tbuckley/cabot-search huggingface dataset:
circPTCH1 promotes invasion and metastasis in renal cell carcinoma via regulating miR-485-5p/MMP14 axis
Authors: Huan Liu, Guanghui Hu, Zaoyu Wang, Qunlong Liu, Jin Zhang, Yonghui Chen, Yiran Huang, Wei Xue, Yunfei Xu, Wei Zhai
Journal: Theranostics (2020)

Background: Circular RNAs (circRNAs) are a new class of non-coding RNAs (ncRNAs) that are derived from exons or introns by special selective shearing. circRNAs have been shown to play critical roles in various human cancers. However, their roles in renal cell carcinoma (RCC) and the underlying mechanisms remain largely unknown. Methods: A novel circRNA-circPTCH1, was identified from a microarray analysis of five paired RCC tissues. Then, we validated its expression and characterization through qRT-PCR, gel electrophoresis, RNase R digestion assays and Sanger sequencing. Functional experiments were performed to determine the effect of circPTCH1 on RCC progression both in vitro and in vivo. The interactions between circPTCH1 and miR-485-5p were clarified by RNA pull-down, luciferase reporter and RNA immunoprecipitation (RIP) assays. Results: We observed that circPTCH1 was up-regulated in RCC cell lines and tumor samples, and higher levels of circPTCH1 were significantly correlated with worse patient survival, advanced Fuhrman grade and greater risk of metastases. Elevated circPTCH1 expression led to increased migration and invasion of RCC cells both in vitro and in vivo whereas silencing circPTCH1 decreased migration and invasion and impeded the epithelial-mesenchymal transition (EMT) of RCC cells. Mechanistically, we elucidated that circPTCH1 could directly bind miR-485-5p and subsequently suppress expression of the target gene MMP14. Conclusion: circPTCH1 promotes RCC metastasis via the miR-485-5p/MMP14 axis and activation of the EMT process. Targeting circPTCH1 may represent a promising therapeutic strategy for metastatic RCC.
Out-of-Hospital Tranexamic Acid for Traumatic Brain Injury
Authors: David C. Cone, Daniel W. Spaite, Timothy J. Coats
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma
Authors: Seth M. Pollack, Mary W. Redman, Kelsey K. Baker, Michael J. Wagner, Brett A. Schroeder, Elizabeth T. Loggers, Kathryn Trieselmann, Vanessa C. Copeland, Shihong Zhang, Graeme Black, Sabrina McDonnell, Jeffrey Gregory, Rylee Johnson, Roxanne Moore, Robin L. Jones, Lee D. Cranmer
Journal: JAMA Oncology (2020)

<h3>Importance</h3> Anthracycline-based therapy is standard first-line treatment for most patients with advanced and metastatic sarcomas. Although multiple trials have attempted to show improved outcomes in patients with soft-tissue sarcoma over doxorubicin monotherapy, each has fallen short of demonstrating improved outcomes. <h3>Objective</h3> To evaluate the safety and efficacy of doxorubicin in combination with pembrolizumab in patients with advanced, anthracycline-naive sarcomas. <h3>Design, Setting, and Participants</h3> This nonrandomized clinical trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients were adults with good performance status and end-organ function. Patients with all sarcoma subtypes were allowed to enroll with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma. <h3>Interventions</h3> Two dose levels of doxorubicin (45 and 75 mg/m<sup>2</sup>) were tested for safety in combination with pembrolizumab. <h3>Main Outcomes and Measures</h3> Objective response rate (ORR) was the primary end point. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines. <h3>Results</h3> A total of 37 patients (22 men; 15 women) were treated in the combined phase 1/2 trial. The median (range) patient age was 58.4 (25-80) years. The most common histologic subtype was leiomyosarcoma (11 patients). Doxorubicin plus pembrolizumab was well tolerated without significant unexpected toxic effects. The ORR was 13% for phase 2 patients and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months. Median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses. Tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rank<i>P</i> = .03). No dose-limiting toxic effects were observed. <h3>Conclusions and Relevance</h3> In this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary end point for ORR was not reached, the PFS and OS observed compared favorably with prior published studies. Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02888665
Association of Clinician Health System Affiliation With Outpatient Performance Ratings in the Medicare Merit-based Incentive Payment System
Authors: Kenton J. Johnston, Timothy L. Wiemken, Jason M. Hockenberry, Jose F. Figueroa, Karen E. Joynt Maddox
Journal: JAMA (2020)

<h3>Importance</h3> Integration of physician practices into health systems composed of hospitals and multispecialty practices is increasing in the era of value-based payment. It is unknown how clinicians who affiliate with such health systems perform under the new mandatory Centers for Medicare &amp; Medicaid Services Merit-based Incentive Payment System (MIPS) relative to their peers. <h3>Objective</h3> To assess the relationship between the health system affiliations of clinicians and their performance scores and value-based reimbursement under the 2019 MIPS. <h3>Design, Setting, and Participants</h3> Publicly reported data on 636 552 clinicians working at outpatient clinics across the US were used to assess the association of the affiliation status of clinicians within the 609 health systems with their 2019 final MIPS performance score and value-based reimbursement (both based on clinician performance in 2017), adjusting for clinician, patient, and practice area characteristics. <h3>Exposures</h3> Health system affiliation vs no affiliation. <h3>Main Outcomes and Measures</h3> The primary outcome was final MIPS performance score (range, 0-100; higher scores intended to represent better performance). The secondary outcome was MIPS payment adjustment, including negative (penalty) payment adjustment, positive payment adjustment, and bonus payment adjustment. <h3>Results</h3> The final sample included 636 552 clinicians (41% female, 83% physicians, 50% in primary care, 17% in rural areas), including 48.6% who were affiliated with a health system. Compared with unaffiliated clinicians, system-affiliated clinicians were significantly more likely to be female (46% vs 37%), primary care physicians (36% vs 30%), and classified as safety net clinicians (12% vs 10%) and significantly less likely to be specialists (44% vs 55%) (<i>P</i> &lt; .001 for each). The mean final MIPS performance score for system-affiliated clinicians was 79.0 vs 60.3 for unaffiliated clinicians (absolute mean difference, 18.7 [95% CI, 18.5 to 18.8]). The percentage receiving a negative (penalty) payment adjustment was 2.8% for system-affiliated clinicians vs 13.7% for unaffiliated clinicians (absolute difference, −10.9% [95% CI, −11.0% to −10.7%]), 97.1% vs 82.6%, respectively, for those receiving a positive payment adjustment (absolute difference, 14.5% [95% CI, 14.3% to 14.6%]), and 73.9% vs 55.1% for those receiving a bonus payment adjustment (absolute difference, 18.9% [95% CI, 18.6% to 19.1%]). <h3>Conclusions and Relevance</h3> Clinician affiliation with a health system was associated with significantly better 2019 MIPS performance scores. Whether this represents differences in quality of care or other factors requires additional research.
Hepatitis C–Related Hepatocellular Carcinoma Incidence in the Veterans Health Administration After Introduction of Direct-Acting Antivirals
Authors: Lauren A. Beste, Pamela Green, Kristin Berry, Pamela Belperio, George N. Ioannou
Journal: JAMA (2020)

This study describes trends in the incidence of hepatocellular carcinoma within the Veterans Health Administration from 2002 to 2018 before and after widespread direct-acting anti–hepatitis C virus (HCV) treatment.
CD25-targeted antibody–drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity
Authors: Francesca Zammarchi, Karin Havenith, Francois Bertelli, Balakumar Vijayakrishnan, Simon Chivers, Patrick H van Berkel
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Regulatory T cells (T regs ) contribute to an immunosuppressive tumor microenvironment. They play an important role in the establishment and progression of tumors with high T regs infiltration and present a major obstacle to tumor eradication by immunotherapies. Numerous strategies have been attempted to deplete or block T regs , although their success has been limited. Methods A CD25-targeted, pyrrolobenzodiazepine (PBD) dimer-based antibody–drug conjugate (ADC) was investigated for its ability to deplete T regs and induce antitumor immunity. Antitumor activity of CD25-ADC either alone or in combination with an anti-programmed cell death protein 1 (PD-1) antibody was evaluated in CD25-negative syngeneic models that exhibit tumor infiltration of CD25-expressing T regs , and its pharmacodynamics and pharmacokinetics were assessed. Results Single low doses of CD25-ADC resulted in potent and durable antitumor activity in established syngeneic solid tumor models and the combination of a suboptimal dose was synergistic with PD-1 blockade. Tumor eradication by the CD25-targeted ADC was CD8+ T cell-dependent and CD25-ADC induced protective immunity. Importantly, while CD25-ADC mediated a significant and sustained intratumoral T regs depletion, accompanied by a concomitant increase in the number of activated and proliferating tumor-infiltrating CD8+ T effector cells, systemic T regs depletion was transient, alleviating concerns of potential autoimmune side effects. Conclusions This study shows that a PBD dimer-based, CD25-targeted ADC is able to deplete T regs and eradicate established tumors via antitumor immunity. This represents a novel approach to efficiently deplete T regs via a very potent DNA damaging toxin known to induce immunogenic cell death. Moreover, this study provides proof of concept for a completely new application of ADCs as immunotherapeutic agents, as the main mode of action relies on the ADC directly targeting immune cells, rather than tumor cells. These strong preclinical data warrant the clinical evaluation of camidanlumab tesirine (ADCT-301), a PBD-based ADC targeting human CD25, either alone or in combination with checkpoint inhibitors in solid tumors with known T regs infiltration. A phase I trial ( NCT03621982 ) of camidanlumab tesirine in patients with selected advanced solid tumors is ongoing.
First autochthonous dengue outbreak in Italy, August 2020
Authors: Luca Lazzarini, Luisa Barzon, Felice Foglia, Vinicio Manfrin, Monia Pacenti, Giacomina Pavan, Mario Rassu, Gioia Capelli, Fabrizio Montarsi, Simone Martini, Francesca Zanella, Maria Teresa Padovan, Francesca Russo, Federico Gobbi
Journal: Eurosurveillance (2020)

In August 2020, during the coronavirus disease (COVID-19) pandemic, five locally acquired cases of dengue virus type 1 were detected in a family cluster in Vicenza Province, North-East Italy where Aedes albopictus mosquitoes are endemic. The primary case was an importation from West Sumatra, Indonesia. This is the first outbreak of autochthonous dengue reported in Italy. During the COVID-19 pandemic, screening of febrile travelers from endemic countries is crucial in areas where competent vectors are present.
RFWD2 induces cellular proliferation and selective proteasome inhibitor resistance by mediating P27 ubiquitination in multiple myeloma
Authors: Chunyan Gu, Ting Lu, Wang Wang, Miaomiao Shao, Rongfang Wei, Mengjie Guo, Rui Li, Li Qiao, Ye Hu, Fenghuang Zhan, Anja Seckinger, Dirk Hose, Ye Yang
Journal: Leukemia (2020)
Should We Simplify Computed Tomography Angiography Reporting as Black or White vs Describing All Shades of Gray?
Authors: Sabin Parajuli, Pedro De Araujo Gonçalves, Hector M. Garcia-Garcia
Journal: JAMA Cardiology (2020)

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ALICE: a hybrid AI paradigm with enhanced connectivity and cybersecurity for a serendipitous encounter with circulating hybrid cells
Authors: Kok Suen Cheng, Rongbin Pan, Huaping Pan, Binglin Li, Stephene Shadrack Meena, Huan Xing, Ying Jing Ng, Kaili Qin, Xuan Liao, Benson Kiprono Kosgei, Zhipeng Wang, Ray P.S. Han
Journal: Theranostics (2020)

A fully automated and accurate assay of rare cell phenotypes in densely-packed fluorescently-labeled liquid biopsy images remains elusive. Methods: Employing a hybrid artificial intelligence (AI) paradigm that combines traditional rule-based morphological manipulations with modern statistical machine learning, we deployed a next generation software, ALICE (Automated Liquid Biopsy Cell Enumerator) to identify and enumerate minute amounts of tumor cell phenotypes bestrewed in massive populations of leukocytes. As a code designed for futurity, ALICE is armed with internet of things (IOT) connectivity to promote pedagogy and continuing education and also, an advanced cybersecurity system to safeguard against digital attacks from malicious data tampering. Results: By combining robust principal component analysis, random forest classifier and cubic support vector machine, ALICE was able to detect synthetic, anomalous and tampered input images with an average recall and precision of 0.840 and 0.752, respectively. In terms of phenotyping enumeration, ALICE was able to enumerate various circulating tumor cell (CTC) phenotypes with a reliability ranging from 0.725 (substantial agreement) to 0.961 (almost perfect) as compared to human analysts. Further, two subpopulations of circulating hybrid cells (CHCs) were serendipitously discovered and labeled as CHC-1 (DAPI+/CD45+/E-cadherin+/vimentin-) and CHC-2 (DAPI+ /CD45+/E-cadherin+/vimentin+) in the peripheral blood of pancreatic cancer patients. CHC-1 was found to correlate with nodal staging and was able to classify lymph node metastasis with a sensitivity of 0.615 (95% CI: 0.374-0.898) and specificity of 1.000 (95% CI: 1.000-1.000). Conclusion: This study presented a machine-learning-augmented rule-based hybrid AI algorithm with enhanced cybersecurity and connectivity for the automatic and flexibly-adapting enumeration of cellular liquid biopsies. ALICE has the potential to be used in a clinical setting for an accurate and reliable enumeration of CTC phenotypes.
“Tricks and tips for home mechanical ventilation” Home mechanical ventilation: set-up and monitoring protocols
Authors: M.L. Duiverman
Journal: Pulmonology (2020)

In this part of the review series "Tricks and tips for home mechanical ventilation", we will discuss the evidence with regard to the place and manner of home mechanical ventilation initiation and follow-up. Outsourcing more and more of this chronic care to the home situation is a big challenge for the future: especially for the home situation, monitoring has to be non-invasive, reliable and easy to use, data security needs to be ensured, signals need to be integrated and preferably automatically processed and algorithms need to be developed based on clinically relevant outcomes.
BRAF inhibitor resistance of melanoma cells triggers increased susceptibility to natural killer cell-mediated lysis
Authors: Alexandra Frazao, Louise Rethacker, Géraldine Jeudy, Marina Colombo, Eric Pasmant, Marie-Françoise Avril, Antoine Toubert, Helene Moins-Teisserenc, Marie Roelens, Sophie Dalac, Eve Maubec, Anne Caignard
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Targeted therapies and immunotherapies are first-line treatments for patients with advanced melanoma. Serine–threonine protein kinase B-RAF (BRAF) and mitogen-activated protein kinase (MEK) inhibition leads to a 70% response rate in patients with advanced melanoma with a BRAF V600E / K mutation. However, acquired resistance occurs in the majority of patients, leading to relapse. Immunotherapies that activate immune cytotoxic effectors induce long-lasting responses in 30% of patients. In that context, combination of targeted therapies with immunotherapy (IT) is a promising approach. We considered boosting natural killer (NK) cell tumor immunosurveillance, as melanoma cells express stress-induced molecules and activate NK cell lysis. Methods Here we have generated vemurafenib (a BRAF inihibitor)-resistant (R) cells from BRAF V600E SK28 and M14-sensitive (S) melanoma cell lines and investigated how resistance interferes with immunogenicity to NK cells. We determined the levels of several soluble molecules including NK ligands in 61 melanoma patients at baseline and 6 months M post-treatment with targeted therapies or immunotherapies. Results Vemurafenib resistance involved activation of p-AKT in SK28R and of p-MEK/p-ERK in M14R cells and was accompanied by modulation of NK ligands. Compared with S cells, SK28R displayed an increased expression of natural killer group 2 D (NKG2D) receptor ligands (major histocompatibility complex class (MHC) I chain-related protein A (MICA) and UL16-binding protein 2 (ULBP2)) whereas M14R exhibited decreased ULBP2 . SK28R and M14R cells induced higher NK degranulation and interferon gamma secretion and were more efficiently lysed by donor and patient NK cells. SK28R showed increased tumor necrosis factor-related apoptosis-inducing ligand receptor II (TRAIL-RII) expression and TRAIL-induced apoptosis, and TRAIL-induced apoptosis of M14R was decreased. Combined BRAF/MEK inhibitors abrogated the growth of SK28S, M14S, and M14R cells, while growth of SK28R was maintained. BRAF/MEK inhibition attenuated NK activity but R cell lines activated polyfunctional NK cells and were lysed with high efficiency. We investigated the relationship of soluble NK ligands and response to treatment in a series of melanoma patients. Soluble NKG2D ligands known to regulate the receptor function have been associated to cancer progression. Serum analysis of patients treated with target therapies or IT indicates that soluble forms of NK ligands (MICA, B7H6, programmed cell death ligand 1, and carcinoembryonic antigen cell adhesion molecule 1) may correlate with clinical response. Conclusion These results support strategies combining targeted therapies and NK-based immunotherapies.
Dance for Respiratory Patients in Low-Resource Settings
Authors: Keir E. J. Philip, Winceslaus Katagira, Rupert Jones
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
5-Fluorouracil Enhances the Antitumor Activity of the Glutaminase Inhibitor CB-839 against <i>PIK3CA</i>-Mutant Colorectal Cancers
Authors: Yiqing Zhao, Xiujing Feng, Yicheng Chen, J. Eva Selfridge, Shashank Gorityala, Zhanwen Du, Janet M. Wang, Yujun Hao, Gino Cioffi, Ronald A. Conlon, Jill S. Barnholtz-Sloan, Joel Saltzman, Smitha S. Krishnamurthi, Shaveta Vinayak, Martina Veigl, Yan Xu, David L. Bajor, Sanford D. Markowitz, Neal J. Meropol, Jennifer R. Eads, Zhenghe Wang
Journal: Cancer Research (2020)

Abstract PIK3CA encodes the p110α catalytic subunit of PI3K and is frequently mutated in human cancers, including ∼30% of colorectal cancer. Oncogenic mutations in PIK3CA render colorectal cancers more dependent on glutamine. Here we report that the glutaminase inhibitor CB-839 preferentially inhibits xenograft growth of PIK3CA-mutant, but not wild-type (WT), colorectal cancers. Moreover, the combination of CB-839 and 5-fluorouracil (5-FU) induces PIK3CA-mutant tumor regression in xenograft models. CB-839 treatment increased reactive oxygen species and caused nuclear translocation of Nrf2, which in turn upregulated mRNA expression of uridine phosphorylase 1 (UPP1). UPP1 facilitated the conversion of 5-FU to its active compound, thereby enhancing the inhibition of thymidylate synthase. Consistently, knockout of UPP1 abrogated the tumor inhibitory effect of combined CB-839 and 5-FU administration. A phase I clinical trial showed that the combination of CB-839 and capecitabine, a prodrug of 5-FU, was well tolerated at biologically-active doses. Although not designed to test efficacy, an exploratory analysis of the phase I data showed a trend that PIK3CA-mutant patients with colorectal cancer might derive greater benefit from this treatment strategy as compared with PIK3CA WT patients with colorectal cancer. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant colorectal cancers and warrants further clinical evaluation. Significance: Preclinical and clinical trial data suggest that the combination of CB-839 with capecitabine could serve as an effective treatment for PIK3CA-mutant colorectal cancers.