Jain, Michael R. Strickland, Javier Remolina Serrano, Marco Colonna, Jason D. Ulrich, David M. Holtzman
Journal: The Journal of Experimental Medicine (2021)

In Alzheimer's disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque-associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased Aβ-driven tau seeding and spreading. We show that both TREM2KO and microglial ablation dramatically enhance tau seeding and spreading around plaques. Interestingly, although repopulated microglia clustered around plaques, they had a reduction in disease-associated microglia (DAM) gene expression and elevated tau seeding/spreading. Together, these data suggest that TREM2-dependent activation of the DAM phenotype is essential in delaying Aβ-induced pathological tau propagation.
Fibroblast growth factor receptor (FGFR) inhibitor rogaratinib in patients with advanced pretreated squamous-cell non-small cell lung cancer over-expressing FGFR mRNA: The SAKK 19/18 phase II study.
Authors: Alfredo Addeo, Markus Joerger, Sacha Rothschild, Eric I. Eboulet, Gilles Godar, Christine Waibel-Pachinger, Simon Haefliger, Michael Thomas Mark, Eugenio Fernandez, Nicolas Mach, Laetitia A. Mauti, Martin Frueh
Journal: Journal of Clinical Oncology (2021)

e21119 Background: A substantial proportion of patients with squamous lung cell carcinoma (SQCLC) (46%) exhibit tumor overexpression of fibroblast growth factor receptor (FGFR) messenger ribonucleic acid (mRNA). Rogaratinib is a novel pan-FGFR inhibitor with anti-tumor activity in pre-clinical models as a single agent in FGFR pathway-addicted tumor models. Phase I data showed promising activity and good safety profile. The objective of the SAKK 19-18 trial was to determine clinical activity and safety of rogaratinib in patients with advanced SQCLC overexpressing tumor FGFR1-3 mRNA. Methods: Patients with metastatic SQCLC, previously treated with systemic treatment, overexpressing tumour FGFR mRNA were treated with rogaratinib 600 mg BID until progression of disease or drug intolerance. A rate ≤15% of PFS at 6 months was considered uninteresting, whereas a PFS rate at 6 months ≥38% was considered promising. Ten patients were needed in the first stage with at least 2 achieving 6 months PFS in order to continue the accrual. Results: Between May and November 2020, 49 patients were screened and 20 were classified FGFR positive. Among them15 patients were registered in the trial and the first 10 were assessed for the first stage analysis. Most commons treatment related adverse events (TRAEs) were hyperphosphatemia (60%), diarrhoea (20%), and dry mouth (20%). Grade ≥3 TRAEs occurred in 50% of the patents with Hypercalcemia being the most frequent one (20%). Among 10 first patients only 1 achieved 6 months PFS while 2 was the boundary required for continuing this trial. Conclusions: Despite preliminary signal of activity, rogaratinib failed to improve PFS in patients overexpressing tumor FGFR mRNA. Further studies on a more reliable biomarker are needed, the development of rogaratinib in SQCLC has been put on hold by Bayer and the SAKK 19/18 study was terminated early due to lack of efficacy. Clinical trial information: NCT03762122.
Chemotherapy-elicited exosomal miR-378a-3p and miR-378d to promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling.
Authors: Jin Zhang
Journal: Journal of Clinical Oncology (2021)

e12615 Background: Not all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chemotherapy-resistant phenotype in tumors. However, the role of BC chemo-elicited exosomes in regulating chemoresistance is poorly understood. Methods: Using commercial kits, serum exosomes were extracted from patients before neoadjuvant chemotherapy, after one cycle of chemotherapy and after four cycles of chemotherapy consisting of doxorubicin (DOX) and paclitaxel (PTX). Their miRNAs were sequenced, and the correlation between the sequencing results and chemotherapy effects was further verified by RT-qPCR using patient serum exosomes. Cell Counting Kit-8 (CCK-8) was used to detect chemosensitivity. Stemness was assessed by CD44+/CD24- population analysis and mammosphere formation assays. Chromatin immunoprecipitation (ChIP) experiments were performed to verify the binding of signal transducer and activator of transcription 3 (STAT3) to the promoter of miRNAs. Results: Here, we provide clinical evidence that chemotherapy-elicited exosomal miR-378a-3p and miR-378d are closely related to the chemotherapy response and that exosomes produced by BC cells after stimulation with DOX or PTX deliver miR-378a-3p and miR-378d to neighboring cells to activate WNT and NOTCH stemness pathways and induce drug resistance by targeting Dickkopf 3 (DKK3) and NUMB. In addition, STAT3, which is enhanced by zeste homolog 2 (EZH2), bound to the promoter regions of miR-378a-3p and miR-378d, thereby increasing their expression in exosomes. More importantly, chemotherapeutic agents combined with the EZH2 inhibitor tazemetostat reversed chemotherapy-elicited exosome induced drug resistance in a nude mouse tumor xenograft model. Conclusions: This study revealed a novel mechanism of acquired chemoresistance whereby chemotherapy activates the EZH2/STAT3 axis in BC cells, which then secrete chemotherapy-elicited exosomes enriched in miR-378a-3p and miR-378d. These exosomes are absorbed by chemotherapy-surviving BC cells, leading to activation of WNT and NOTCH stem cell pathways via the targeting of DKK3 and NUMB and subsequently resulting in drug resistance. Therefore, blocking this adaptive mechanism during chemotherapy may reduce the development of chemotherapy resistance and maximize the therapeutic effect.
Circulating tumor DNA (ctDNA) in patients with advanced adrenocortical carcinoma.
Authors: Bassel Nazha, Hiba I. Dada, Leylah Drusbosky, Jacqueline T Brown, Deepak Ravindranathan, Bradley Curtis Carthon, Omer Kucuk, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2021)

4585 Background: Adrenocortical Carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited treatments in the advanced setting. Molecular pathways with tumor suppressor genes (e.g. TP53, CDKN2A) and oncogenes (e.g. CTNNB1 and RAS) are implicated in oncogenesis. To our knowledge, the genomic landscape of ctDNA alterations for ACC has not been described in a large cohort. We report plasma-based ctDNA alterations in patients with advanced ACC. Methods: We retrospectively evaluated genomic data from 102 patients with ACC who had ctDNA testing between 12/2016 – 10/2020 using Guardant360 (Guardant Health, CA). ctDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes. We evaluated the frequency of genomic alterations, the landscape of co-occurring mutations, and pathogenic or likely pathogenic alterations with potential targeted therapies. The prevalence of alterations identified in ctDNA were compared to those detected in tissue using a publicly available database (cBioPortal). Results: The median age was 54 years (range 24-81), and 55% of patients were male. Among the entire cohort, 84 pts (82.4%) had ≥1 somatic alteration detected. Mutations were most frequently detected in TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%). The frequencies detected in ctDNA were similar to the results detected in tissue. Pathogenic and/or likely pathogenic mutations in therapeutically relevant alterations were observed in 36 patients (35%), including EGFR, BRAF, MET, CDKN2A, and CDK4/6 (Table 1). The most frequently co-occurring mutations were EGFR + TP53 (14%), EGFR + MET (11%), BRAF + MET (10%). Conclusions: Blood-based ctDNA profiling in advanced ACC provided comprehensive genomic data in most patients, with a similar profile to tumor tissue analyses. Over one third of patients had actionable mutations with approved therapies in other cancers. This approach might inform the development of personalized treatment options for this aggressive malignancy.[Table: see text]
Effects of weekly selinexor, bortezomib, dexamethasone (XVd) versus standard twice weekly bortezomib and dexamethasone (Vd) on <i>RAS</i>-mutated previously treated multiple myeloma (MM).
Authors: Christopher James Walker, Shirong Li, Yi Chai, Jatin J. Shah, Sharon Shacham, Suzanne Lentzsch, Yosef Landesman
Journal: Journal of Clinical Oncology (2021)

8027 Background: Activating mutations of the RAS genes NRAS, KRAS, and HRAS ( RAS mut ) occur in up to 50% of MM and portend poor survival and high recurrence rates. MM cells with RAS mut are susceptible to inhibition of germinal center kinase (GCK), resulting in IKAROS degradation independent of cereblon (CRBN). Selinexor is a selective inhibitor of nuclear export (SINE) compound that can induce IKAROS degradation through CRBN-independent pathways to overcome immunomodulatory drug resistance. We explored the benefit of selinexor treatment for pts with RAS mut MM. Methods: In the randomized BOSTON study, pts with MM after 1-3 therapies received weekly XVd or twice weekly Vd. In the single-arm STORM study pts with penta-treated, triple class refractory MM were treated with twice weekly Xd. Both treatment regimens are now FDA approved. Mutations were assessed post-hoc by exome sequencing of 119 and 52 pts from BOSTON and STORM, respectively. Pts were considered RAS mut if their MM had NRAS, KRAS or HRAS mutations in codons 12, 13 or 61. Results: There were 54 pts (45%) with RAS mut in BOSTON (XVd = 26, Vd = 28), and 17 (33%) in STORM. In BOSTON, pts with RAS mut MM treated with XVd had significantly longer progression-free survival (PFS) than those treated with Vd (median [med] = 12.9 vs 6.7 months [mo], hazard ratio [HR] = 0.48 [95% CI 0.24-0.97], p = 0.039). For pts treated with Vd, those with RAS mut had significantly shorter overall survival (OS) compared to RAS wild-type (WT) (med = 16.8 mo vs not reached [NR], HR = 2.87 [95% CI 1.03-7.99], p = 0.035). PFS was not significantly different (med = 6.74 vs 9.82 mo, HR = 1.64 [95% CI 0.88-3.07], p = 0.122). Amongst pts on XVd, there was no difference in survival between RAS mut and RAS WT pts (PFS: med = 12.8 vs 12.9 mo, HR = 1.08 [95% CI 0.52-2.26], p = 0.83; OS: med = NR vs NR, HR = 0.94 [95% CI 0.36-2.45], p = 0.91). In STORM, pts with RAS mut had shorter OS compared to RAS wt pts (med = 6.1 vs NR, HR = 2.05 [95% CI 1.22-5.19], p = 0.010). Preliminary studies to explore the mechanisms of action related to RAS mut MM sensitivity to XVd demonstrated that selinexor treatment in vitro leads to downregulation of GCK. Conclusions: Despite typically having the worst outcomes, pts with RAS mut MM had a similar benefit from XVd as RAS WT MM, showing that the XVd combination can overcome RAS mut . Mechanistically, selinexor induced down regulation of GCK and enhanced killing of RAS mut MM cells. With a manageable safety profile, the XVd regimen could provide a viable treatment option to improve survival of pts with MM with RAS mutations. Clinical trial information: NCT03110562. [Table: see text]