tbuckley/cabot-search huggingface dataset:
Anticancer Immunotherapy by MFAP5 Blockade Inhibits Fibrosis and Enhances Chemosensitivity in Ovarian and Pancreatic Cancer
Authors: Tsz-Lun Yeung, Cecilia S. Leung, Kay-Pong Yip, Jianting Sheng, Long Vien, Laura C. Bover, Michael J. Birrer, Stephen T.C. Wong, Samuel C. Mok
Journal: Clinical Cancer Research (2019)

Recent studies demonstrate the role of the tumor microenvironment in tumor progression. However, strategies used to overcome the malignant phenotypes of cancer cells modulated by the microenvironment have not been thoroughly explored. In this study, we evaluated the therapeutic efficacy of a newly developed mAb targeting microfibril-associated protein 5 (MFAP5), which is secreted predominately by cancer-associated fibroblast (CAF), in ovarian and pancreatic cancer models.Experimental Design: MAbs were developed using human MFAP5 recombinant protein as an antigen in mice, and antibodies from hybridoma clones were evaluated for their specificity to human and murine MFAP5. An Octet RED384 system was used to determine the kinetics of binding affinity and the specificity of the antibody clones, which were followed by epitope mapping and functional characterization by in vitro assays. The therapeutic efficacy of a lead anti-MFAP5 antibody clone 130A in tumor suppression was evaluated by ovarian tumor- and pancreatic tumor-bearing mouse models.Three hybridoma clones, which produced antibodies with high affinity and specificity to MFAP5, were selected for functional studies. Antibody clone 130A, which recognizes a common epitope shared between human and murine MFAP5 protein, was further selected for in vivo studies. Results showed that clone 130A downregulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models.These data suggest that MFAP5 blockade using an immunologic approach inhibits fibrosis, induces tumor vessel normalization, and enhances chemosensitivity in ovarian and pancreatic cancer, and can be used as a novel therapeutic agent.
Febrile neutropenia in hematologic malignancies: Validation of a model to select patients manageable in the outpatient setting safely.
Authors: Sarina Bains, Andre Goy, Barry Fuchs, Gabriella Gadaleta, Arun Singavi, Brenda Hurtubise, Rani Sebti, Tatyana Feldman, Stuart Goldberg, Andrew Pecora, Anthony R. Mato
Journal: Journal of Clinical Oncology (2012)

e19641 Background: Febrile neutropenia (FN) is usually treated in an inpatient setting with empiric IV antibiotics. Accurate identification of low-risk hematologic malignancy (HM) pts (highest risk for life-threatening events) appropriate for outpatient management may reduce healthcare costs without impacting outcomes adversely. Prior studies using predictive models to identify low risk FN pts have not been validated in HM pts. Aim: To identify low risk HM pts as candidates for safe outpatient management. Methods: To determine parameters associated with an uncomplicated FN course in HM pts we tested the association between Talcott’s criteria (Talcott et al JCO Oct 2011) and additional candidate risk factors with the development of a medical event (ME) requiring urgent intervention. We conducted a retrospective cohort study of stable HM pts, admitted for FN management. Utilizing Cox regression, we examined the following factors: Talcott criteria, age, insurance status, prophylactic G-CSF/antibiotics, vitals signs and organ function. Results: We identified 97 consecutively admitted pts who met eligibility criteria of whom 27 pts developed a ME during the admission (validated by 2 investigators blinded to exposure status). In univariate analysis, Talcott’s criteria successfully identified pts at low risk for developing a ME (HR .4, p=.04 CI .17-.97). Additionally a preserved DPB (&gt;65 mmHg) was also protective (HR .22 p&lt;.01 CI .11-.51). Talcott’s criteria and DBP remained independent predictors of uncomplicated FN in a multivariate cox regression (AUROC curve=75%). Conclusions: This study provides support for the use of Talcott’s criteria in HM pts. The addition of DBP to Talcott’s model further improves its ability to identify low risk HM pts. Once prospectively validated, this approach may have important clinical and financial implications. [Table: see text]
Autistics appear different, but also are different, and this should be valued
Authors: Michelle Dawson, Tyler Cowen
Journal: Behavioral and Brain Sciences (2019)

Abstract We agree that autistics’ unusual overt behaviors don't necessarily mean reduced social motivation. But Jaswal &amp; Akhtar maintain that, while autistics may appear socially uninterested, their social interest is in fact typical and indeed must be to avoid multiple poor outcomes. This problematic idealization of social typicality deflects attention from important differences in autistic cognition and interests, which should be valued.
Cdk5 knocking out mediated by CRISPR-Cas9 genome editing for PD-L1 attenuation and enhanced antitumor immunity
Authors: Huan Deng, Songwei Tan, Xueqin Gao, Chenming Zou, Chenfeng Xu, Kun Tu, Qingle Song, Fengjuan Fan, Wei Huang, Zhiping Zhang
Journal: Acta Pharmaceutica Sinica B (2019)

Blocking the programmed death-ligand 1 (PD-L1) on tumor cells with monoclonal antibody therapy has emerged as powerful weapon in cancer immunotherapy. However, only a minority of patients presented immune responses in clinical trials. To develop an alternative treatment method based on immune checkpoint blockade, we designed a novel and efficient CRISPR-Cas9 genome editing system delivered by cationic copolymer aPBAE to downregulate PD-L1 expression on tumor cells via specifically knocking out Cyclin-dependent kinase 5 (Cdk5) gene in vivo. The expression of PD-L1 on tumor cells was significantly attenuated by knocking out Cdk5, leading to effective tumor growth inhibition in murine melanoma and lung metastasis suppression in triple-negative breast cancer. Importantly, we demonstrated that aPBAE/Cas9-Cdk5 treatment elicited strong T cell-mediated immune responses in tumor microenvironment that the population of CD8+ T cells was significantly increased while regulatory T cells (Tregs) was decreased. It may be the first case to exhibit direct in vivo PD-L1 downregulation via CRISPR-Cas9 genome editing technology for cancer therapy. It will provide promising strategy for preclinical antitumor treatment through the combination of nanotechnology and genome engineering.
SPIO-enhanced MR imaging at 3T for the detection of metastases in sentinel nodes in patients with breast cancer.
Authors: Kazuyoshi Motomura, Hiroyo Takahashi, Takahiro Nakayama, Yasuhiro Tamaki, Katsuyuki Nakanishi
Journal: Journal of Clinical Oncology (2013)

1107 Background: We previously demonstrated the usefulness of SPIO-enhanced MR imaging at 1.5T for the detection of metastases in sentinel nodes localized by computed tomography lymphography (CT-LG) in patients with breast cancer (Ann Surg Oncol 2011, ASCO 2012). The aim of this study was to evaluate the accuracy of MR imaging at 3T with SPIO enhancement for the detection of metastases in sentinel nodes. Methods: This study included 60 patients with breast cancer and clinically negative nodes. Sentinel nodes identified by CT-LG were evaluated prospectively using SPIO-enhanced MR imaging at 3T. A node was considered non-metastatic if it showed a homogenous low signal intensity and metastatic if the entire node or a focal area did not show a low signal intensity on MR imaging. Sentinel nodes located by CT-LG were removed, and imaging results and histopathological findings were compared. Results: The mean patient age was 54.2 years (range, 33-78). Sentinel nodes were identified by CT-LG successfully in 59 (98.3%) of 60 patients. The mean number of sentinel nodes identified by CT-LG was 1.43 (range, 1-3). All 16 patients with positive sentinel nodes definitively diagnosed by pathology demonstrated metastases on SPIO-enhanced MR imaging. Five (31.3%) of them had micrometastases. Forty-one of 43 patients with negative sentinel nodes definitively diagnosed by pathology were non-metastatic on imaging studies. The sensitivity, specificity and accuracy of MR imaging for the diagnosis of sentinel node metastases were 100%, 95.3%, and 96.6%, respectively. No adverse events were associated with either CT or MR imaging. Conclusions: SPIO-enhanced MR imaging at 3T is useful for accurate diagnosis of sentinel node metastases, and therefore sentinel node biopsy may be avoided for most patients with breast cancer.
High-throughput peptide-MHC complex generation and kinetic screenings of TCRs with peptide-receptive HLA-A*02:01 molecules
Authors: Andreas Moritz, Raghavendra Anjanappa, Claudia Wagner, Sebastian Bunk, Martin Hofmann, Gabriele Pszolla, Ankur Saikia, Maria Garcia-Alai, Rob Meijers, Hans-Georg Rammensee, Sebastian Springer, Dominik Maurer
Journal: Science Immunology (2019)

Functionally empty and peptide-receptive soluble HLA-A*02:01 enables high-throughput analysis of TCR binding to peptide-MHCs. See the related Research Article by Saini et al . in this issue.
Prognostic impact of short‐term changes of E/E' ratio and left atrial size in dilated cardiomyopathy
Authors: Marco Merlo, Davide Stolfo, Marco Gobbo, Giacomo Gabassi, Giulia Barbati, Paola Naso, Gabriele Secoli, Andrea Boscutti, Federica Ramani, Marta Gigli, Bruno Pinamonti, Gianfranco Sinagra
Journal: European Journal of Heart Failure (2019)
Cognitive–behavioural therapy for IBS comes home: mapping a route for efficacy and efficiency in the digital age
Authors: Jeffrey M Lackner, James Jaccard
Journal: Gut (2019)

On any given day, a gastroenterologist will enter a consulting room and have a 25% chance of seeing a patient presented with IBS symptoms. She/he will describe abdominal pain, diarrhoea and/or constipation as severe, disruptive and a significant source of angst. Their exact cause will be as perplexing as the uncertainty that whatever treatment is prescribed will provide much relief.

This much will be clear: One of the only treatments with the strongest empirical support for the full range of IBS symptoms—cognitive–behavioural therapy (CBT)—will be unavailable unless the gastroenterologist happens to work in close proximity to one of the relatively few academic medical centres that dispense CBT. This state of affairs has led to the development of CBT regimens that retain the efficacy of ‘gold standard’ clinic-based CBT delivered one-to-one but are more efficient and easier to implement.

An early approach addressed this issue by dramatically reducing therapist time, featuring a largely home-based version of CBT.1 Other teams emphasised digital technology (eg, internet) to deliver CBT.2 This issue of Gut describes the most recent effort to tackle this problem: the Assessing Cognitive Behavioural Therapy in Irritable Bowel Syndrome (ACTIB).3 The trial has many strengths, chief of which is it is the largest CBT for IBS trial conducted to date. The two CBT treatments (web -based, telephone delivered) were superior to treatment as usual (TAU) at both post-treatment and 12-month follow-up. Like the recently completed National Institutes of Health-funded IBS Outcome Study4 (IBSOS) that pitted home-based CBT against face-to-face CBT, both CBT arms were associated with substantial reductions in scores on the Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS). Unlike the IBSOS, ACTIB leaves unanswered the most pressing and practical question of whether higher intensity CBT (8 hours of clinician time) was equivalent to the lower intensity (2 hours) version. …
W-doped TiO<sub>2</sub> nanoparticles with strong absorption in the NIR-II window for photoacoustic/CT dual-modal imaging and synergistic thermoradiotherapy of tumors
Authors: Ke Gao, Wenzhi Tu, Xujiang Yu, Farooq Ahmad, Xiannan Zhang, Weijie Wu, Xiao An, Xiaoyuan Chen, Wanwan Li
Journal: Theranostics (2019)

Multifunctional nanomaterials that have integrated diagnostic and therapeutic functions and low toxicity, and can enhance treatment efficacy through combination therapy have drawn tremendous amounts of attention.Herein, a newly developed multifunctional theranostic agent is reported, which is PEGylated W-doped TiO 2 (WTO) nanoparticles (NPs) synthesized via a facile organic route, and the results demonstrated strong absorbance of these WTO NPs in the second near-infrared (NIR-II) window due to successful doping with W. These PEGylated WTO NPs can absorb both NIR-II laser and ionizing radiation, rendering them well suited for dual-modal computed tomography/NIR-II photoacoustic imaging and synergistic NIR-II photothermal/radiotherapy of tumors.In addition, the long-term in vivo studies indicated that these PEGylated WTO NPs had no obvious toxicity on mice in vivo, and they can be cleared after a 30-day period.In summary, this multifunctional theranostic agent can absorb both NIR-II laser and ionizing radiation with negligible toxicity and rapid clearance, therefore it has great promise for applications in imaging and therapeutics in biomedicine.
Glucocorticoids in elite sport: current status, controversies and innovative management strategies—a narrative review
Authors: Alan Vernec, Andrew Slack, Peter Rex Harcourt, Richard Budgett, Martine Duclos, Audrey Kinahan, Katja Mjøsund, Christian J Strasburger
Journal: British Journal of Sports Medicine (2019)

The use of systemic glucocorticoids (GCs), as well as local injections, continues to be a controversial issue in the sport/anti-doping community. There is widespread and legitimate use of GCs for numerous health conditions, yet there are concerns about side effects and the possibility of enhanced athletic performance in limited settings. This is compounded by the uncertainty regarding the prevalence of GC use, mechanisms underlying physiological effects and complex pharmacokinetics of different formulations. While WADA continues to promote research in this complex area, some international sporting federations, major event organisers and professional sports leagues have introduced innovative rules such as needle policies, mandatory rest periods and precompetition guidelines to promote judicious use of GCs, focusing on athlete health and supervision of medical personnel. These complementary sport-specific rules are helping to ensure the appropriate use of GCs in athletes where overuse is a particular concern. Where systemic GCs are medically necessary, Therapeutic Use Exemptions (TUEs) may be granted after careful evaluation by TUE Committees based on specific and strict criteria. Continued vigilance and cooperation between physicians, scientists and anti-doping organisations is essential to ensure that GC use in sport respects not only principles of fairness and adherence to the rules but also promotes athlete health and well-being. The purpose of this narrative review is to summarise the use and management of GCs in sport illustrating several innovative programmes by sport leagues and federations.
Allele-Specific Silencing Ameliorates Restrictive Cardiomyopathy Attributable to a Human Myosin Regulatory Light Chain Mutation
Authors: Kathia Zaleta-Rivera, Alexandra Dainis, Alexandre J.S. Ribeiro, Pablo Cordero, Gabriel Rubio, Ching Shang, Jing Liu, Thomas Finsterbach, Victoria N. Parikh, Shirley Sutton, Kinya Seo, Nikita Sinha, Nikhil Jain, Yong Huang, Roger J. Hajjar, Mark A. Kay, Danuta Szczesna-Cordary, Beth L. Pruitt, Matthew T. Wheeler, Euan A. Ashley
Journal: Circulation (2019)

Background: Restrictive cardiomyopathy is a rare heart disease associated with mutations in sarcomeric genes and with phenotypic overlap with hypertrophic cardiomyopathy. There is no approved therapy directed at the underlying cause. Here, we explore the potential of an interfering RNA (RNAi) therapeutic for a human sarcomeric mutation in MYL2 causative of restrictive cardiomyopathy in a mouse model. Methods: A short hairpin RNA (M7.8L) was selected from a pool for specificity and efficacy. Two groups of myosin regulatory light chain N47K transgenic mice were injected with M7.8L packaged in adeno-associated virus 9 at 3 days of age and 60 days of age. Mice were subjected to treadmill exercise and echocardiography after treatment to determine maximal oxygen uptake and left ventricular mass. At the end of treatment, heart, lung, liver, and kidney tissue was harvested to determine viral tropism and for transcriptomic and proteomic analysis. Cardiomyocytes were isolated for single-cell studies. Results: A one-time injection of AAV9-M7.8L RNAi in 3-day-old humanized regulatory light chain mutant transgenic mice silenced the mutated allele (RLC-47K) with minimal effects on the normal allele (RLC-47N) assayed at 16 weeks postinjection. AAV9-M7.8L RNAi suppressed the expression of hypertrophic biomarkers, reduced heart weight, and attenuated a pathological increase in left ventricular mass. Single adult cardiac myocytes from mice treated with AAV9-M7.8L showed partial restoration of contraction, relaxation, and calcium kinetics. In addition, cardiac stress protein biomarkers, such as calmodulin-dependent protein kinase II and the transcription activator Brg1 were reduced, suggesting recovery toward a healthy myocardium. Transcriptome analyses further revealed no significant changes of argonaute ( AGO1 , AGO2 ) and endoribonuclease dicer ( DICER1 ) transcripts, and endogenous microRNAs were preserved, suggesting that the RNAi pathway was not saturated. Conclusions: Our results show the feasibility, efficacy, and safety of RNAi therapeutics directed towards human restrictive cardiomyopathy. This is a promising step toward targeted therapy for a prevalent human disease.
Effect of combination of systemic therapy and local therapy with cryoablation on outcome in metastatic renal cell cancer (mRCC): An extended follow-up report.
Authors: Hema M. Vankayala, Peter Litrup, Lance K. Heilbrun, Brenda Dickow, Hyun J Bang, Daryn W. Smith, Barbara Adam, Ulka N. Vaishampayan
Journal: Journal of Clinical Oncology (2012)

e15081 Background: Resection of metastasis in renal cancer (mRCC) yields 5-year survival rates of 20% to 30%. Yet most patients (pts) poor surgical candidates or have unresectable disease. Percutaneous cryoablation is a minimally invasive procedure employed for local therapy of metastatic foci, but its role in inducing long term remissions in combination with systemic therapy is unknown. Methods: Following IRB approval and HIPAA compliance, a retrospective review of records for pts receiving cryotherapy and systemic targeted therapy from 2004-2007 at Karmanos Cancer Institute was performed to enable a minimum follow up of 3 years. OS was estimated using the Kaplan-Meier methodology. Results: Of the 27 patients identified 85% were male, 88% Caucasian, and 77% had clear cell histology. 2 pts had sarcomatoid mRCC. All patients had prior nephrectomy. 24 patients had multiple metastatic sites: 9 with 2 sites, 8 with 3 sites and 7 with ≥ 4 sites. 15%, 52%, 11%, and 22% had favorable, intermediate, poor, and indeterminate MSKCC risk score, respectively. Systemic therapy was interrupted for at least 1 week prior to and after cryotherapy and resumed after complete healing. One major complication of nerve paresis was noted from lumbar paravertebral mass cryotherapy. Median number of ablations was 2 (range 1-4). Of the 60 total ablations 13%, 28%, 27%, 17%, and 15% were renal bed, visceral, soft tissue, bone, and lymph nodes respectively. The median OS from diagnosis of metastatic disease was 49.6 months (95% confidence interval: 21.2- 54.9 months).The 2 yr OS rate is 90% (95% CI: 78-100%) and 5 yr OS rate is 68% (49-87%). 8 patients (30%) are alive to date. Conclusions: The strategy of combining systemic therapy and local control of metastasis with cryoablation had favorable impact on OS in mRCC even after longer follow up. Cryoabalation is a minimally invasive, well tolerated technique, applicable to the majority of mRCC patients. Prospective investigation or case-control studies to evaluate the incorporation of cryoabalation with targeted systemic therapy in advanced RCC is warranted.
Genomic Characteristics Clinical Phenotype and Disease Course of TP53 Mutated Diffuse Large B Cell Lymphoma at Diagnosis and Relapse
Authors: Erel Joffe, Connie L. Batlevi, Andrew M Intlekofer, Andrew D. Zelenetz, Craig H. Moskowitz, Maria L. Palomba, Ariela Noy, David J. Straus, Carol S. Portlock, John Gerecitano, Steven M. Horwitz, Alison J. Moskowitz, Paul A. Hamlin, Matthew J. Matasar, Anita Kumar, Jie He, Vincent A Miller, Franck Rapaport, Elli Papaemmanuil, Ahmet Dogan, Anas Younes
Journal: Blood (2017)
Insulin analogues to stimulate cell growth in human cancer initiating cells (CICs).
Authors: Esther Holgado, Maria Cortes Semperes, Olga Pernia, Olatz Arrizabalaga, Inmaculada Ibañez de Cáceres, Ricardo Hitt, Javier De Castro, Angel Ayuso Sacido, Rosario Perona, Cristobal Belda-Iniesta
Journal: Journal of Clinical Oncology (2013)

1575 Background: Conflicting epidemiologic studies have suggested insulin and their analogues currently used in the management of type 2 diabetes to be involved in tumor progression and development. Surprisingly, time of exposure to insulin analogs reported in those retrospective studies is too short for be a carcinogen. We hypothesized that differential affinity that insulin analogs display for insulin receptor and IGF-1R at CICs may account for this possibility. [AspB10]insulin (X10) is a long-acting insulin analog that displays greater affinity for IGF1R than either the long-acting insulin analog GLA or human insulin (HI) in vitro. X10 is tumorigenic in animal models whereas GLA is not. GLA is rapidly metabolized to the metabolites, M1 and M2 that exhibit metabolic and mitogenic profiles similar to that of HI in vitro. CICs are cancer cells with self-renewing, stem cell-like properties with the ability to proliferate and differentiate into specific cells found in tumor types and thus they are able to maintain tumor bulk. Many cancers are thought to be initiated by CICs, and there is evidence that they cause cancer recurrence, metastatic progression and resistance to therapies. Our aim was to compare the mitogenic activity of HI, GLA, X10, M1 and M2 on human CICs in vitro. Methods: CICs derived from 10 human cell lines including glioma, lung, breast, colon, and prostatic cancers were isolated and grown in defined growth medium (no serum) with either HI, GLA, X10, M1 or M2. Growth was estimated using the MTS colorimetric assay. Results: HI, GLA and X10 stimulated CIC growth to a similar extend, whereas M1 and M2 had growth promoting activity similar to medium without HI. Similar results were obtained when measuring diametric sphere growth. Additionally, AKT phosphorylation levels were increased 2-fold after stimulation with HI, GLA or X10, whereas stimulation with M1 or M2 did not produce a significant increase. Conclusions: This is the first study that has explored the biology of CICs treated with insulin analogs. The data show that GLA displays a mitogenic profile comparable to that of human insulin for all CIC lines tested, whereas M1, has even less growth promoting activity.