tbuckley/cabot-search huggingface dataset:
RETRACTED: Precise editing of FGFR3-TACC3 fusion genes with CRISPR-Cas13a in glioblastoma
Authors: Ye Wu, Weili Jin, Qixue Wang, Junhu Zhou, Yunfei Wang, Yanli Tan, Xiaoteng Cui, Fei Tong, Eryan Yang, Jian Wang, Chunsheng Kang
Journal: Molecular Therapy (2021)

FGFR3-TACC3 (F3-T3) gene fusions are regarded as a "low-hanging fruit" paradigm for precision therapy in human glioblastoma (GBM). Small molecules designed to target the kinase in FGFR currently serve as one form of potential treatment but cause off-target effects and toxicity. Here, CRISPR-Cas13a, which is known to directly suppress gene expression at the transcriptional level and induce a collateral effect in eukaryotes, was leveraged as a possible precision therapy in cancer cells harboring F3-T3 fusion genes. A library consisting of crRNAs targeting the junction site of F3-T3 was designed, and an in silico simulation scheme was created to select the optimal crRNA candidates. An optimal crRNA, crRNA1, showed efficiency and specificity in inducing the collateral effect in only U87 cells expressing F3-T3 (U87-F3-T3). Expression profiles obtained with microarray analysis were consistent with induction of the collateral effect by the CRISPR-Cas13a system. Tumor cell proliferation and colony formation were decreased in U87-F3-T3 cells expressing the Cas13a-based tool, and tumor growth was suppressed in an orthotopic tumor model in mice. These findings demonstrate that the CRISPR-Cas13a system induces the collateral damage effect in cancer cells and provides a viable strategy for precision tumor therapy based on the customized design of a CRISPR-Cas13a-based tool against F3-T3 fusion genes.
18F-Fluoroestradiol Tumor Uptake Is Influenced by Structural Components in Breast Cancer
Authors: Mizuho Takahashi, Hiroyuki Maeda, Tetsuya Tsujikawa, Hiroko Kono, Tetsuya Mori, Yasushi Kiyono, Hidehiko Okazawa, Sakon Noriki, Yoshiaki Imamura, Takanori Goi
Journal: Clinical Nuclear Medicine (2021)

Estrogen receptor (ER) is expressed in the majority of invasive breast cancer and is an important prognostic indicator. The tumor stroma also plays an important role in disease progression. This study evaluated the effect of stromal components on 16α-[18F]-fluoro-17β-estradiol (18F-FES) uptake in breast cancer and proposed a partial-volume correction method for 18F-FES PET based on histopathological analyses.Fifteen patients with biopsy-confirmed breast cancer underwent preoperative 18F-FES PET. Estrogen receptor expression in biopsy specimens was assayed by immunohistochemistry, cellular components in surgical specimens were measured using hematoxylin-eosin staining, and nuclear components in surgical and biopsy specimens were measured using Azan-Mallory staining. The relationship between 18F-FES SUV of the primary tumor and histopathological findings including ER expression, the Allred score, ER-positive cellular component ratio, and ER-positive nuclear component ratio (NCR) was examined. The relationship between stroma-free 18F-FES SUV and ER expression was also examined.18F-FES uptake was not significantly positively correlated with ER expression (r = 0.44, P = 0.10). 18F-FES uptake was significantly correlated with the Allred score, ER-positive cellular component ratio, and ER-positive NCR in surgical specimens (ρ = 0.60, P = 0.02; r = 0.55, P = 0.03; and r = 0.65, P = 0.01, respectively). 18F-FES uptake was predominantly correlated with ER-positive NCR in biopsy specimens (r = 0.84, P < 0.001). Stroma-free 18F-FES SUV was significantly correlated with ER expression (r = 0.78, P < 0.01).18F-FES PET predominantly demonstrates the level of ER expression in breast cancer cell nucleus. Although tumor 18F-FES uptake is affected by the degree of stromal components, the partial volume effect on the uptake can be corrected by stroma-volume fraction in Azan-Mallory staining.
Patient-Reported Outcomes from the Randomized Phase 3 CROWN Study of First-Line Lorlatinib versus Crizotinib in ALK plus NSCLC
Authors: J Mazieres, L Iadeluca, A Shaw, B Solomon, T Bauer, F De Marinis, E Felip, Y Goto, D Kim, T Mok, A Reisman, H Thurm, A Polli, G Liu
Journal: Journal of Thoracic Oncology (2021)
Hedgehog Signaling Regulates Metabolism and Polarization of Mammary Tumor-Associated Macrophages
Authors: Dominique C. Hinshaw, Ann Hanna, Tshering Lama-Sherpa, Brandon Metge, Sarah C. Kammerud, Gloria A. Benavides, Atul Kumar, Heba Allah Alsheikh, Mateus Mota, Dongquan Chen, Scott W. Ballinger, Jeffrey C. Rathmell, Selvarangan Ponnazhagan, Victor Darley-Usmar, Rajeev S. Samant, Lalita A. Shevde
Journal: Cancer Research (2021)

Elevated infiltration of immunosuppressive alternatively polarized (M2) macrophages is associated with poor prognosis in patients with cancer. The tumor microenvironment remarkably orchestrates molecular mechanisms that program these macrophages. Here we identify a novel role for oncogenic Hedgehog (Hh) signaling in programming signature metabolic circuitries that regulate alternative polarization of tumor-associated macrophages. Two immunocompetent orthotopic mouse models of mammary tumors were used to test the effect of inhibiting Hh signaling on tumor-associated macrophages. Treatment with the pharmacologic Hh inhibitor vismodegib induced a significant shift in the profile of tumor-infiltrating macrophages. Mass spectrometry-based metabolomic analysis showed Hh inhibition induced significant alterations in metabolic processes, including metabolic sensing, mitochondrial adaptations, and lipid metabolism. In particular, inhibition of Hh in M2 macrophages reduced flux through the UDP-GlcNAc biosynthesis pathway. Consequently, O-GlcNAc-modification of STAT6 decreased, mitigating the immune-suppressive program of M2 macrophages, and the metabolically demanding M2 macrophages shifted their metabolism and bioenergetics from fatty acid oxidation to glycolysis. M2 macrophages enriched from vismodegib-treated mammary tumors showed characteristically decreased O-GlcNAcylation and altered mitochondrial dynamics. These Hh-inhibited macrophages are reminiscent of inflammatory (M1) macrophages, phenotypically characterized by fragmented mitochondria. This is the first report highlighting the relevance of Hh signaling in controlling a complex metabolic network in immune cells. These data describe a novel immunometabolic function of Hh signaling that can be clinically exploited. SIGNIFICANCE: These findings illustrate that Hh activity regulates a metabolic and bioenergetic regulatory program in tumor-associated macrophages that promotes their immune-suppressive polarization.
Whole-Genome Sequencing Reveals Lactase Persistence Adaptation in European Dogs
Authors: Yan-Hu Liu, Lu Wang, Zhiguo Zhang, Newton O Otecko, Saber Khederzadeh, Yongqin Dai, Bin Liang, Guo-Dong Wang, Ya-Ping Zhang
Journal: Molecular Biology and Evolution (2021)

Coexistence and cooperation between dogs and humans over thousands of years have supported convergent evolutionary processes in the two species. Previous studies found that Eurasian dogs evolved into a distinct geographic cluster. In this study, we used the genomes of 242 European dogs, 38 Southeast Asian indigenous (SEAI) dogs, and 41 gray wolves to identify adaptation of European dogs . We report 86 unique positively selected genes in European dogs, among which is LCT (lactase). LCT encodes lactase, which is fundamental for the digestion of lactose. We found that an A-to-G mutation (chr19:38,609,592) is almost fixed in Middle Eastern and European dogs. The results of two-dimensional site frequency spectrum (2D SFS) support that the mutation is under soft sweep . We inferred that the onset of positive selection of the mutation is shorter than 6,535 years and behind the well-developed dairy economy in central Europe. It increases the expression of LCT by reducing its binding with ZEB1, which would enhance dog's ability to digest milk-based diets. Our study uncovers the genetic basis of convergent evolution between humans and dogs with respect to diet, emphasizing the import of the dog as a biomedical model for studying mechanisms of the digestive system.
Autologous Stem Cell Transplant in the Era of Bortezomib-Based Induction for AL Amyloidosis Results in Improved Hematologic Response Rates: a Single Institution 11 Year Experience
Authors: Carlton D. Scharman, Joseph J. Shatzel, Richard T. Maziarz, Eva Medvedova, Alex Stentz, Gloria Rhyne, Chafic Karam, Rupali S. Avasare, Stephen B. Heitner, Emma C. Scott
Journal: Blood (2017)
Abstract 8837: Markers of Extracellular Matrix Turnover and the Development of Right Ventricular Failure After Ventricular Assist Device Implantation in Patients with Advanced Heart Failure
Authors: Tomoko S Kato, Aalap Chokshi, Parvati Singh, Tuba Khawaja, Faisal Cheema, Jonathan Yang, Hiroo Takayama, Yoshifumi Naka, Maryjane Farr, Donna Mancini, P. Christian Schulze
Journal: Circulation (2011)

Background. The development of right ventricular failure (RVF) is one of major causes of morbidity and mortality of patients following LVAD placement. The cardiac extracellular matrix (ECM) is a dynamic and metabolically active collagenous network that responds to mechanical strain. Hypothesis. We assessed the hypothesis that there would be an association between ECM turnover and development of RVF after LVAD implantation in patients with advanced heart failure (HF). Methods. Circulating levels of osteopontin (OPN), metalloproteinases (MMP)-2 and -9 and tissue inhibitor of MMP (TIMP)-1 and -4 were measured in 61 patients at the time of LVAD implantation and explantation. Serum ECM markers were also measured in 10 normal control subjects. RVF was defined as the need for right ventricular assist device, nitric oxide inhalation&gt;48 hours and/or inotropic support &gt;14 days or re-starting after 14 days. Results. All ECM markers were elevated in patients with HF compared to controls (all p&lt;0.05). 23 patients (37.7%) developed RVF on LVAD support. All ECM markers decreased on LVAD support in patients without RVF (all p&lt;0.05), but serum MMP-2, TIMP-1 and -4 and OPN remained elevated in patients with RVF. Post-LVAD OPN and TIMP-1 was higher in patients with RVH than those without RVF (316.4±84.6 vs. 202.4±69.1 ng/mL, p&lt;0.01, 210.7±62.4 vs. 164.3±45.2, p&lt;0.01, respectively). Multivariate analysis showed right ventricular stroke work index (RVSWI) [odds ratio (OR) 0.41, 95%confidence interval (CI) 0.207-0.670, p&lt;0.01], pre-LVAD circulating BNP (OR 1.02, 95%CI 1.00-1.04, p&lt;0.05) and OPN (OR 1.32, 95%CI, 1.01-1.61, p&lt;0.05) were significantly associated with RVF. OPN correlated inversely with RVSWI (r=-0.44, p&lt;0.001). OPN levels of &gt;260 ng/mL could discriminate patients developing RVF from those without RVF (83% sensitivity and 82% specificity). Conclusions. Elevated levels of OPN before LVAD placement are associated with the development of RVF. Persistent elevation of circulating ECM markers after LVAD implantation characterizes patients who develop RVF. These novel biomarkers would have a potential role in the pathogenesis of RVF development in patients undergoing LVAD implantation.
Advanced mesoporous silica nanocarriers in cancer theranostics and gene editing applications
Authors: Kristina Živojević, Minja Mladenović, Mila Djisalov, Mirjana Mundzic, Eduardo Ruiz-Hernandez, Ivana Gadjanski, Nikola Ž. Knežević
Journal: Journal of Controlled Release (2021)

Targeted nanomaterials for cancer theranostics have been the subject of an expanding volume of research studies in recent years. Mesoporous silica nanoparticles (MSNs) are particularly attractive for such applications due to possibilities to synthesize nanoparticles (NPs) of different morphologies, pore diameters and pore arrangements, large surface areas and various options for surface functionalization. Functionalization of MSNs with different organic and inorganic molecules, polymers, surface-attachment of other NPs, loading and entrapping cargo molecules with on-desire release capabilities, lead to seemingly endless prospects for designing advanced nanoconstructs exerting multiple functions, such as simultaneous cancer-targeting, imaging and therapy. Describing composition and multifunctional capabilities of these advanced nanoassemblies for targeted therapy (passive, ligand-functionalized MSNs, stimuli-responsive therapy), including one or more modalities for imaging of tumors, is the subject of this review article, along with an overview of developments within a novel and attractive research trend, comprising the use of MSNs for CRISPR/Cas9 systems delivery and gene editing in cancer. Such advanced nanconstructs exhibit high potential for applications in image-guided therapies and the development of personalized cancer treatment.
Extended Aromatase Inhibitors in Hormone-Receptor–Positive Breast Cancer
Authors: Pamela J. Goodwin
Journal: New England Journal of Medicine (2021)

Advances in the diagnosis and adjuvant treatment of breast cancer have led to improved outcomes, with the large majority of women who have operable cancer today expected to be alive and recurrence-free in 5 years. However, women with hormone-receptor–positive breast cancer remain at constant annual risk of recurrence for at least 20 years after diagnosis.1 Researchers who are investigating the extension of adjuvant hormonal therapies beyond the typically prescribed 5 years — often involving aromatase inhibitors in postmenopausal women — have provided some evidence of benefit, particularly among women who received only tamoxifen during the first 5 years and in . . .
Abstract 14853: Beta Blockers After HFrEF Hospitalization Decrease 1-Year Mortality Across the Age Spectrum Beta Blockers After HFrEF Hospitalization Decrease 1-Year Mortality Across the Age Spectrum
Authors: Lauren Gilstrap, Andrea Austin, Barbara Gladders, James O’Malley, Amber Barnato, Anna N Tosteson, Jonathan Skinner
Journal: Circulation (2019)

Introduction: Beta-blockers are a standard therapy for heart failure with reduced ejection fraction (HFrEF) and their use after hospitalization for HFrEF is a current measure HF quality. However, a...
Molecular imaging of fibroblast activation protein after myocardial infarction using the novel radiotracer [<sup>68</sup>Ga]MHLL1
Authors: Laura B.N. Langer, Annika Hess, Zekiye Korkmaz, Jochen Tillmanns, Laura M. Reffert, Jens P. Bankstahl, Frank M. Bengel, James T. Thackeray, Tobias L. Ross
Journal: Theranostics (2021)

Background: Myocardial infarction (MI) evokes an organized remodeling process characterized by the activation and transdifferentiation of quiescent cardiac fibroblasts to generate a stable collagen rich scar.Early fibroblast activation may be amenable to targeted therapy, but is challenging to identify in vivo.We aimed to non-invasively image active fibrosis by targeting the fibroblast activation protein (FAP) expressed by activated (myo)fibroblasts, using a novel positron emission tomography (PET) radioligand [ 68 Ga]MHLL1 after acute MI.Methods: One-step chemical synthesis and manual as well as module-based radiolabeling yielded [ 68 Ga]MHLL1.Binding characteristics were evaluated in murine and human FAP-transfected cells, and stability tested in human serum.Biodistribution in healthy animals was interrogated by dynamic PET imaging, and metabolites were measured in blood and urine.The temporal pattern of FAP expression was determined by serial PET imaging at 7 d and 21 d after coronary artery ligation in mice as percent injected dose per gram (%ID/g).PET measurements were validated by ex vivo autoradiography and immunostaining for FAP and inflammatory macrophages.Results: [ 68 Ga]MHLL1 displayed specific uptake in murine and human FAP-positive cells (p = 0.0208).In healthy mice the tracer exhibited favorable imaging characteristics, with low blood pool retention and dominantly renal clearance.At 7 d after coronary artery ligation, [ 68 Ga]MHLL1 uptake was elevated in the infarct relative to the non-infarcted remote myocardium (1.3 ± 0.3 vs. 1.0 ± 0.2 %ID/g, p < 0.001) which persisted to 21 d after MI (1.3 ± 0.4 vs. 1.1 ± 0.4 %ID/g, p = 0.013).Excess unlabeled compound blocked tracer accumulation in both infarct and non-infarct remote myocardium regions (p < 0.001).Autoradiography and histology confirmed the regional uptake of [ 68 Ga]MHLL1 in the infarct and especially border zone regions, as identified by Masson trichrome collagen staining.Immunostaining further delineated persistent FAP expression at 7 d and 21 d post-MI in the border zone, consistent with tracer distribution in vivo. Conclusion:The simplified synthesis of [ 68 Ga]MHLL1 bears promise for non-invasive characterization of fibroblast activation protein early in remodeling after MI.
Early Enrichment and Subsequent Dysfunction of Marrow ILC Subsets in Monoclonal Gammopathy: Target for IMiD Therapy
Authors: Jithendra Kini Bailur, Sameet Mehta, Lin Zhang, Natalia Neparidze, Terri L Parker, Noffar Bar, Tara Anderson, Mina Xu, Kavita Dhodapkar, Madhav V Dhodapkar
Journal: Blood (2017)
Author’s reply to McMahon
Authors: Adriane Fugh-Berman
Journal: BMJ (2021)

It’s simply not true that the Accreditation Council for Continuing Medical Education (ACCME) rules “safeguard continuing medical education (CME) from commercial bias,”12 a statement that McMahon references to an unpublished white paper commissioned by ACCME.3 We have documented clear promotional messaging that supports specific drugs in accredited CME activities on hypoactive sexual desire disorder,4 breakthrough pain,5 and binge eating disorder.6 Every other study examining commercial bias or changes in prescribing behaviour related to industry-funded CME has found bias because, well, …
Continuous monitoring of colonoscopy performance in the Netherlands: first results of a nationwide registry
Authors: Karlijn J. Nass, Peter J. van der Schaar, Manon van der Vlugt, Michiel Ledeboer, Aura A. J. van Esch, Sander van der Beek, Miangela M. Lacle, Monique E. van Leerdam, Rob J. T. Ouwendijk, Manon C. W. Spaander, Michel W. J. M. Wouters, Paul Fockens, Evelien Dekker
Journal: Endoscopy (2021)

To optimize colonoscopy quality, several performance measures have been developed. These are usually assessed without distinction between the indications for colonoscopy. This study aimed to assess the feasibility of linking two national registries (one for colonoscopy and one for adverse events of gastrointestinal endoscopies in the Netherlands), and to describe the results of colonoscopy quality per indication.This retrospective study was conducted with prospectively collected data of the Dutch Gastrointestinal Endoscopy Audit (DGEA) and the Dutch Registration of Complications in Endoscopy (DRCE). Data between 01-01-2016 and 01-01-2019 were analyzed. To calculate adverse event rates, data were linked at the level of endoscopy service.During the 3-year study period, 266 981 colonoscopies were recorded in DGEA. Of all indications, cecal intubation rate was highest in fecal immunochemical test (FIT)-positive screening colonoscopies (97.1 %), followed by surveillance (93.2 %), diagnostic (90.7 %), and therapeutic colonoscopies (83.1 %). The highest rate of adequate bowel preparation was observed in FIT-positive screening colonoscopies (97.1 %). A total of 1540 colonoscopy-related adverse events occurred (0.58 % of all colonoscopies). Bleeding and perforation and rates were highest for therapeutic (1.56 % and 0.51 %, respectively) and FIT-positive screening (0.72 % and 0.06 %, respectively) colonoscopies. The colonoscopy-related mortality was 0.006 %.This study describes the first results of the Dutch national colonoscopy registry, which was successfully linked to data from the national registry for adverse events of gastrointestinal endoscopies. In this large dataset, performance varied between indications. Our results emphasize the importance of defining benchmarks per indication in future guidelines.
SY17-5 Potential biomarkers for immunotherapy of gastric cancer
Authors: Yutaka Kawakami, Naoki Izawa, Shigeki Ohta, Shigenori Kadowaki, Keiko Minashi, Tomohiro Nishina, Takeharu Yamanaka, Takako Eguchi Nakajima
Journal: Annals of Oncology (2021)
Chemotherapeutic effects on breast tumor hemodynamics revealed by eigenspectra multispectral optoacoustic tomography (eMSOT)
Authors: Evangelos Liapis, Angelos Karlas, Uwe Klemm, Vasilis Ntziachristos
Journal: Theranostics (2021)

Non-invasive monitoring of hemodynamic tumor responses to chemotherapy could provide unique insights into the development of therapeutic resistance and inform therapeutic decision-making in the clinic.Methods: Here, we examined the longitudinal and dynamic effects of the common chemotherapeutic drug Taxotere on breast tumor (KPL-4) blood volume and oxygen saturation using eigenspectra multispectral optoacoustic tomography (eMSOT) imaging over a period of 41 days.Tumor vascular function was assessed by dynamic oxygen-enhanced eMSOT (OE-eMSOT).The obtained in vivo optoacoustic data were thoroughly validated by ex vivo cryoimaging and immunohistochemical staining against markers of vascularity and hypoxia.Results: We provide the first preclinical evidence that prolonged treatment with Taxotere causes a significant drop in mean whole tumor oxygenation.Furthermore, application of OE-eMSOT showed a diminished vascular response in Taxotere-treated tumors and revealed the presence of static blood pools, indicating increased vascular permeability.Conclusion: Our work has important translational implications and supports the feasibility of eMSOT imaging for non-invasive assessment of tumor microenvironmental responses to chemotherapy.
Green tea polyphenol enhances the anticancer activity of chemotherapeutic drug, cisplatin in CaSki cell line and a murine cervical cancer model
Authors: Sumi Bae, Byoung-Rai Lee, Sei-Jun Han, Insu Peter Lee, Joon Mo Lee, Sung Eun Namkoong, Byoung Don Han, Woong Shick Ahn
Journal: Cancer Research (2005)

5114  Objective: Green tea polyphenol (GTP) has been known to possess anti-cancer properties. In the present study, we assessed the utility of GTP along with cisplatin for enhances the antitumor activity against papillomavirus (HPV)-16 associated tumor cells, and TC-1 using an animal model. Methods: Human papillomavirus (HPV) 16-infected human cervical cancer cell line, CaSki was used. Cells were incubated with and without GTP (100ug/ml) and at different concentration of ciaplatin (0-12.5uM). Cell viability was determined using MTT assay after 2days. Animals were divided into three treatments and control group, with C57BL/6 mice (n=40) and inoculated with TC-1 cells. In the control group, mice received saline solution. In treatment Group I, mice were injected i.p. with 10mgkg-1 body weight of cisplatin. One day before the same dosage of cisplatin administration, 100mgkg-1 body weight of GTP was given to mice in group II. Mice in treatment Group III received GTP only. Mice were injected at four times for every week and monitored twice per week for tumor growth. Results: The viability of CaSki cells was decreased to 82.6, 73.6 and 64.83% at 3.125, 6.25 and 12.5uM concentration of cisplatin. However, in the co-culture with GTP (100ug/ml), the cell viability was more decreased to 52.9, 42.4 and 40.78%, respectively. In TC-1 tumor-bearing mice, the rates of tumor inhibition following treatment with GTP alone, cisplatin alone and combination of GTP and cisplatin were 93.88%, 71.72% and 62.94 %; 84.27%, 49.83% and 39.35 %; 88.38%, 44.58% and 34.14 % and 98.18%, 46.78% and 41.28% by tumor mean diameters in comparison to control mice on day 7, 14, 21 and 28, respectively. When combined with GTP, a significant reduction in growth of subcutaneous transplanted tumors more was observed without an increase in the cisplatin dosage. Conclusions: In vitro experiments showed the GTP has potentiating effect on cisplatin cytotoxicity. And the combination of GTP with cisplatin significantly reduced tumor growth in a murine cervical cancer model. These data promise the positive effects of the combination of GTP and cisplatin chemotherapy for cervical cancer.