tbuckley/cabot-search huggingface dataset:
Clinical and Biological Subtypes of B-cell Lymphoma Revealed by Microenvironmental Signatures
Authors: Nikita Kotlov, Alexander Bagaev, Maria V. Revuelta, Jude M. Phillip, Maria Teresa Cacciapuoti, Zoya Antysheva, Viktor Svekolkin, Ekaterina Tikhonova, Natalia Miheecheva, Natalia Kuzkina, Grigorii Nos, Fabrizio Tabbo, Felix Frenkel, Paola Ghione, Maria Tsiper, Nava Almog, Nathan Fowler, Ari M. Melnick, John P. Leonard, Giorgio Inghirami, Leandro Cerchietti
Journal: Cancer Discovery (2021)

Abstract Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment. Significance: In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies. This article is highlighted in the In This Issue feature, p. 1307
Regulation of extracellular bioactive cations in bone tissue microenvironment induces favorable osteoimmune conditions to accelerate in situ bone regeneration
Authors: Zhengjie Lin, Danni Shen, Weixiao Zhou, Yufeng Zheng, Tiantian Kong, Xuanyong Liu, Shuilin Wu, Paul K. Chu, Ying Zhao, Jun Wu, Kenneth M.C. Cheung, Kelvin W.K. Yeung
Journal: Bioactive Materials (2021)

The design of orthopedic biomaterials has gradually shifted from "immune-friendly" to "immunomodulatory," in which the biomaterials are able to modulate the inflammatory response via macrophage polarization in a local immune microenvironment that favors osteogenesis and implant-to-bone osseointegration. Despite the well-known effects of bioactive metallic ions on osteogenesis, how extracellular metallic ions manipulate immune cells in bone tissue microenvironments toward osteogenesis and subsequent bone formation has rarely been studied. Herein, we investigate the osteoimmunomodulatory effect of an extracellular bioactive cation (Mg2+) in the bone tissue microenvironment using custom-made poly lactic-co-glycolic acid (PLGA)/MgO-alendronate microspheres that endow controllable release of magnesium ions. The results suggest that the Mg2+-controlled tissue microenvironment can effectively induce macrophage polarization from the M0 to M2 phenotype via the enhancement of anti-inflammatory (IL-10) and pro-osteogenic (BMP-2 and TGF-β1) cytokines production. It also generates a favorable osteoimmune microenvironment that facilitates the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. The in vivo results further verify that a large amount of bony tissue, with comparable bone mineral density and mechanical properties, has been generated at an early post-surgical stage in rat intramedullary bone defect models. This study demonstrates that the concept of in situ immunomodulated osteogenesis can be realized in a controlled magnesium tissue microenvironment.
Response to: ‘Correspondence on ‘Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis’’ by Parikh<i>et al</i>
Authors: Rona M Smith, Peter A Merkel, David Jayne
Journal: Annals of the Rheumatic Diseases (2021)

We appreciate the thorough and thoughtful review of our work, and the interesting points raised by Drs Parikh, Kumar and Rjasekhar.1

We recognise that there were more serious and non-serious infections in the lower dose glucocorticoid group in the induction phase of the RITAZAREM trial, which contrasts with the results of the PEXIVAS trial, where serious infections were less frequent in the reduced dose glucocorticoid group.2 3 However, in the RITAZAREM trial, the glucocorticoid induction regimen was not randomised. Reflecting the divergence of opinion on glucocorticoid dosing for disease relapse, the protocol permitted investigators to select, at enrolment, either a higher dose (starting at prednisone/prednisolone 1 mg/kg/day, maximum 60 mg) or a lower dose (starting at 0.5 mg/kg/day, maximum dose 30 mg) glucocorticoid induction regimen. Therefore, the selection of glucocorticoid dose is susceptible to bias. Trial participants with a perceived greater risk of infection (such as those with pre-existing comorbidities, older age, or greater prior burden of immunosuppression) may have been enrolled into the lower dose group. Per our prespecified statistical analysis plan, we reported the data but did …
Prevalence of Underlying Medical Conditions Associated With Severe COVID-19 Illness in Adult Cancer Survivors in the United States
Authors: Changchuan Jiang, K Robin Yabroff, Lei Deng, Stuthi Perimbeti, Xuesong Han
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Cancer, and other underlying medical conditions including chronic obstructive pulmonary disease, heart diseases, diabetes, chronic kidney disease, and obesity, are associated with increased risk of severe coronavirus disease 2019 (COVID-19) illness. We identified 6411 cancer survivors and 77 748 adults without a cancer history from the 2016-2018 National Health Interview Survey and examined the prevalence and sociodemographic factors associated with these conditions in the United States. Most survivors reported having 1 or more of the conditions (56.4%, 95% confidence interval [CI] = 54.8% to 57.9%, vs 41.6%, 95% CI = 40.9% to 42.2%, in adults without a cancer history), and nearly one-quarter (22.9%, 95% CI = 21.6% to 24.3%) reported 2 or more, representing 8.7 million and 3.5 million cancer survivors, respectively. These conditions were more prevalent in survivors of kidney, liver, and uterine cancers as well as Black survivors and those with low socioeconomic status and public insurance. Findings highlight the need to protect survivors against COVID-19 transmission in health-care facilities and to prioritize cancer patients, survivors, caregivers, and their health-care providers in vaccine allocation.
Pre‐transplantation cytoreduction does not benefit advanced myelodysplastic syndrome patients after myeloablative transplantation with grafts from family donors
Authors: Yu‐Qian Sun, Lan‐Ping Xu, Kai‐Yan Liu, Xiao‐Hui Zhang, Chen‐Hua Yan, Jian Jin, Xiao‐Jun Huang, Yu Wang
Journal: Cancer Communications (2021)

Abstract Background The role of pre‐hematopoietic stem cell transplantation (HSCT) cytoreduction with either induction chemotherapy (IC) or hypomethylating agents (HMAs) in treating advanced myelodysplastic syndrome (MDS) remains debatable. We aimed to evaluate pre‐HSCT strategies by comparing the endpoints related to disease control between advanced MDS patients with pre‐HSCT cytoreduction and those with best supportive care. Methods We described 228 consecutive advanced MDS patients who received HSCT from a haploidentical donor (HID, n = 162) or matched related donor (MSD, n = 66) with uniform myeloablative conditioning regimens between January 2015 and December 2018. Of these 228 patients, 131 (57.5%) were treated exclusively with pre‐HSCT best supportive care (BSC), 49 (22.5%) were given HMA, and 48 (21.1%) received both IC and HMA. Propensity score‐matching analysis, multivariate analyses, and subgroup analyses were performed to elucidate the impact of pre‐HSCT strategies on transplant outcomes. Results The 3‐year relapse‐free survival (RFS) rates were 78.2% and 70.0% for the BSC and cytoreduction cohorts ( P = 0.189) and were 78.2%, 66.7%, and 73.2% for the BSC, HMA, and HMA+IC groups, respectively ( P = 0.269). A propensity score‐matching analysis confirmed that the 3‐year RFS rates were 81.9%, 87.5%, and 66.9% for BSC, cytoreduction complete remission (CR), and cytoreduction non‐CR groups, respectively ( P = 0.051). Multivariate analyses demonstrated that pre‐HSCT cytoreduction, older patient age, monosomal karyotype, and interval between diagnosis and HSCT were poor prognostic factors for RFS. In the subgroup analyses, BSC was associated with longer RFS compared to cytoreduction among the younger patients, those with international prognostic scoring system intermediate‐2/high risk at diagnosis, and those with intermediate/poor cytogenetics. Conclusions Different pre‐HSCT therapies did not yield discrepant post‐HSCT outcomes. No benefit in terms of post‐HSCT outcomes were correlated with pre‐HSCT cytoreduction in advanced MDS even for cytoreduction CR patients. Early referral to HSCT is essential for advanced MDS patients.
What went wrong in the global governance of covid-19?
Authors: Clare Wenham
Journal: BMJ (2021)

Obesity is the most common medical condition in women of reproductive age. Obesity during pregnancy has short term and long term adverse consequences for both mother and child. Obesity causes problems with infertility, and in early gestation it causes spontaneous pregnancy loss and congenital anomalies. Metabolically, obese women have increased insulin resistance in early pregnancy, which becomes manifest clinically in late gestation as glucose intolerance and fetal overgrowth. At term, the risk of cesarean delivery and wound complications is increased. Postpartum, obese women have an increased risk of venous thromboembolism, depression, and difficulty with breast feeding. Because 50-60% of overweight or obese women gain more than recommended by Institute of Medicine gestational weight guidelines, postpartum weight retention increases future cardiometabolic risks and prepregnancy obesity in subsequent pregnancies. Neonates of obese women have increased body fat at birth, which increases the risk of childhood obesity. Although there is no unifying mechanism responsible for the adverse perinatal outcomes associated with maternal obesity, on the basis of the available data, increased prepregnancy maternal insulin resistance and accompanying hyperinsulinemia, inflammation, and oxidative stress seem to contribute to early placental and fetal dysfunction. We will review the pathophysiology underlying these data and try to shed light on the specific underlying mechanisms.
Identification of severe eosinophilic chronic rhinosinusitis based on eosinophil, mast cell and basophil microparticles in nasal lavage fluids
Authors: Toru Takahashi, Atsushi Kato, Lydia Suh, Roderick Carter, Whitney Stevens, Caroline Price, James Norton, Anju Peters, Leslie Grammer, Kevin Welch, Stephanie Shintani Smith, David Conley, Sergejs Berdnikovs, Bruce Tan, Robert Kern, Robert Schleimer
Journal: Journal of Allergy and Clinical Immunology (2021)
Impact of insomnia and obstructive sleep apnea on the risk of acute exacerbation of chronic obstructive pulmonary disease
Authors: Shi Qi Li, Xian Wen Sun, Liu Zhang, Yong Jie Ding, Hong Peng Li, Ya Ru Yan, Ying Ni Lin, Jian Ping Zhou, Qing Yun Li
Journal: Sleep Medicine Reviews (2021)
Covid-19: India’s slow moving treatment guidelines are misleading and harming patients
Authors: Priyanka Pulla
Journal: BMJ (2021)

Covid-19: India's slow moving treatment guidelines are misleading and harming patientsThe science of covid-19 treatments is fast moving.However, India's health ministry is failing to keep pace, leaving a confusing and harmful vacuum, writes Priyanka Pulla Priyanka Pulla freelance journalist When Santosh Gaggar was admitted to hospital in
Activity-dependent regulome of human GABAergic neurons reveals new patterns of gene regulation and neurological disease heritability
Authors: Gabriella L. Boulting, Ershela Durresi, Bulent Ataman, Maxwell A. Sherman, Kevin Mei, David A. Harmin, Ava C. Carter, Daniel R. Hochbaum, Adam J. Granger, Jesse M. Engreitz, Sinisa Hrvatin, Michael R. Blanchard, Marty G. Yang, Eric C. Griffith, Michael E. Greenberg
Journal: Nature Neuroscience (2021)
Roles of peptidyl-prolyl isomerase Pin1 in disease pathogenesis
Authors: Jingyi Li, Chunfen Mo, Yifan Guo, Bowen Zhang, Xiao Feng, Qiuyue Si, Xiaobo Wu, Zhe Zhao, Lixin Gong, Dan He, Jichun Shao
Journal: Theranostics (2021)

Pin1 belongs to the peptidyl-prolyl cis-trans isomerases (PPIases) superfamily and catalyzes the cis-trans conversion of proline in target substrates to modulate diverse cellular functions including cell cycle progression, cell motility, and apoptosis. Dysregulation of Pin1 has wide-ranging influences on the fate of cells; therefore, it is closely related to the occurrence and development of various diseases. This review summarizes the current knowledge of Pin1 in disease pathogenesis.
Abstract 15033: Left Ventricular Global Longitudinal Strain Provides Incremental Prognostic Utility in Asymptomatic Patients With Significant Chronic Aortic Regurgitation and Preserved Left Ventricular Ejection Fraction
Authors: Alaa Alashi, Amgad Mentias, ke Feng, Amjad Abdallah, A Marc Gillinov, L Leonardo Rodriguez, Joseph F Sabik, Lars G Svensson, Zoran B Popovic, Brian P Griffin, Milind Y Desai
Journal: Circulation (2016)

Background: Chronic severe aortic regurgitation (AR) results in long-term left ventricular (LV) volume and pressure overload, with a long asymptomatic stage. In un-operated patients, survival is re...
Promoting Ethical Payment in Human Infection Challenge Studies
Authors: Holly Fernandez Lynch, Thomas C. Darton, Jae Levy, Frank McCormick, Ubaka Ogbogu, Ruth O. Payne, Alvin E. Roth, Akilah Jefferson Shah, Thomas Smiley, Emily A. Largent
Journal: The American Journal of Bioethics (2021)

To prepare for potential human infection challenge studies (HICS) involving SARS-CoV-2, we convened a multidisciplinary working group to address ethical questions regarding whether and how much SARS-CoV-2 HICS participants should be paid. Because the goals of paying HICS participants, as well as the relevant ethical concerns, are the same as those arising for other types of clinical research, the same basic framework for ethical payment can apply. This framework divides payment into reimbursement, compensation, and incentives, focusing on fairness and promoting adequate recruitment and retention as counterweights to concerns about undue inducement. Within the basic framework, several factors are especially salient for HICS, and for SARS-CoV-2 HICS in particular, including the nature of participant confinement, anticipated discomfort, risks and uncertainty, participant motivations, and trust. These factors are reflected in a payment worksheet created to help sponsors, researchers, and ethics reviewers systematically develop and assess ethically justifiable payment amounts.
Clinical and Economic Burden of Patients with Uncontrolled Severe Asthma with Low Blood Eosinophil Levels in the United States
Authors: Laren Tan, Joan Reibman, Chris Ambrose, Yen Chung, Pooja Desai, Jean-Pierre Llanos Ackert, Meghan Moynihan, Joseph Tkacz
Journal: Journal of Allergy and Clinical Immunology (2021)
Abstract 13260: Prognosis and Prognostic Predictors of Atrial Functional Mitral Regurgitation; In Comparison With Ventricular Functional Mitral Regurgitation
Authors: Chisato Okamoto, Atsushi Okada, Yasuhiro Hamatani, Masashi Amano, Hiroyuki Takahama, Makoto Amaki, Takuya Hasegawa, Hideaki Kanzaki, Tomoyuki Fujita, Junjiro Kobayashi, Satishi Yasuda, Chisato Izumi
Journal: Circulation (2019)

Background: Atrial functional mitral regurgitation (A-fMR) has been under-recognized until recently recognized as an important cause of fMR. Therefore, its prognosis or prognostic predictors has no...
Abstract 12247: Initial Assessment of Diagnostic Yield of Arrhythmogenic Right Ventricular Cardiomyopathy in Patients Ascertained Through Secondary Genomic Findings
Authors: Dominik Beer, Marci Schwartz, Melissa Kelly, Megan McMinn, Eric Carruth, Amro Alsaid, Martin Matsumura, Brandon Fornwalt, Amy C Sturm, Christopher M Haggerty
Journal: Circulation (2019)

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with variants in desmosomal genes. Secondary findings of pathogenic or likely pathogenic (P/LP) variants in these ...
Covid-19: Black people over 80 in England are half as likely as white people to have been vaccinated
Authors: Adrian O’Dowd
Journal: BMJ (2021)

Targeted activity might be needed to tackle the disparities in accessing covid-19 vaccines, authors of a large study have said after finding that ethnic minorities, people living in areas of high deprivation, and those with severe mental health illness or learning disabilities seem to be less likely to have been vaccinated.1

Between 8 December 2020 and 13 January of this year, 41% of people aged 80 and over in England who do not live in care homes were vaccinated against covid-19. But the researchers from the University of Oxford and the London School of Hygiene and Tropical Medicine found a sizeable divergence in vaccination by ethnicity within this group of 476 375 people (of 1 160 062 over 80s). While 42.5% of white people were …
A Treacherous Course
Authors: Nikolaus Jilg, Emily S. Lau, Meghan A. Baker, Bruce D. Levy, Joseph Loscalzo
Journal: New England Journal of Medicine (2021)

A 33-year-old man with a history of smoking and heavy alcohol use presented to the emergency department in September 2019 with fever, vomiting, abdominal pain, and hemoptysis. Two days before admission, malaise, fevers, and chills had developed, followed by diffuse abdominal pain, nausea, and bilious vomiting.
Glycans in Immunologic Health and Disease
Authors: Julie Y. Zhou, Brian A. Cobb
Journal: Annual Review of Immunology (2021)

The surfaces of all living organisms and most secreted proteins share a common feature: They are glycosylated. As the outermost-facing molecules, glycans participate in nearly all immunological processes, including driving host-pathogen interactions, immunological recognition and activation, and differentiation between self and nonself through a complex array of pathways and mechanisms. These fundamental immunologic roles are further cast into sharp relief in inflammatory, autoimmune, and cancer disease states in which immune regulation goes awry. Here, we review the broad impact of glycans on the immune system and discuss the changes and clinical opportunities associated with the onset of immunologic disease.
Functional Diversification, Redundancy, and Epistasis among Paralogs of the <i>Drosophila melanogaster Obp50a–d</i> Gene Cluster
Authors: Joel A Johnstun, Vijay Shankar, Sneha S Mokashi, Lakshmi T Sunkara, Ugonna E Ihearahu, Roberta L Lyman, Trudy F C Mackay, Robert R H Anholt
Journal: Molecular Biology and Evolution (2021)

Large multigene families, such as the insect odorant-binding proteins (OBPs), are thought to arise through functional diversification after repeated gene duplications. Whereas many OBPs function in chemoreception, members of this family are also expressed in tissues outside chemosensory organs. Paralogs of the Obp50 gene cluster are expressed in metabolic and male reproductive tissues, but their functions and interrelationships remain unknown. Here, we report the genetic dissection of four members of the Obp50 cluster, which are in close physical proximity without intervening genes. We used CRISPR technology to excise the entire cluster while introducing a PhiC31 reintegration site to reinsert constructs in which different combinations of the constituent Obp genes were either intact or rendered inactive. We performed whole transcriptome sequencing and assessed sexually dimorphic changes in transcript abundances (transcriptional niches) associated with each gene-edited genotype. Using this approach, we were able to estimate redundancy, additivity, diversification, and epistasis among Obp50 paralogs. We analyzed the effects of gene editing of this cluster on organismal phenotypes and found a significant skewing of sex ratios attributable to Obp50a, and sex-specific effects on starvation stress resistance attributable to Obp50d. Thus, there is functional diversification within the Obp50 cluster with Obp50a contributing to development and Obp50d to stress resistance. The deletion-reinsertion approach we applied to the Obp50 cluster provides a general paradigm for the genetic dissection of paralogs of multigene families.
Clonal evolution in liver cancer at single-cell and single-variant resolution
Authors: Xianbin Su, Linan Zhao, Yi Shi, Rui Zhang, Qi Long, Shihao Bai, Qing Luo, Yingxin Lin, Xin Zou, Shila Ghazanfar, Kun Tao, Guoliang Yang, Lan Wang, Kun-Yan He, Xiaofang Cui, Jian He, Jiao-Xiang Wu, Bo Han, Bin Yan, Biao Deng, Na Wang, Xiaolin Li, Pengyi Yang, Shangwei Hou, Jielin Sun, Jean Y. H. Yang, Jinhong Chen, Ze-Guang Han
Journal: Journal of Hematology & Oncology (2021)

Abstract Genetic heterogeneity of tumor is closely related to its clonal evolution, phenotypic diversity and treatment resistance, and such heterogeneity has only been characterized at single-cell sub-chromosomal scale in liver cancer. Here we reconstructed the single-variant resolution clonal evolution in human liver cancer based on single-cell mutational profiles. The results indicated that key genetic events occurred early during tumorigenesis, and an early metastasis followed by independent evolution was observed in primary liver tumor and intrahepatic metastatic portal vein tumor thrombus. By parallel single-cell RNA-Seq, the transcriptomic phenotype of HCC was found to be related with genetic heterogeneity. For the first time we reconstructed the single-cell and single-variant clonal evolution in human liver cancer, and dissection of both genetic and phenotypic heterogeneity will facilitate better understanding of their relationship.
Bilayer dissolving microneedle array containing 5-fluorouracil and triamcinolone with biphasic release profile for hypertrophic scar therapy
Authors: Beibei Yang, Yating Dong, Yifeng Shen, Ailin Hou, Guilan Quan, Xin Pan, Chuanbin Wu
Journal: Bioactive Materials (2021)

Hypertrophic scar (HS) is an undesirable skin abnormality following deep burns or operations. Although intralesional multi-injection with the suspension of triamcinolone acetonide (TA) and 5-fluorouracil (5-Fu) has exhibited great promise to HS treatment in clinical, the difference of metabolic behavior between TA and 5-Fu remarkably compromised the treatment efficacy. Besides, the traditional injection with great pain is highly dependent on the skill of the experts, which results in poor compliance. Herein, a bilayer dissolving microneedle (BMN) containing TA and 5-Fu (TA-5-Fu-BMN) with biphasic release profile was designed for HS therapy. Equipped with several micro-scale needle tips, the BMN could be self-pressed into the HS with uniform drug distribution and less pain. Both in vitro permeation and in vivo HS retention tests revealed that TA and 5-Fu could coexist in the scar tissue for a sufficient time period due to the well-designed biphasic release property. Subsequently, the rabbit ear HS model was established to assess therapeutic efficacy. The histological analysis showed that TA-5-Fu-BMN could significantly reduce abnormal fibroblast proliferation and collagen fiber deposition. It was also found that the value of scar elevation index was ameliorated to a basal level, together with the downregulation of mRNA and protein expression of Collagen I (Col I) and transforming growth factor-β1 (TGF-β1) after application of TA-5-Fu-BMN. In conclusion, the BMN with biphasic release profiles could serve as a potential strategy for HS treatment providing both convenient administrations as well as controlled drug release behavior.