tbuckley/cabot-search huggingface dataset:
Effect of Tafamidis on Serum Transthyretin Levels in Non-Trial Patients With Transthyretin Amyloid Cardiomyopathy
Authors: Rodney H. Falk, Mia Haddad, Crystal R. Walker, Sharmila Dorbala, Sarah A.M. Cuddy
Journal: JACC CardioOncology (2021)

Transthyretin amyloid (ATTR) cardiomyopathy is slowed by tafamidis, which stabilizes the TTR molecule and reduces the formation of amyloidogenic oligomers. Stabilizers in clinical doses raise serum TTR, which may be a surrogate for the degree of stabilization.This study aims to determine, in a non-trial, unselected population of patients with ATTR cardiomyopathy, the effect of tafamidis on serum levels of TTR, and to compare these with published data of changes in TTR.TTR levels were measured before therapy and 3 to 12 months following initiation of tafamidis therapy in all patients seen between May 20, 2019, and March 1, 2021, who had a follow-up visits within 12 months of therapy initiation.Among 72 patients with ATTR cardiomyopathy (67 patients with wild-type and 5 patients with variant TTR), administration of tafamidis increased serum TTR from 21.8 mg ± 0.7 mg/dL to 29.3 ± 0.86 mg/dL, an increase of 34.5%. In 5 patients with variant TTR, the increase was 70.9%, compared to 32.0% in the wild-type patients. Mean N-terminal pro-brain natriuretic peptide increased over a mean follow-up of 21 ± 1.2 weeks, but the change was not statistically significant. Over the same period there was a small increase in high-sensitivity troponin T that was of borderline statistical significance (P = 0.057).Tafamidis consistently increases serum TTR levels in patients with ATTR cardiomyopathy, consistent with its effect on stabilizing TTR. Measurement of TTR level change post-TTR stabilizing therapy might be a surrogate for stabilization and could be a more accurate measure of drug efficacy than an in vitro nonphysiologic test of stabilization.
Robust joint registration of multiple stains and MRI for multimodal 3D histology reconstruction: Application to the Allen human brain atlas
Authors: Adrià Casamitjana, Marco Lorenzi, Sebastiano Ferraris, Loïc Peter, Marc Modat, Allison Stevens, Bruce Fischl, Tom Vercauteren, Juan Eugenio Iglesias
Journal: Medical Image Analysis (2021)
P40.10 Brain Metastases in Patients With Non-Small Cell Lung Cancer Treated With Immunotherapy. Real World Data From a Tertiary Hospital in Spain
Authors: Y. Garitaonaindia, M. Martínez-Cutillas, C. Traseira, V. Calvo, A. Collazo-Lorduy, F. Franco, M. Provencio
Journal: Journal of Thoracic Oncology (2021)
Management of pediatric generalized pustular psoriasis using biologics: An evidence-based review
Authors: Muskaan Sachdeva, Brian D. Rankin, Asfandyar Mufti, Jensen Yeung, Ronald Vender, Nadia J. Luca, Paivi Miettunen, Rebeka Stevenson, Alim R. Devani, Vimal H. Prajapati
Journal: Journal of the American Academy of Dermatology (2021)
Progress and barriers towards maternal and neonatal tetanus elimination in the remaining 12 countries
Authors: Nasir Yusuf, Azhar A Raza, Diana Chang-Blanc, Bilal Ahmed, Tedbabe Hailegebriel, Richard R Luce, Patricia Tanifum, Balcha Masresha, Mehoundo Faton, Mohamed D Omer, Saadia Farrukh, Khin D Aung, Heather M Scobie, Rania A Tohme
Journal: The Lancet Global Health (2021)

This Review assessed the progress and barriers towards maternal and neonatal tetanus elimination in the 12 countries that are yet to achieve elimination, globally. Coverage of at least 80% (the coverage level required for elimination) was assessed among women of reproductive age for five factors: (1) at least two doses of tetanus toxoid-containing vaccine, (2) protection at birth, (3) skilled birth attendance, (4) antenatal care visits, and (5) health facility delivery. A scoping review of the literature and data from Demographic and Health Surveys and Multiple Indicator Cluster Surveys provided insights into the barriers to attaining maternal and neonatal tetanus elimination. Findings showed that none of the 12 countries attained at least 80% coverage for women of reproductive age receiving at least two doses of tetanus toxoid-containing vaccine or protection at birth according to the data from Demographic and Health Surveys or Multiple Indicator Cluster Surveys. Barriers to maternal and neonatal tetanus elimination were mostly related to health systems and socioeconomic factors. Modification to existing maternal and neonatal tetanus elimination strategies, including innovations, will be required to accelerate maternal and neonatal tetanus elimination in these countries.
Prognostic factors for severe and recurrent Clostridioides difficile infection: a systematic review
Authors: Tessel M. van Rossen, Rogier E. Ooijevaar, Christina M.J.E. Vandenbroucke-Grauls, Olaf M. Dekkers, Ed J. Kuijper, Josbert J. Keller, Joffrey van Prehn
Journal: Clinical Microbiology and Infection (2021)

Clostridioides difficile infection (CDI), its subsequent recurrences (rCDIs), and severe CDI (sCDI) provide a significant burden for both patients and the healthcare system. Identifying patients diagnosed with initial CDI who are at increased risk of developing sCDI/rCDI could lead to more cost-effective therapeutic choices. In this systematic review we aimed to identify clinical prognostic factors associated with an increased risk of developing sCDI or rCDI.PubMed, Embase, Emcare, Web of Science and COCHRANE Library databases were searched from database inception through March, 2021. The study eligibility criteria were cohort and case-control studies. Participants were patients ≥18 years old diagnosed with CDI, in which clinical or laboratory factors were analysed to predict sCDI/rCDI. Risk of bias was assessed by using the Quality in Prognostic Research (QUIPS) tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool modified for prognostic studies. Study selection was performed by two independent reviewers. Overview tables of prognostic factors were constructed to assess the number of studies and the respective effect direction and statistical significance of an association.136 studies were included for final analysis. Greater age and the presence of multiple comorbidities were prognostic factors for sCDI. Identified risk factors for rCDI were greater age, healthcare-associated CDI, prior hospitalization, proton pump inhibitors (PPIs) started during or after CDI diagnosis, and previous rCDI.Prognostic factors for sCDI and rCDI could aid clinicians to make treatment decisions based on risk stratification. We suggest that future studies use standardized definitions for sCDI/rCDI and systematically collect and report the risk factors assessed in this review, to allow for meaningful meta-analysis of risk factors using data of high-quality trials.
The chromatin remodeler Ino80 mediates RNAPII pausing site determination
Authors: Youngseo Cheon, Sungwook Han, Taemook Kim, Daehee Hwang, Daeyoup Lee
Journal: Genome biology (2021)

Promoter-proximal pausing of RNA polymerase II (RNAPII) is a critical step for the precise regulation of gene expression. Despite the apparent close relationship between promoter-proximal pausing and nucleosome, the role of chromatin remodeler governing this step has mainly remained elusive.Here, we report highly confined RNAPII enrichments downstream of the transcriptional start site in Saccharomyces cerevisiae using PRO-seq experiments. This non-uniform distribution of RNAPII exhibits both similar and different characteristics with promoter-proximal pausing in Schizosaccharomyces pombe and metazoans. Interestingly, we find that Ino80p knockdown causes a significant upstream transition of promoter-proximal RNAPII for a subset of genes, relocating RNAPII from the main pausing site to the alternative pausing site. The proper positioning of RNAPII is largely dependent on nucleosome context. We reveal that the alternative pausing site is closely associated with the + 1 nucleosome, and nucleosome architecture around the main pausing site of these genes is highly phased. In addition, Ino80p knockdown results in an increase in fuzziness and a decrease in stability of the + 1 nucleosome. Furthermore, the loss of INO80 also leads to the shift of promoter-proximal RNAPII toward the alternative pausing site in mouse embryonic stem cells.Based on our collective results, we hypothesize that the highly conserved chromatin remodeler Ino80p is essential in establishing intact RNAPII pausing during early transcription elongation in various organisms, from budding yeast to mouse.
Cardiac SARS-CoV-2 infection is associated with pro-inflammatory transcriptomic alterations within the heart
Authors: Hanna Bräuninger, Bastian Stoffers, Antonia D E Fitzek, Kira Meißner, Ganna Aleshcheva, Michaela Schweizer, Jessica Weimann, Björn Rotter, Svenja Warnke, Carolin Edler, Fabian Braun, Kevin Roedl, Katharina Scherschel, Felicitas Escher, Stefan Kluge, Tobias B Huber, Benjamin Ondruschka, Heinz-Peter Schultheiss, Paulus Kirchhof, Stefan Blankenberg, Klaus Püschel, Dirk Westermann, Diana Lindner
Journal: Cardiovascular Research (2021)

Abstract Aims Cardiac involvement in COVID-19 is associated with adverse outcome. However, it is unclear whether cell-specific consequences are associated with cardiac SARS-CoV-2 infection. Therefore, we investigated heart tissue utilizing in situ hybridization, immunohistochemistry, and RNA-sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19. Methods and results In this study, 95 SARS-CoV-2-positive autopsy cases were included. A relevant SARS-CoV-2 virus load in the cardiac tissue was detected in 41/95 deceased (43%). Massive analysis of cDNA ends (MACE)-RNA-sequencing was performed to identify molecular pathomechanisms caused by the infection of the heart. A signature matrix was generated based on the single-cell dataset ‘Heart Cell Atlas’ and used for digital cytometry on the MACE-RNA-sequencing data. Thus, immune cell fractions were estimated and revealed no difference in immune cell numbers in cases with and without cardiac infection. This result was confirmed by quantitative immunohistological diagnosis. MACE-RNA-sequencing revealed 19 differentially expressed genes (DEGs) with a q-value &amp;lt;0.05 (e.g. up: IFI44L, IFT3, TRIM25; down: NPPB, MB, MYPN). The upregulated DEGs were linked to interferon pathways and originate predominantly from endothelial cells. In contrast, the downregulated DEGs originate predominately from cardiomyocytes. Immunofluorescent staining showed viral protein in cells positive for the endothelial marker ICAM1 but rarely in cardiomyocytes. The Gene Ontology (GO) term analysis revealed that downregulated GO terms were linked to cardiomyocyte structure, whereas upregulated GO terms were linked to anti-virus immune response. Conclusion This study reveals that cardiac infection induced transcriptomic alterations mainly linked to immune response and destruction of cardiomyocytes. While endothelial cells are primarily targeted by the virus, we suggest cardiomyocyte destruction by paracrine effects. Increased pro-inflammatory gene expression was detected in SARS-CoV-2-infected cardiac tissue but no increased SARS-CoV-2 associated immune cell infiltration was observed.
Characterizing immune cell subsets of tumour infiltrating lymphocytes (TILs) in brain metastases
Authors: Priyakshi Kalita-de Croft, Haarika Chittoory, Peter Simpson, Sunil Lakhani
Journal: Neuro-Oncology (2021)

Abstract Aims The heterogeneity of TILs are not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues. Method We performed multiplex immunofluorescence (mIF) on a limited cohort of brain metastases arising from breast cancers (n=20). Using RNA-interference validated antibodies, we quantitated the subsets of immune cells in formalin-fixed paraffin embedded whole sections. The panel of proteins analyzed included PanCK, CD8, CD4, Vista and Iba1 and an average of 15000 cells per sample were analysed. We also analysed an independent publicly available cohort at the RNA level to corroborate our findings. Results We found that increased density of tils (high&amp;gt;30%; low &amp;lt;30%) correlated with survival and they were two distinct phenotypes. The tumours with low tils had significantly higher expression of the immune-checkpoint molecule Vista in tumour cells (p&amp;lt;0.01) as well as in their microenvironment (p&amp;lt;0.001). Contrastingly, the brain metastatic tumours with high tils displayed higher expression of microglia. Low tils-tumours display CD8+ T-cells that exclusively co-express Vista (p&amp;lt;0.01) compared to high tils group where CD8+ T-cells significantly co-express Iba1 (p&amp;lt;0.05). Interestingly no definite phenotypes were observed in CD4+ T-cells. These results were also found in an independent cohort where Vista was a highly ranked gene within the CD8+ T-cell population. Conclusion Variety of immune escape routes may be involved in brain metastasis. This may be executed by increasing the expression of T-cell inhibitory molecule Vista or by increased activated microglia which may release immunosuppressive cytokines. Further studies are required to provide mechanistic insights into these phenomena.
WHO and the global health community call for urgent action on the climate crisis
Authors: Jacqui Wise
Journal: BMJ (2021)

The World Health Organization is calling for countries to take decisive action at the upcoming COP26 meeting in Glasgow as the climate crisis is the single biggest health threat facing humanity.1

WHO’s COP26 special report on climate change and health, The Health Argument for Climate Action , comes as an open letter signed by more than 400 health and medical organisations from around the world also urges governments to step up climate action.2

“Wherever we deliver care, in our hospitals, clinics, and communities around the world, we are already responding to the health harms caused by climate change,” the letter says. “We call on the leaders of every …
Black and Asian doctors still face discrimination when applying for jobs in the NHS
Authors: Samara Linton
Journal: BMJ (2021)

New data reveal the shocking extent to which black and Asian doctors are at a disadvantage when applying for medical jobs. Samara Linton reports “You have a very good CV, but there is something about you that you cannot change,” said the white consultant conducting the interview. He pointed to the applicant’s skin. “Even though he is black, they all love him, and they don’t see him as different from us,” a referee wrote in response to the same doctor’s application for a consultant role. And at a consultant interview a panel member asked him, “Do you know this is a white area?” These accounts show the discrimination experienced by a senior registrar who arrived in the British Isles in the 1980s and began looking for senior roles (box 1). New figures show that black and Asian doctors and those of mixed ethnic backgrounds still experience discrimination when applying for jobs as NHS doctors in London in 2021. Box 1 ### Asked why he kept such meticulous records, he responded, “For days like this” L was a senior registrar when he first came to the British Isles in the 1980s. He worked as a registrar while he looked for a senior post. “I don’t know how many applications I wrote; I don't know how many hospitals I visited,” he says. One white consultant told him, “You have a very good CV, but there is something about you that you cannot change,” pointing to L’s skin. L eventually found a higher specialty training post and applied for a consultant role on completion of his training. One referee wrote, “Even though he is black, they all love him, and they don’t see him as different from us.” At a consultant interview a panel member asked, “Do you know this is a white area?” L responded, “Yes, I do. And I don’t have any problems with that.” “I probably … RETURN TO TEXT
P70.15 Mutational Subtypes and Prognosis of East Asian Non-Small-Cell Lung Cancer Harboring NF2 Mutations
Authors: L. Miao, C. Xu, W. Wang, D. Wang, Y. Zhu, W. Zhuang, M. Fang, G. Wang, Q. Wang, Y. Song, S. Lu
Journal: Journal of Thoracic Oncology (2021)
Case 32-2021: A 14-Year-Old Girl with Swelling of the Jaw and Hypercalcemia
Authors: Thomas O. Carpenter, Hillary R. Kelly, Jordan S. Sherwood, Zachary S. Peacock, Vania Nosé
Journal: New England Journal of Medicine (2021)

A 14-year-old girl presented with progressive swelling of the jaw. Six weeks before this admission, a nonpainful lump in the left lower jaw developed. The mass increased in size, and swelling of the left side of the face and neck developed. A biopsy specimen from the mass showed abundant giant cells. The calcium level was 11.8 mg per deciliter. A diagnosis was made.
A novel mouse model for hedgehog signaling-mediated carcinogenesis
Authors: Jingwu Xie, Xiaoli Zhang
Journal: Cancer Research (2007)

3886  The hedgehog (Hh) pathway plays a critical role in embryonic development and tissue polarity. Activation of Hh signaling, usually due to loss-of-function somatic mutations of PTCH1 and less often to activating mutations of SMO, is the pivotal abnormality in sporadic basal cell carcinomas (BCCs). A natural product, cyclopamine, can specifically inhibit Hh signaling and is shown to be effective in prevention and treatment of BCCs in animal models. There are several mouse models for Hh signaling-mediated BCC formation, with Ptch1+/- mice as one of the best models. However, about 30% of Ptch1+/- mice die from medulloblastoma and a long-term UV irradiation is required for BCC formation in this model, which prevents widely use of this mouse model for drug testing. To establish more efficient mouse models, we have generated mice with skin-specific activation of Hh signaling using K14 promoter. In this model, activation of hedgehog signaling was achieved by either skin-specific knockout of Ptch1 or skin-specific knockin of activated SMO. We found that these mice develop skin cancers in the first week. By day 28, most mice develop alopecia. These mice only have one third of the weight of the wild type mice. Skin of these mice is filled with BCC-like tumors. Further analysis of these tumors indicated that Hh signaling is activated. In summary, we have established novel mouse models for Hh signaling-mediated skin cancers. These mice can be readily used for testing therapeutic drugs for BCCs.
P12.03 The Time of Anti-PD-1 Infusion Improves Survival Outcomes by Fasting Conditions Simulation in Non-Small Cell Lung Cancer
Authors: A. Vilalta-Lacarra, M. Rodriguez-Remirez, I. Lopez-Erdozain, A. Puyalto, I. Baraibar, J. Corral, A. Gúrpide, J.M. López-Picazo, J.L. Pérez-Gracia, M.P. Andueza, V. Catalan, G. Fruhbeck, R. Pio, D. Ajona, I. Gil-Bazo
Journal: Journal of Thoracic Oncology (2021)
Dichotomous metabolic networks govern human ILC2 proliferation and function
Authors: Laura Surace, Jean-Marc Doisne, Carys A. Croft, Anna Thaller, Pedro Escoll, Solenne Marie, Natalia Petrosemoli, Vincent Guillemot, Valerie Dardalhon, Davide Topazio, Antonia Cama, Carmen Buchrieser, Naomi Taylor, Ido Amit, Olimpia Musumeci, James P. Di Santo
Journal: Nature Immunology (2021)

Abstract Group 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (T H 2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings.
Pharmacological manipulation of macrophage autophagy effectively rejuvenates the regenerative potential of biodegrading vascular graft in aging body
Authors: Wanli Chen, Weiwei Xiao, Xuzheng Liu, Pingping Yuan, Siqian Zhang, Yinggang Wang, Wei Wu
Journal: Bioactive Materials (2021)

Declined regenerative potential and aggravated inflammation upon aging create an inappropriate environment for arterial regeneration. Macrophages are one of vital effector cells in the immune microenvironment, especially during biomaterials mediated repairing process. Here, we revealed that the macrophage autophagy decreased with aging, which led to aggravated inflammation, thereby causing poor vascular remodeling of artificial grafts in aging body. Through loading the autophagy-targeted drugs, rapamycin and 3-MA (3-methyladenine), in PCL (polycaprolactone) sheath of the PGS (poly glycerol sebacate) - PCL vascular graft, the essential role of macrophage autophagy was confirmed in regulating macrophage polarization and biomaterial degradation. Moreover, the utilization of rapamycin promoted anti-inflammatory polarization of macrophage by activating autophagy, which further promoted myogenic differentiation of vascular progenitor cells and accelerated endothelialization. Our study elucidated the contribution of pharmacological manipulation of macrophage autophagy in promoting regeneration of small caliber artery, which may pave a new avenue for clinical translation of vascular grafts in aging body.
High-risk subtypes of chronic lymphocytic leukemia are detectable as early as 16 years prior to diagnosis
Authors: P. Martijn Kolijn, Fatemeh Saberi Hosnijeh, Florentin Späth, Paul J. Hengeveld, Andreas Agathangelidis, Manal Saleh, Delphine Casabonne, Yolanda Benavente, Mats Jerkeman, Antonio Agudo, Aurelio Barricarte, Caroline Besson, Maria-Jose Sánchez, María-Dolores Chirlaque, Giovanna Masala, Carlotta Sacerdote, Sara Grioni, Matthias B. Schulze, Alexandra Nieters, Peter Engelfriet, Magnus Hultdin, James D. McKay, Roel C.H. Vermeulen, Anton W. Langerak
Journal: Blood (2021)

Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.
The antecedents and outcomes of persistent and remitting adolescent depressive symptom trajectories: a longitudinal, population-based English study
Authors: Bryony Weavers, Jon Heron, Ajay K Thapar, Alice Stephens, Jessica Lennon, Rhys Bevan Jones, Olga Eyre, Richard JL Anney, Stephan Collishaw, Anita Thapar, Frances Rice
Journal: The Lancet Psychiatry (2021)