tbuckley/cabot-search huggingface dataset:
JS01.3.A Oncogenic chaperoning of Hsp90 in glioma with FGFR3-TACC3
Authors: T Li, F Mehraein-Ghomi, M Forbes, S Namjoshi, E Ballard, Q Song, P Chou, X Wang, X Yang, W Zhang
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Fusion genes are chromosomal aberrations in malignancies that can be used as prognostic markers as well as therapeutic targets. The FGFR3-TACC3 (F3-T3) was initially discovered as an oncogenic molecule in glioblastoma and bladder cancer and subsequently found in many other cancer types. Based on clinical evidence, F3-T3 was found in glioblastoma patients before and after TMZ and radiotherapy treatment, suggesting that targeting F3-T3 is a valid strategy for glioblastoma treatment. MATERIAL AND METHODS We profiled the proteins that interacted with F3-T3 fusion protein in U-251 MG cells with F3-T3 through 2-D liquid chromatography-tandem mass spectrometry. To validate the result of proteomic analysis, we performed reverse immunoprecipitation by pulling down Hsp90 or Cdc37 in U-251 MG cells stably expressing F3-T3. To inhibit the association between F3-T3 and the Hsp90-Cdc37 complex, we treated U-251 MG and LN-229 cells stably expressing F3-T3 with Hsp90 inhibitors or siRNA of Cdc37. We applied the CCK8 assay to evaluate the sensitivity of glioblastoma cells stably expressing F3-T3, wild-type FGFR3, kinase-dead F3-T3 (K508R), and empty vectors to TMZ. Immunoblot and immunofluorescence staining were used to detect DNA damage marker pH2AX. The drug combination effect index was analyzed using software CalcuSyn. U-251 MG cells stably expressing F3-T3 infected with luciferase virus were intracranially injected in nude mice. The experimental group was administered with temozolomide (5mg/kg/day) by oral gavage, Hsp90 inhibitor Onalespib (30mg/kg/day) by tail vein injection or the combination of the two for indicated days. RESULTS We identified the proteins that showed increased binding ratios to F3-T3 over full-length FGFR3, the molecular chaperone proteins encoded by the genes HSP90AB1, HSP90AA1, and CDC37 emerged as 5th, 6th, and 7th on the top ten list, showing an approximately 4-fold increase in normalized spectral counts. Using Hsp90 inhibitors or Cdc37 siRNA disrupted the formation of the F3-T3/Hsp90/Cdc37 complex. Disruption of Hsp90-Cdc37 chaperoning caused a ubiquitination-mediated degradation of the glycosylated form of F3-T3 and abrogated the maturation of nascent F3-T3, resulting in suppression of F3-T3 signaling pathways. Additionally, our results provide evidence that the F3-T3 signaling pathway confers drug resistance to TMZ induced DNA damage. However, the resistance of TMZ was disrupted in glioblastoma cells harboring kinase-dead F3-T3 (K508R). We also demonstrated Hsp90 inhibitor significantly sensitized glioblastoma cells harboring the F3-T3 fusion gene to TMZ treatment and improved survival of xenograft model bearing F3-T3 tumor in vivo. CONCLUSION F3-T3 is a strong Hsp90 client that shows strong addiction to the Hsp90-Cdc37 chaperone system. Combination therapy with Hsp90 inhibitor overcomes the TMZ resistance conferred by F3-T3.
Bone Mineral Density Loss and Fracture Risk After Discontinuation of Anti-osteoporotic Drug Treatment: A Narrative Review
Authors: Laura P. B. Elbers, Hennie G. Raterman, Willem F. Lems
Journal: Drugs (2021)

The number of patients on long-term anti-osteoporotic drug therapy is rising. Unfortunately, there are few data to guide decisions about duration of pharmacologic therapy for osteoporosis. Many practitioners discontinue therapy after a period of 5 years because of the risk of rare but severe side effects that may occur in long-term users. The objective of this narrative review was to describe the effects of discontinuation of anti-osteoporotic drugs and to investigate what is not yet known on this topic. For each anti-osteoporotic agent, PubMed was searched for evidence from randomized clinical trials in patients with osteoporosis on osteoporotic drugs lasting ≥ 3 years, followed by ≥ 1 year of follow-up after discontinuation of therapy and reported at least one item of the following: changes in bone mineral density, bone turnover markers and/or the risk of vertebral and/or nonvertebral fractures after discontinuation of therapy. The% change in bone mineral density (BMD) after 1 year of discontinuation of therapy is − 0.4% or less at the hip and femoral neck in both alendronate- and zoledronic acid-treated patients. In the other reported agents (risedronate, ibandronate, raloxifene, teriparatide, denosumab and romosozumab) this percentage of bone loss at the femoral neck and total hip was at least 1%, with the largest decrease in BMD after discontinuation of denosumab and romosozumab. In all studies reporting bone turnover markers, a substantial rapid rise in these markers was observed after discontinuation of therapy, with a large rebound increase to far above baseline levels in the denosumab-treated patients. There were few data on fracture risk after discontinuation of therapy; data showed that discontinuing alendronate, zoledronic acid and especially denosumab significantly increases the risk of vertebral fractures. In conclusion, osteoporosis should be considered more as a chronic condition. Therefore, in modern fracture risk management, continuous monitoring and treatment is required, as is the case with other chronic diseases, to sustain the benefits of therapy, especially in denosumab- and romosozumab-treated patients. The exception is alendronate and zoledronic acid, in these patients a discontinuation of drug therapy of 1 year or more might be acceptable.
P04.06 Can BraTS Toolkit Brain Tumor Segmentation Algorithms be relevant when dealing with post-operative MRI in clinical practice?
Authors: L Piram, C Acquitter, U Sabatini, B Lemasson, E Moyal, S El Idrissi, S Ken
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Segmentation of brain tumors is crucial for radiotherapy plans and treatment outcome evaluation. As manual segmentation (MS) is a time-consuming task, many algorithms to automate the process were proposed over the past decades. BraTS toolkit (BTK) offers a solution for automatic brain tumor segmentation in 3 steps: a Preprocessor for image conversion and registration, a Segmentor generating segmentations from 4 deep-learning based algorithms and a Fusionator combining the results. As most algorithms published, BTK was trained on pre-operative data. Yet, as surgery is the first treatment of glioblastomas, most MRIs in clinical practice are post-operative images. This study aimed to assess whether segmentation of post-operative brain tumors could benefit from an initial automatic segmentation (AS) using BTK. MATERIAL AND METHODS MRI dataset from the multicenter, STERIMGLI clinical trial provided 92 series from 25 patients with a unifocal recurrence of glioblastoma. AS were generated using BTK Preprocessor and Segmentor. Out of the 4 algorithms output, the best AS was selected after visual appraisal. AS contained 3 labels: T1w contrast enhanced tumor (ET), flair edema (ED) and non-enhanced tumor (NET). AS were then reviewed by a radiation oncologist and a neuroradiologist to produce the MS. ET and ED were corrected; surgical cavity (SC) was also segmented, either from the NET label or de novo. Dice-score, Hausdorff Distance (HD) and Average Hausdorff Distance (AHD) were used to quantify the similarity between AS and MS for each label. RESULTS AS succeeded to label 89.3% (82/92), 100% (92/92) and 85.8% (79/92) of ET, ED and NET respectively. Among the 4 algorithms in BTK, Zyx_2019 produced 36% of AS, mic-dkfz 32%, xfeng 18%, lfb_rwth 14%. Mean Dice-scores of 75.8%, 94.8% were found for ET and ED respectively. Mean HD and AHD were 25.2mm (±39.7), 2.8mm (±10.9) for ET; 14.9mm (±25.8), 0.9mm (±5.8) for ED. Concerning SC, Dice-scores were &amp;lt;0.1 for 49% (39/79), &amp;gt;0.6 for 30% (42/79). CONCLUSION BraTS Toolkit was trained to segment necrosis as the label NET. Still, it detected the surgical cavity and saved time for the MS in 51% of post-operative cases. Even though BTK was designed to segment pre-operative brain tumors, similarity metrics show that minimal or no manual corrections are necessary most of the time when used to segment ET and ED on post-operative MRI acquired in clinical routine. The development of a unique AS tool for pre and post-operative images would be useful in clinical practice.
Liberating host–virus knowledge from biological dark data
Authors: Nathan S Upham, Jorrit H Poelen, Deborah Paul, Quentin J Groom, Nancy B Simmons, Maarten P M Vanhove, Sandro Bertolino, DeeAnn M Reeder, Cristiane Bastos-Silveira, Atriya Sen, Beckett Sterner, Nico M Franz, Marcus Guidoti, Lyubomir Penev, Donat Agosti
Journal: The Lancet Planetary Health (2021)
Abstract 14096: The Immune Transcriptional Factor Irf4 is a Key Regulator of Thermogenesis
Authors: Xingxing Kong, Alexander Banks, Tiemin Liu, Xun Wang, Sander Kleiner, Sona Kang, Evan D Rosen
Journal: Circulation (2013)

Adipocytes can be broadly classed as white or brown fat cells. While white fat cells are specialized to store energy in the form of triglyceride, brown adipocytes use their high mitochondrial conte...
Real-world comparison of febrile neutropenia rates with same-day versus next-day administration of pegfilgrastim.
Authors: Kyle Kitchen, Michael C. Mosier
Journal: Journal of Clinical Oncology (2021)

299 Background: Febrile neutropenia (FN) is a common side effect of myelosuppressive chemotherapy. Per guidelines, prophylactic pegfilgrastim is to be given 24-72 hours after chemotherapy in each cycle, but administering pegfilgrastim within 24 hours of chemotherapy (same day) is commonly done to reduce the burden on patients (pts) and healthcare systems. The ideal timing is under debate in the supportive oncology care field, but an increasing body of knowledge supports same-day administration as an option. The objective of this study was to compare the incidence of FN after same-day vs next-day administration of pegfilgrastim in pts with cancer receiving cytotoxic chemotherapy. Methods: A real-world, retrospective study of electronic health records of pts treated at Utah Cancer Specialists (Salt Lake City, UT) between February 2018 and December 2020 was conducted. Pts included in the study had a diagnosis of breast cancer, diffuse large B-cell lymphoma, or other cancers (eg. other lymphomas, prostate cancer); received a myelosuppressive chemotherapy regimen; and were administered either same-day or next-day prophylactic pegfilgrastim. FN was physician diagnosed; differences in FN incidence with same-day vs next-day pegfilgrastim were evaluated using a Chi-square test and Wald confidence limits. Results: 297 pts were included in this analysis. Most pts (63.6%) had a diagnosis of breast cancer, 23.6% had lymphoma, and 12.8% had other cancers. Pts received a broad range of chemotherapy regimens, with dose-dense doxorubicin and cyclophosphamide being the most common (43.4%). In cycle 1, pegfilgrastim administration timing was balanced between same-day (39.7% [118/297]) and next-day (60.3% [179/297]). The pegfilgrastim administration day changed in subsequent cycles in 27 pts (9.1%): 4 pts in the cycle 1 same-day group and 23 pts in the cycle 1 next-day group. In cycle 1, 7/117 pts (6.0%) in the same-day pegfilgrastim group and 12/180 (6.7%) pts in the next-day group experienced ≥1 episode of FN. Across all cycles, 11/118 pts (9.3%) in the same-day pegfilgrastim group and 16/179 (8.9%) pts in the next-day group experienced ≥1 episode of FN. The difference in incidence of FN between same-day vs next-day pegfilgrastim was not statistically significant in cycle 1 (0.68% [95% CI –5.0% to 6.3%]; P=.814) and across all cycles (–0.38% [95% CI –7.1% to 6.3%]; P=.910). Conclusions: The overall incidence of FN was low in this pt population receiving prophylactic pegfilgrastim, and no significant differences were detected between same-day and next-day pegfilgrastim administration. These data support the same-day administration of prophylactic pegfilgrastim.
KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases
Authors: Brad H. Rovin, Sharon G. Adler, Jonathan Barratt, Frank Bridoux, Kelly A. Burdge, Tak Mao Chan, H. Terence Cook, Fernando C. Fervenza, Keisha L. Gibson, Richard J. Glassock, David R.W. Jayne, Vivekanand Jha, Adrian Liew, Zhi-Hong Liu, Juan Manuel Mejía-Vilet, Carla M. Nester, Jai Radhakrishnan, Elizabeth M. Rave, Heather N. Reich, Pierre Ronco, Jan-Stephan F. Sanders, Sanjeev Sethi, Yusuke Suzuki, Sydney C.W. Tang, Vladimir Tesar, Marina Vivarelli, Jack F.M. Wetzels, Jürgen Floege
Journal: Kidney International (2021)

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline on the topic. The aim is to assist clinicians caring for individuals with glomerular disease, both adults and children. The scope includes various glomerular diseases, including IgA nephropathy (IgAN) and IgA vasculitis (IgAV), membranous nephropathy, nephrotic syndrome in children, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related glomerulonephritis (GN), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, lupus nephritis, and anti-glomerular basement membrane (anti-GBM) antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations with valuable infographics based on a rigorous formal systematic literature review. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad audience of clinicians treating glomerular disease while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process of evidence review. Treatment approaches and guideline recommendations are based on systematic reviews and evidence synthesis of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the “Grading of Recommendations Assessment, Development, and Evaluation” (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented.
Dual-Time-Point 18F-Fluorocholine PET/CT Improves Characterization of Thyroid Nodules in Patients Referred for Primary Hyperparathyroidism
Authors: Jacob Bani, David Morland, Fabrice Hubelé, Mihaela Ignat, Adrien Latge, Khalil Bourahla, Mohamad Zalzali, Michel Vix, David Taïeb, Alessio Imperiale
Journal: Clinical Nuclear Medicine (2021)

Purpose Thyroid nodules frequently coexist with primary hyperparathyroidism (pHPT). Because of the increasing use of 18 F-fluorocholine ( 18 F-FCH) PET/CT in patients with pHPT, evaluation of its clinical utility for thyroid nodules characterization in this population is of paramount importance. Herein, we investigate the value of dual-point 18 F-FCH PET/CT in the diagnosis of thyroid cancer in patients referred for pHPT imaging who have thyroid nodules. Patients and Methods All pHPT patients who underwent a dual-time point 18 F-FCH PET/CT (at 5 and 60 minutes postinjection) between July 2019 and December 2020 were analyzed. Only those with a thyroid nodule greater than 10-mm and pathological analysis (criterion standard) were included. Nodule-to-thyroid SUV max ratio was calculated at the 2 study points, as well as the 18 F-FCH washout index (WO%). Results Twenty-seven patients (32 nodules) were included in this study. The final diagnoses were as follows: 27 benign nodules including 2 NIFTPs (noninvasive follicular thyroid neoplasm with papillary-like nuclear features) and 5 cancers of follicular origin. Early uptake ratio was significantly higher in malignant lesions than in benign nodules ( P = 0.0008). Thyroid cancers were also characterized by a marked 18 F-FCH washout index (WO% benign vs cancer: 2.9% ± 4.1% vs 45.5% ± 13.4%, P = 0.0001). Using a WO% threshold of 22.1%, 25/27 benign nodules and 5/5 malignant lesions were accurately classified (sensitivity of 100%, specificity of 92.6%, positive predictive value of 71.4%, and negative predictive value of 100%). The false-positive findings were related to the 2 NIFTPs that share similarities with thyroid cancer. Conclusions Our preliminary results suggest to perform a dual-time-point PET/CT acquisition protocol in pHPT patients with uncharacterized centimeter thyroid nodules. However, the real impact of these promising results should be assessed by prospective studies on a larger cohort of patients.
NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity
Authors: Rebecca M. Richards, Feifei Zhao, Katherine A. Freitas, Kevin R. Parker, Peng Xu, Amy Fan, Elena Sotillo, Mads Daugaard, Htoo Zarni Oo, Jie Liu, Wan-Jen Hong, Poul H. Sorensen, Howard Y. Chang, Ansuman T. Satpathy, Robbie G. Majzner, Ravindra Majeti, Crystal L. Mackall
Journal: Blood Cancer Discovery (2021)

Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR T cells engineered from a novel humanized CD93-specific binder potently kill AML in vitro and in vivo but spare hematopoietic stem and progenitor cells (HSPC). No toxicity is seen in murine models, but CD93 is expressed on human endothelial cells, and CD93 CAR T cells recognize and kill endothelial cell lines. We identify other AML CAR T-cell targets with overlapping expression on endothelial cells, especially in the context of proinflammatory cytokines. To address the challenge of endothelial-specific cross-reactivity, we provide proof of concept for NOT-gated CD93 CAR T cells that circumvent endothelial cell toxicity in a relevant model system. We also identify candidates for combinatorial targeting by profiling the transcriptome of AML and endothelial cells at baseline and after exposure to proinflammatory cytokines.CD93 CAR T cells eliminate AML and spare HSPCs but exert on-target, off-tumor toxicity to endothelial cells. We show coexpression of other AML targets on endothelial cells, introduce a novel NOT-gated strategy to mitigate endothelial toxicity, and demonstrate use of high-dimensional transcriptomic profiling for rational design of combinatorial immunotherapies.See related commentary by Velasquez and Gottschalk, p. 559. This article is highlighted in the In This Issue feature, p. 549.
The immunogenomic landscape of resected intrahepatic cholangiocarcinoma
Authors: Fernando Carapeto, Behnaz Bozorgui, Rachna T. Shroff, Sharmeen Chagani, Luisa Solis Soto, Wai Chin Foo, Ignacio Wistuba, Funda Meric‐Bernstam, Ahmed Shalaby, Milind Javle, Anil Korkut, Lawrence N. Kwong
Journal: Hepatology (2021)

Background and Aims Cholangiocarcinoma (CCA) is a deadly and highly therapy‐refractory cancer of the bile ducts, with early results from immune checkpoint blockade trials showing limited responses. Whereas recent molecular assessments have made bulk characterizations of immune profiles and their genomic correlates, spatial assessments may reveal actionable insights. Approach and Results Here, we have integrated immune checkpoint‐directed immunohistochemistry with next‐generation sequencing of resected intrahepatic CCA samples from 96 patients. We found that both T‐cell and immune checkpoint markers are enriched at the tumor margins compared to the tumor center. Using two approaches, we identify high programmed cell death protein 1 or lymphocyte‐activation gene 3 and low CD3/CD4/inducible T‐cell costimulator specifically in the tumor center as associated with poor survival. Moreover, loss‐of‐function BRCA1‐associated protein‐1 mutations are associated with and cause elevated expression of the immunosuppressive checkpoint marker, B7 homolog 4. Conclusions This study provides a foundation on which to rationally improve and tailor immunotherapy approaches for this difficult‐to‐treat disease.
2021 Update on allogeneic hematopoietic stem cell transplant for myelofibrosis: A review of current data and applications on risk stratification and management
Authors: Haris Ali, Andrea Bacigalupo
Journal: American Journal of Hematology (2021)

The number of patients with myelofibrosis (MF) undergoing an allogeneic hemopoietic stem cell transplantation (HSCT) is increasing: in the analysis of the European Group for Blood and Marrow Transplantation (EBMT) the number of MF has increased from 515 in 2014 to 748 in 2018 . This reflects the fact that HSCT is currently the only curative treatment, capable of inducing prolonged disease-free survival. Nevertheless, several problems prevent more patients from undergoing an allogeneic HSCT: we will be discussing indications for HSCT, comorbidities, splenomegaly, older age and disease phase. Donor type and stem cell source are less of a problem. Several transplant platforms exist, including different strategies for graft versus host disease (GvHD) prophylaxis, Age tailored conditioning regimens need to be implemented, to allow older and fragile patients to undergo an allogeneic HSCT.