tbuckley/cabot-search huggingface dataset:
Vascular Dysfunction of COVID-19 Is Partially Reverted in the Long-Term
Authors: Luca Zanoli, Agostino Gaudio, Dimitri P. Mikhailidis, Niki Katsiki, Niccolò Castellino, Lorenzo Lo Cicero, Giulio Geraci, Concetto Sessa, Letizia Fiorito, Francesca Marino, Maria Antonietta Di Rosolini, Michele Colaci, Antonio Longo, Arturo Montineri, Lorenzo Malatino, Pietro Castellino, Paola Aparo, Andrea Arena, Martina Barchitta, Federica Castelletti, Martina Di Noto, Antonino Di Pino, Ornella Giarrusso, Ivan Isaia, Paolo Lentini, Paola Magnano San Lio, Rosa Manuele, Elisa Marino, Walter Morale, Alice Sciuto, Salvatore Sebastiano Scuto, Anastasia Xourafa, Sabrina Zocco
Journal: Circulation Research (2022)

Background: COVID-19 is characterized by severe inflammation during the acute phase and increased aortic stiffness in the early postacute phase. In other models, aortic stiffness is improved after the reduction of inflammation. We aimed to evaluate the mid- and long-term effects of COVID-19 on vascular and cardiac autonomic function. The primary outcome was aortic pulse wave velocity (aPWV). Methods: The cross-sectional Study-1 included 90 individuals with a history of COVID-19 and 180 matched controls. The longitudinal Study-2 included 41 patients with COVID-19 randomly selected from Study-1 who were followed-up for 27 weeks. Results: Study-1: Compared with controls, patients with COVID-19 had higher aPWV and brachial PWV 12 to 24 (but not 25–48) weeks after COVID-19 onset, and they had higher carotid Young’s elastic modulus and lower distensibility 12 to 48 weeks after COVID-19 onset. In partial least squares structural equation modeling, the higher the hs-CRP (high-sensitivity C-reactive protein) at hospitalization was, the higher the aPWV 12 to 48 weeks from COVID-19 onset (path coefficient: 0.184; P =0.04). Moreover, aPWV (path coefficient: −0.186; P =0.003) decreased with time. Study-2: mean blood pressure and carotid intima-media thickness were comparable at the end of follow-up, whereas aPWV (−9%; P =0.01), incremental Young’s elastic modulus (−17%; P =0.03), baroreflex sensitivity (+28%; P =0.049), heart rate variability triangular index (+15%; P =0.01), and subendocardial viability ratio (+12%; P =0.01×10 −4 ) were significantly improved. There was a trend toward improvement in brachial PWV (−6%; P =0.14) and carotid distensibility (+18%; P =0.05). Finally, at the end of follow-up (48 weeks after the onset of COVID-19) aPWV (+6%; P =0.04) remained significantly higher in patients with COVID-19 than in control subjects. Conclusions: COVID-19-related arterial stiffening involves several arterial tree portions and is partially resolved in the long-term.
Stronger efforts are needed to safeguard the nutrition of school aged children
Authors: Maria Nilsson, Cecilia Emilsson, Annie Jonsson, Göran Tomson, Sebastiaan Meijer, Leif Östman, Ulf Magnusson
Journal: BMJ (2022)

Undernutrition is an increasingly critical and urgent challenge facing school aged children, particularly in resource poor settings, as a result of climate change, say Maria Nilsson and colleagues.
Uncommon Metastases From Occult Breast Cancer Revealed by 18F-FDG and 68Ga-FAPI PET/CT
Authors: Weizhi Xu, Tinghua Meng, Qihang Shang, Yizhen Pang, Haojun Chen
Journal: Clinical Nuclear Medicine (2022)

Metastases to gastrointestinal tract from breast cancer are very rare and can be diagnostically challenging. In this case, we reported 18 F-FDG and 68 Ga-FAPI PET/CT findings in a 54-year-old women with such uncommon metastases from breast cancer. Although the primary tumor of breast cancer remained radiologically occult, 68 Ga-FAPI PET/CT showed a far better tumor-to-background ratio than 18 F-FDG PET/CT for detecting the metastatic lesions, especially for detecting the retroperitoneal lymph node and rectal metastases.
ENDOVASCULAR TREATMENT AND OUTCOMES FOR FEMOROPOPLITEAL IN-STENT RESTENOSIS: INSIGHTS FROM THE XLPAD REGISTRY
Authors: Michael Vu, Glaiza-Mae Sande-Docor, Cheryl Chamathil, Yu-Lun Liu, Shirling Tsai, Mitul P. Patel, Peter Philip Monteleone, Mohamad Alaiti, Christopher Metzger, Emmanouil S. Brilakis, Mehdi H. Shishehbor, Subhash Banerjee
Journal: Journal of the American College of Cardiology (2022)
Tislelizumab for Relapsed/Refractory Classical Hodgkin Lymphoma: 3-Year Follow-up and Correlative Biomarker Analysis
Authors: Yuqin Song, Quanli Gao, Huilai Zhang, Lei Fan, Jianfeng Zhou, Dehui Zou, Wei Li, Haiyan Yang, Ting Liu, Quanshun Wang, Fangfang Lv, Haiyi Guo, Xia Zhao, Dan Wang, Pei Zhang, Yidi Wang, Lei Wang, Tengfei Liu, Yun Zhang, Zhirong Shen, Jane Huang, Jun Zhu
Journal: Clinical Cancer Research (2021)

Tislelizumab is an anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibody specifically designed to minimize binding to Fcγ receptors (FcγR).Here, we present the extended 3-year follow-up of a phase II study of tislelizumab in 70 patients with relapsed/refractory classical Hodgkin lymphoma (cHL) who failed or were ineligible for autologous stem cell transplantation.With a median follow-up of 33.8 months, the overall response rate by the independent review committee was 87.1%, and the complete response (CR) rate was 67.1%. Responses were durable as shown by a median duration of response of 31.3 months, and median progression-free survival (PFS) of 31.5 months. The 3-year PFS and overall survival rates were 40.8% and 84.8%, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 97.1% of patients; the grade ≥3 TRAE rate was low (31.4%), and only 8.6% of patients experienced adverse events leading to treatment discontinuation. Correlative biomarker analysis showed that FcγRΙ-expressing macrophages had no observed impact on either the CR rate or PFS achieved with tislelizumab, which may be potentially related to its engineered Fc region.With extended follow-up, tislelizumab yielded long-term benefits and demonstrated a favorable safety profile for patients with relapsed/refractory cHL. This trial was registered at clinicaltrials.gov as NCT03209973.
Phosphorylation of SHP2 at Tyr62 Enables Acquired Resistance to SHP2 Allosteric Inhibitors in FLT3-ITD–Driven AML
Authors: Anamarija Pfeiffer, Giulia Franciosa, Marie Locard-Paulet, Ilaria Piga, Kristian Reckzeh, Vidyasiri Vemulapalli, Stephen C. Blacklow, Kim Theilgaard-Mönch, Lars J. Jensen, Jesper V. Olsen
Journal: Cancer Research (2022)

Abstract The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases. SHP2 is required for full RAS-ERK activation to promote cell proliferation and survival programs. Allosteric SHP2 inhibitors act by stabilizing SHP2 in its autoinhibited conformation and are currently being tested in clinical trials for tumors with overactivation of the RAS/ERK pathway, alone and in various drug combinations. In this study, we established cells with acquired resistance to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD (internal tandem duplication)-positive AML cell lines. Label-free and isobaric labeling quantitative mass spectrometry–based phosphoproteomics of these resistant models demonstrated that AML cells can restore phosphorylated ERK (pERK) in the presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induced tyrosine phosphorylation and feedback-driven activation of the FLT3 receptor, which in turn phosphorylated SHP2 on tyrosine 62. This phosphorylation stabilized SHP2 in its open conformation, preventing SHP099 binding and conferring resistance. Combinatorial inhibition of SHP2 and MEK or FLT3 prevented pERK rebound and resistant cell growth. The same mechanism was observed in a FLT3-mutated B-cell acute lymphoblastic leukemia cell line and in the inv(16)/KitD816Y AML mouse model, but allosteric inhibition of Shp2 did not impair the clonogenic ability of normal bone marrow progenitors. Together, these results support the future use of SHP2 inhibitor combinations for clinical applications. Significance: These findings suggest that combined inhibition of SHP2 and FLT3 effectively treat FLT3-ITD–positive AML, highlighting the need for development of more potent SHP2 inhibitors and combination therapies for clinical applications.
Deep Learning and Medical Image Analysis for COVID-19 Diagnosis and Prediction
Authors: Tianming Liu, Eliot Siegel, Dinggang Shen
Journal: Annual Review of Biomedical Engineering (2022)

The coronavirus disease 2019 (COVID-19) pandemic has imposed dramatic challenges to health-care organizations worldwide. To combat the global crisis, the use of thoracic imaging has played a major role in the diagnosis, prediction, and management of COVID-19 patients with moderate to severe symptoms or with evidence of worsening respiratory status. In response, the medical image analysis community acted quickly to develop and disseminate deep learning models and tools to meet the urgent need of managing and interpreting large amounts of COVID-19 imaging data. This review aims to not only summarize existing deep learning and medical image analysis methods but also offer in-depth discussions and recommendations for future investigations. We believe that the wide availability of high-quality, curated, and benchmarked COVID-19 imaging data sets offers the great promise of a transformative test bed to develop, validate, and disseminate novel deep learning methods in the frontiers of data science and artificial intelligence.
Causes of death of patients with follicular lymphoma in the Netherlands by stage and age groups: a population-based study in the pre- and post-rituximab era
Authors: Manette A. W. Dinnessen, Carolien C. H. M. Maas, Sanne H. Tonino, Otto Visser, Eduardus F. M. Posthuma, Nicole M. A. Blijlevens, Marie José Kersten, Pieternella J. Lugtenburg, Avinash G. Dinmohamed
Journal: Leukemia (2022)
COVID-19 vaccine dose sparing: strategies to improve vaccine equity and pandemic preparedness
Authors: Geert V T Roozen, Anna H E Roukens, Meta Roestenberg
Journal: The Lancet Global Health (2022)

Despite tremendous efforts, worldwide COVID-19 vaccination coverage is lagging. Dose-sparing strategies for COVID-19 vaccines can increase vaccine availability to address the global crisis. Several clinical trials evaluating dose sparing are currently underway. However, to rapidly provide solid scientific justification for different dose-sparing strategies, joint coordinated action involving both public and private parties is needed. In this Viewpoint, we provide examples of approaches to vaccine dose-sparing that have previously been evaluated in clinical trials to improve vaccine availability and reflect on the origin of their funding. With a focus on the current COVID-19 pandemic, we stress the need for expedited testing of vaccine dose-sparing strategies in endemic or epidemic infectious diseases. However, we argue that the establishment of a mechanism through which dose-sparing opportunities are systematically identified, scientifically tested, and ultimately implemented will prove to be valuable beyond the current pandemic for infectious diseases product development and pandemic preparedness in the future.
Inducers and Cardiovascular Risk—Potential Role for Lowered Drug Exposure
Authors: Lorenz Van der Linden, Julie Hias, Isabel Spriet
Journal: JAMA Neurology (2022)

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The economic challenges of new drug development
Authors: Laurence S.J. Roope
Journal: Journal of Controlled Release (2022)

The COVID-19 pandemic has witnessed highly successful efforts to produce effective vaccines and treatments at an unprecedented pace. This perspective discusses factors that made this possible, from long-term investments in research infrastructure to major government interventions that absorbed much of the risk from research and development. We discuss key economic obstacles in the discovery of new drugs for infectious diseases, from novel antibiotics to diseases that primarily affect the poor. The world's collective experience of the pandemic may present an opportunity to reform traditional economic models of drug discovery to better address unmet needs. A tax-funded global institution could provide incentives for drug discovery based on their global health impact. International co-operation would be needed to agree and commit to adequate funding mechanisms, and the necessary political will would require strong public support. With the current heightened appreciation of the need for global health system resilience, there may be no better opportunity than now.
Cytogenetic abnormalities in essential thrombocythemia: Clinical and molecular correlates and prognostic relevance in 809 informative cases
Authors: Naseema Gangat, Yamna Jadoon, Natasha Szuber, Curtis A. Hanson, Alexandra P. Wolanskyj-Spinner, Rhett P. Ketterling, Animesh Pardanani, Ayalew Tefferi
Journal: Blood Cancer Journal (2022)

Abstract Cytogenetic studies among 809 consecutive patients with essential thrombocythemia (ET; median age 59 years; 65% females) revealed normal karyotype in 754 (93%), loss of chromosome Y only (-Y) in 16 (2%), and abnormalities other than -Y in 39 (4.8%), the most frequent being sole 20q- ( n = 8). At presentation, abnormal karyotype, excluding -Y, was associated with older age ( p = 0.04), higher leukocyte count ( p = 0.03) and arterial thrombosis history ( p = 0.02); no associations were apparent for JAK2/CALR/MPL mutations whereas ASXL1 mutations clustered with normal karyotype/-Y and TP53 with abnormal karyotype. Survival was significantly shorter in patients with abnormal karyotype or -Y, compared to those with normal karyotype (median 12, 10, and 21 years, respectively; p &lt; 0.0001). During multivariable analysis that included IPSET (international prognostic score for ET) variables, abnormal karyotype ( p &lt; 0.01, HR 2.0), age &gt;60 years ( p &lt; 0.01, HR 4.5), leukocytosis &gt;11 × 10 9 /L ( p &lt; 0.01, HR 1.5), and male gender ( p &lt; 0.01, HR 1.4) were independently associated with inferior survival; abnormal karyotype and age &gt;60 years remained significant, along with SF3B1/SRSF2/U2AF1/TP53 mutations ( p = 0.04; HR 2.9), when the latter was included in the multivariable model. The current study suggests prognostic relevance for karyotype in ET.
Selected Articles from This Issue
Journal: Clinical Cancer Research (2022)

Approximately 20% of breast cancers harbor human epidermal growth factor receptor 2 (HER2/ERBB2) overexpression or amplification.KN026, a novel HER2 bispecific antibody, has been shown to overcome resistance to HER2 target therapies in preclinical models.Zhang and colleagues conducted a phase I trial of KN026 in patients with HER2-positive metastatic breast cancer who had progressed on prior anti-HER2 therapies.KN026 was well tolerated, and treatment led to an objective response rate of 28.1%.Furthermore, the authors associated CDK12 co-amplification with an improved response to KN026, supporting further assessment of this potential biomarker.Although these results are interesting, further clinical trials of this novel bispecific antibody are warranted.
A novel unconventional T cell population enriched in Crohn’s disease
Authors: Elisa Rosati, Gabriela Rios Martini, Mikhail V Pogorelyy, Anastasia A Minervina, Frauke Degenhardt, Mareike Wendorff, Soner Sari, Gabriele Mayr, Antonella Fazio, Christel Marie Dowds, Charlotte Hauser, Florian Tran, Witigo von Schönfels, Julius Pochhammer, Maria A Salnikova, Charlot Jaeckel, Johannes Boy Gigla, Sanaz Sedghpour Sabet, Matthias Hübenthal, Esther Schiminsky, Stefan Schreiber, Philip C Rosenstiel, Alexander Scheffold, Paul G Thomas, Wolfgang Lieb, Bernd Bokemeyer, Maria Witte, Konrad Aden, Alexander Hendricks, Clemens Schafmayer, Jan-Hendrick Egberts, Ilgar Z Mamedov, Petra Bacher, Andre Franke
Journal: Gut (2022)

Objective One of the current hypotheses to explain the proinflammatory immune response in IBD is a dysregulated T cell reaction to yet unknown intestinal antigens. As such, it may be possible to identify disease-associated T cell clonotypes by analysing the peripheral and intestinal T-cell receptor (TCR) repertoire of patients with IBD and controls. Design We performed bulk TCR repertoire profiling of both the TCR alpha and beta chains using high-throughput sequencing in peripheral blood samples of a total of 244 patients with IBD and healthy controls as well as from matched blood and intestinal tissue of 59 patients with IBD and disease controls. We further characterised specific T cell clonotypes via single-cell RNAseq. Results We identified a group of clonotypes, characterised by semi-invariant TCR alpha chains, to be significantly enriched in the blood of patients with Crohn’s disease (CD) and particularly expanded in the CD8 + T cell population. Single-cell RNAseq data showed an innate-like phenotype of these cells, with a comparable gene expression to unconventional T cells such as mucosal associated invariant T and natural killer T (NKT) cells, but with distinct TCRs. Conclusions We identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population. The potential implications of this population for CD or a subset thereof remain to be elucidated, and the immunophenotype and antigen reactivity of CAIT cells need further investigations in future studies.
Pericyte-to-endothelial cell signaling via vitronectin-integrin regulates blood-CNS barrier
Authors: Swathi Ayloo, Christopher Gallego Lazo, Shenghuan Sun, Wei Zhang, Bianxiao Cui, Chenghua Gu
Journal: Neuron (2022)

Endothelial cells of blood vessels of the central nervous system (CNS) constitute blood-CNS barriers. Barrier properties are not intrinsic to these cells; rather they are induced and maintained by CNS microenvironment. Notably, the abluminal surfaces of CNS capillaries are ensheathed by pericytes and astrocytes. However, extrinsic factors from these perivascular cells that regulate barrier integrity are largely unknown. Here, we establish vitronectin, an extracellular matrix protein secreted by CNS pericytes, as a regulator of blood-CNS barrier function via interactions with its integrin receptor, α5, in endothelial cells. Genetic ablation of vitronectin or mutating vitronectin to prevent integrin binding, as well as endothelial-specific deletion of integrin α5, causes barrier leakage in mice. Furthermore, vitronectin-integrin α5 signaling maintains barrier integrity by actively inhibiting transcytosis in endothelial cells. These results demonstrate that signaling from perivascular cells to endothelial cells via ligand-receptor interactions is a key mechanism to regulate barrier permeability.
Lower Exome Sequencing Coverage of Ancestrally African Patients in The Cancer Genome Atlas
Authors: Daniel P Wickland, Mark E Sherman, Derek C Radisky, Aaron S Mansfield, Yan W Asmann
Journal: JNCI Journal of the National Cancer Institute (2022)

In the United States, cancer disproportionately impacts Black and African American individuals. Identifying genetic factors underlying cancer disparities has been an important research focus and requires data that are equitable in both quantity and quality across racial groups. It is widely recognized that DNA databases quantitatively underrepresent minorities. However, the differences in data quality between racial groups have not been well studied.We compared the qualities of germline and tumor exomes between ancestrally African and European patients in The Cancer Genome Atlas of 7 cancers with at least 50 self-reported Black patients in the context of sequencing depth, tumor purity, and qualities of germline variants and somatic mutations.Germline and tumor exomes from ancestrally African patients were sequenced at statistically significantly lower depth in 6 out of the 7 cancers. For 3 cancers, most ancestrally European exomes were sequenced in early sample batches at higher depth, whereas ancestrally African exomes were concentrated in later batches and sequenced at much lower depth. For the other 3 cancers, the reasons of lower sequencing coverage of ancestrally African exomes remain unknown. Furthermore, even when the sequencing depths were comparable, African exomes had disproportionally higher percentages of positions with insufficient coverage, likely because of the known European bias in the human reference genome that impacted exome capture kit design.Overall and positional lower sequencing depths of ancestrally African exomes in The Cancer Genome Atlas led to underdetection and lower quality of variants, highlighting the need to consider epidemiological factors for future genomics studies.
DEEP NEURAL NETWORK PREDICTION OF 12-MONTH HEART FAILURE ADMISSION FROM CARDIAC MRI 3D MYOCARDIAL DEFORMATION ANALYSIS
Authors: Alessandro Satriano, Aidan Cornhill, Dina Labib, Matthew Magyar-Ng, Yoko Mikami, Steven Dykstra, Jacqueline Flewitt, Andrew G. Howarth, Carmen Lydell, Nowell Mark Fine, Russell Greiner, James White
Journal: Journal of the American College of Cardiology (2022)
A New Ethical Framework for Assessing the Unique Challenges of Fetal Therapy Trials: Response to Commentaries
Authors: Saskia Hendriks, Christine Grady, David Wasserman, David Wendler, Diana W. Bianchi, Benjamin Berkman
Journal: The American Journal of Bioethics (2022)

This article refers to:A New Ethical Framework for Assessing the Unique Challenges of Fetal Therapy TrialsThe Fetus as a Research SubjectConsidering Reprogenomics in the Ethical Future of Fetal Therapy TrialsConsents (and Contents) Under Pressure: Maintaining Space for Moral Engagement in Research ProtocolsMaternal-Fetal Therapy: The (Psycho)Social DilemmaWhat Lies Beneath the Framework: The Importance of Grounding Ethical Discussions of Maternal-Fetal TherapyThe Relational and Gendered Nature of Reproductive MedicineMultidisciplinary Ethics Review for Liminal Cases in Maternal-Fetal Surgery: A Model