tbuckley/cabot-search huggingface dataset:
Effects of nintedanib by inclusion criteria for progression of interstitial lung disease
Authors: Toby M. Maher, Kevin K. Brown, Michael Kreuter, Anand Devaraj, Simon L.F. Walsh, Lisa H. Lancaster, Elizabeth A. Belloli, Maria Padilla, Juergen Behr, Rainer-Georg Goeldner, Kay Tetzlaff, Rozsa Schlenker-Herceg, Kevin R. Flaherty
Journal: European Respiratory Journal (2021)

Background The INBUILD trial investigated nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs). We investigated the decline in forced vital capacity (FVC) in subgroups based on the inclusion criteria for ILD progression. Methods Subjects had a fibrosing ILD other than idiopathic pulmonary fibrosis and met the following criteria for ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice: Group A, relative decline in FVC ≥10% predicted; Group B, relative decline in FVC ≥5–&lt;10% predicted with worsened respiratory symptoms and/or increased extent of fibrosis on high-resolution computed tomography (HRCT); Group C, worsened respiratory symptoms and increased extent of fibrosis on HRCT only. Results In the placebo group, the rates of FVC decline over 52 weeks in Groups A, B and C, respectively, were −241.9, −133.1 and −115.3 mL per year in the overall population (p=0.0002 for subgroup-by-time interaction) and −288.9, −156.2 and −100.1 mL per year among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on HRCT (p=0.0005 for subgroup-by-time interaction). Nintedanib had a greater absolute effect on reducing the rate of FVC decline in Group A than in Group B or C. However, the relative effect of nintedanib versus placebo was consistent across the subgroups (p&gt;0.05 for heterogeneity). Conclusions The inclusion criteria used in the INBUILD trial, based on FVC decline or worsening of symptoms and extent of fibrosis on HRCT, were effective at identifying patients with progressive fibrosing ILDs. Nintedanib reduced the rate of decline in FVC across the subgroups based on the inclusion criteria related to ILD progression.
Increased 68Ga-FAPI Uptake in Intramuscular Gluteal Hematoma in a Patient With Hemophagocytic Syndrome
Authors: Xiao Yang, Huipan Liu, Zhouxiang You, Weidong Gong, Yue Chen
Journal: Clinical Nuclear Medicine (2021)

Abstract A 39-year-old man was diagnosed clinically with hemophagocytic syndrome, which was suspected to be secondary to a malignancy. Therefore, the patient underwent a 68 Ga-FAPI PET/CT scan as part of an ongoing clinical trial (ChiCTR2100044131). Increased tracer uptake was noted the gluteal region. Medical history revealed recent iliac bone marrow aspiration on the same side. On further examination, the lesion was confirmed to be a hematoma. The present case highlights that puncture operations may result in intramuscular hematomas, which might potentially malignancy on a 68 Ga-FAPI PET/CT.
Abstract SY19-01: TGFβ and immune evasion in metastatic cancer
Authors: Joan Massagué
Journal: Cancer Research (2021)

Abstract TGF-β and Immune Evasion in Metastatic Cancer Transforming growthfactor-β (TGF-β) is a major regulator of development,immune homeostasis, tissue regeneration, and cancer. TGF-β signaling suppresses tumor initiation but promotestumor progression through mechanisms that are increasingly understood. TGF-β inhibitsthe expansion and function of many components of the immune system and itspresence in the tumor microenvironment limits the effectiveness of current immunotherapies. To betterdefine the potential benefit of targeting TGF-β in cancer, we investigated therole of TGF-β in metastasis. Metastasis, the main cause of deathfrom cancer, is driven by stem-like disseminated cancer cells (“metastasisinitiating cells”, MICs) capable of reversible quiescence, immune evasion, organ-specificoutgrowth, and drug resistance. We developed models oflung adenocarcinoma (LUAD) metastatic dormancy and outbreak by isolating MICs thatrecapitulate the developmental and regenerative phenotypes of carcinoma cellsin human metastases. We find that TGF-β in thetumor microenvironment has different tumorigenic effects on early-stageprogenitor MICs and their progenies. In SOX2-rich early progenitor MICs, TGF-βinduces dormancy by imposing a growth-inhibited epithelial to mesenchymaltransition (EMT). Pharmacologic inhibition of TGF-β in this context causes MICsto exit from this immune evasive dormancy and become exposed to immune attack. Incontrast, SOX9-rich MIC progeny cells respond to TGF-β with an EMT that iscoupled to expression of fibrogenic cytokines. Deletion of TGF-β receptor orits fibrogenic target genes in the carcinoma cells prevents intratumoralfibrosis and inhibits metastatic outgrowth. These insights suggest that targetingTGF-β in metastatic cancer can improve treatment outcomes by forcing MICs outof immune evasive quiescence and suppressing intra-tumoral fibrosis, inaddition to relieving innate and adaptive immunity from TGF-β mediated inhibition. Citation Format: Joan Massagué. TGFβ and immune evasion in metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY19-01.
Atrial Fibrillation, Obstructive Sleep Apnea, and Continuous Positive Airway Pressure: No Easy Fix
Authors: Matthew Hind, Tom Wong
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

argument that opiates may have been used secondarily for sedation and portended unfavorable endpoints.It may therefore be prudent to incorporate an analgesia-first approach using validated pain assessment tools to guide the administration of analgesics targeted to treat pain and pain alone (5) and using a multimodal pain management technique (pharmacological and nonpharmacological) to reduce opiate use (1).Once pain is addressed if sedation is required because of agitation and inability to redirect patients, one can then use either propofol or dexmedetomidine-both agents with similar risks for delirium yet with a superior profile over benzodiazepines (9)(10)(11).Although the study by Duprey and colleagues does not prove causation or compare head to head an analgosedation and an analgesia-first approach, it provides clinicians with a clearer understanding of the risks associated with opiates and sets the stage for a comparative trial of these two approaches in critically ill patients to determine the best strategies to address pain in this era of light sedation.
Osmotic core-shell polymeric implant for sustained BDNF AntagoNAT delivery in CNS using minimally invasive nasal depot (MIND) approach
Authors: Smrithi Padmakumar, Gregory Jones, Olga Khorkova, Jane Hsiao, Jonghan Kim, Benjamin S. Bleier, Mansoor M. Amiji
Journal: Biomaterials (2021)
Poster session symptoms associated with COVID-19 positive status in patients with COPD: Looking beyond dyspnea
Authors: W. B. Smith, P. Sen, U. Majumdar, J. G. Zein, U. S. Hatipoglu, A. Attaway
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

RATIONALE Patients with COPD (chronic obstructive pulmonary disease) are at high-risk for severe COVID-19 infection. Assessing when these patients should be evaluated for COVID-19 can be difficult because they often have chronic respiratory symptoms such as cough, dyspnea, and sputum production, at baseline. Very little data exists on how patients with COPD present with COVID-19 and which symptoms are associated with a higher risk for COVID-19 infection. The aim of this study was to investigate the symptoms most associated with positive COVID-19 status in patients with COPD. METHODS We investigated 1468 patients with a diagnosis of COPD who were tested for COVID-19 using the Cleveland Clinic COVID-19 registry from 03/8/2020 to 06/08/2020. Testing for COVID-19 at our facility was only indicated for symptomatic patients. We excluded individuals with the concurrent diagnosis of asthma, those with less than a 10 pack-year smoking history, and those 35 years of age and younger to minimize bias and uncertainty about the diagnosis of COPD. Results were analyzed via a multivariate logistic regression adjusted for gender, race, age, smoking status, and comorbidities associated with increased risk of COVID-19 infection (diabetes mellitus, coronary artery disease, hypertension, and history of malignancy). RESULTS Out of a total of 1468 patients, 223 (15.2%) tested positive for COVID-19. Compared to patients with COPD who tested negative, those who tested positive were more likely to endorse fatigue (62.0% vs 40.3%, p<0.001), flu-like symptoms (57.6% vs 36.0%, p<0.001), diarrhea (26.8% vs 17.2%, p=0.009), and loss of appetite (43.5% vs 14.1%, p<0.001). Respiratory symptoms were commonly reported, but not significantly different compared to COVID negative patients (cough: 76.2% vs 75.3%, p=0.88;sputum production: 37.2% vs 32.9%, p=0.43;dyspnea: 75.3% vs 77.9%, p=0.53). When adjusted in multivariate logistic regression, COPD patients had higher odds of testing positive when reporting fatigue (adj OR 2.57, CI: 1.72-3.87), flu-like symptoms (adj OR 2.95, CI: 1.99-4.41), diarrhea (adj OR 2.05, CI: 1.31-3.16), or loss of appetite (adj OR 5.03, CI: 3.19-7.95). CONCLUSIONS In this study, we found that patients with COPD who were tested for COVID-19 demonstrated that constitutional and gastrointestinal symptoms were more often associated with a positive COVID-19 test compared to respiratory symptoms. These findings highlight the importance of investigating additional symptoms other than respiratory in patients with COPD to help predict COVID-19 positivity. .
Functional Characterization of the Cnidarian Antiviral Immune Response Reveals Ancestral Complexity
Authors: Magda Lewandowska, Ton Sharoni, Yael Admoni, Reuven Aharoni, Yehu Moran
Journal: Molecular Biology and Evolution (2021)

Abstract Animals evolved a broad repertoire of innate immune sensors and downstream effector cascades for defense against RNA viruses. Yet, this system varies greatly among different bilaterian animals, masking its ancestral state. In this study, we aimed to characterize the antiviral immune response of the cnidarian Nematostella vectensis and decipher the function of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) known to detect viral double-stranded RNA (dsRNA) in bilaterians but activate different antiviral pathways in vertebrates and nematodes. We show that polyinosinic:polycytidylic acid (poly(I:C)), a mimic of long viral dsRNA and a primary ligand for the vertebrate RLR melanoma differentiation-associated protein 5 (MDA5), triggers a complex antiviral immune response bearing features distinctive for both vertebrate and invertebrate systems. Importantly, a well-characterized agonist of the vertebrate RIG-I receptor does not induce a significant transcriptomic response that bears signature of the antiviral immune response, which experimentally supports the results of a phylogenetic analysis indicating clustering of the two N. vectensis RLR paralogs (NveRLRa and NveRLRb) with MDA5. Furthermore, the results of affinity assays reveal that NveRLRb binds poly(I:C) and long dsRNA and its knockdown impairs the expression of putative downstream effector genes including RNA interference components. Our study provides for the first time the functional evidence for the conserved role of RLRs in initiating immune response to dsRNA that originated before the cnidarian–bilaterian split and lay a strong foundation for future research on the evolution of the immune responses to RNA viruses.
Audio Interview: Another New Covid-19 Vaccine
Authors: Eric J. Rubin, Lindsey R. Baden, Stephen Morrissey
Journal: New England Journal of Medicine (2021)

Another New Covid-19 Vaccine In this audio interview conducted on June 29, 2021, the editors discuss the encouraging results of a phase 3 study of the Novavax vaccine NVX-CoV2373, as well as new da...
Atezolizumab plus Bevacizumab versus Sorafenib in the Chinese Subpopulation with Unresectable Hepatocellular Carcinoma: Phase 3 Randomized, Open-Label IMbrave150 Study
Authors: Shukui Qin, Zhenggang Ren, Yin-Hsun Feng, Thomas Yau, Baocheng Wang, Haitao Zhao, Yuxian Bai, Shanzhi Gu, Lindong Li, Sairy Hernandez, Derek-Zhen Xu, Sohail Mulla, Yifan Wang, Hui Shao, Ann Lii Cheng
Journal: Liver Cancer (2021)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety data from the Chinese subpopulation are reported. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; IMbrave150, a global, randomized, open-label, phase 3 study in patients with systemic treatment-naive unresectable HCC, included an extension phase that enrolled additional patients from mainland China. Patients were randomized (2:1) to receive intravenous atezolizumab 1,200 mg plus bevacizumab 15 mg/kg once every 3 weeks or sorafenib 400 mg twice a day until unacceptable toxicity or loss of clinical benefit. Co-primary endpoints were OS and independent review facility-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Of 194 Chinese patients enrolled from April 16, 2018, to April 8, 2019 (137 in the global study and 57 in the China extension phase), 133 received atezolizumab plus bevacizumab and 61 received sorafenib. At the data cutoff (August 29, 2019), the stratified hazard ratio for OS was 0.44 (95% CI, 0.25–0.76) and for PFS was 0.60 (95% CI, 0.40–0.90). The respective median OS and PFS with atezolizumab plus bevacizumab were not reached (NR; 95% CI, 13.5 months to NR) and 5.7 months (95% CI, 4.2–8.3) versus 11.4 months (95% CI, 6.7 to NR) and 3.2 months (95% CI, 2.6–4.8) with sorafenib. Grade 3–4 adverse events (AEs) occurred in 78 of 132 (59.1%) atezolizumab plus bevacizumab-treated and 27 of 58 (46.6%) sorafenib-treated patients. The most common grade 3–4 AE with atezolizumab plus bevacizumab was hypertension, occurring in 15.2% of patients; however, other high-grade AEs were infrequent. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Clinically meaningful improvements in OS and PFS observed with atezolizumab plus bevacizumab versus sorafenib suggest that atezolizumab plus bevacizumab may become a practice-changing treatment for Chinese patients with unresectable HCC.
Formulation and delivery solutions for the next generation biotherapeutics
Authors: Enrico Mastrobattista
Journal: Journal of Controlled Release (2021)

In 2018 I was appointed full professor of Pharmaceutical Biotechnology & Delivery at the Pharmaceutics division of the department of Pharmaceutical Sciences at Utrecht University, The Netherlands. In this contribution to the Orations - New Horizons of the Journal of Controlled Release I will introduce my research group (see also www.uu.nl/pharmaceutics) and will highlight my current and future research projects. In coming years the focus of my research will be on the administration of biotherapeutics, aiming to control their fate from the site of injection to the site of action. I will discuss issues related to formulation of biotherapeutics into nanomedicines (NMs), intracellular delivery of nucleic acids as well as protein therapeutics, and targeted delivery of biotherapeutics beyond the liver. In addition, I will provide a forward view on how current developments in the drug delivery and gene therapy field may result in sustainable and cost-effective dosing regimens for biotherapeutics.
Histopathological effects of electrosurgical interventions in an in vivo porcine model of colonic endoscopic mucosal resection
Authors: Anthony M Whitfield, Nicholas G Burgess, Farzan F Bahin, Sharir Kabir, María Pellisé, Rebecca Sonson, Vishnu Subramanian, Hema Mahajan, Duncan McLeod, Karen Byth, Michael J Bourke
Journal: Gut (2021)

Endoscopic mucosal resection (EMR) in the colon has been widely adopted, but there is limited data on the histopathological effects of the differing electrosurgical currents (ESCs) used. We used an in vivo porcine model to compare the tissue effects of ESCs for snare resection and adjuvant margin ablation techniques.Standardised EMR was performed by a single endoscopist in 12 pigs. Two intersecting 15 mm snare resections were performed. Resections were randomised 1:1 using either a microprocessor-controlled current (MCC) or low-power coagulating current (LPCC). The lateral margins of each defect were treated with either argon plasma coagulation (APC) or snare tip soft coagulation (STSC). Colons were surgically removed at 72 hours. Two specialist pathologists blinded to the intervention assessed the specimens.88 defects were analysed (median 7 per pig, median defect size 29×17 mm). For snare ESC effects, 156 tissue sections were assessed. LPCC was comparable to MCC for deep involvement of the colon wall. For margin ablation, 172 tissue sections were assessed. APC was comparable to STSC for deep involvement of the colon wall. Islands of preserved mucosa at the coagulated margin were more likely with APC compared with STSC (16% vs 5%, p=0.010).For snare resection, MCC and LPCC did not produce significantly different tissue effects. The submucosal injectate may protect the underlying tissue, and technique may more strongly dictate the depth and extent of final injury. For margin ablation, APC was less uniform and complete compared with STSC.
Association Between a Common, Benign Genotype and Unnecessary Bone Marrow Biopsies Among African American Patients
Authors: Sara L. Van Driest, Noura S. Abul-Husn, Joseph T. Glessner, Lisa Bastarache, Sharon Nirenberg, Jonathan S. Schildcrout, Meghana S. Eswarappa, Gillian M. Belbin, Christian M. Shaffer, Frank Mentch, John Connolly, Mingjian Shi, C. Michael Stein, Dan M. Roden, Hakon Hakonarson, Nancy J. Cox, Scott C. Borinstein, Jonathan D. Mosley
Journal: JAMA Internal Medicine (2021)

Up to two-thirds of African American individuals carry the benign rs2814778-CC genotype that lowers total white blood cell (WBC) count.To examine whether the rs2814778-CC genotype is associated with an increased likelihood of receiving a bone marrow biopsy (BMB) for an isolated low WBC count.This retrospective genetic association study assessed African American patients younger than 90 years who underwent a BMB at Vanderbilt University Medical Center, Mount Sinai Health System, or Children's Hospital of Philadelphia from January 1, 1998, to December 31, 2020.The rs2814778-CC genotype.The proportion of individuals with the CC genotype who underwent BMB for an isolated low WBC count and had a normal biopsy result compared with the proportion of individuals with the CC genotype who underwent BMB for other indications and had a normal biopsy result.Among 399 individuals who underwent a BMB (mean [SD] age, 41.8 [22.5] years, 234 [59%] female), 277 (69%) had the CC genotype. A total of 35 patients (9%) had clinical histories of isolated low WBC counts, and 364 (91%) had other histories. Of those with a clinical history of isolated low WBC count, 34 of 35 (97%) had the CC genotype vs 243 of 364 (67%) of those without a low WBC count history. Among those with the CC genotype, 33 of 34 (97%) had normal results for biopsies performed for isolated low WBC counts compared with 134 of 243 individuals (55%) with biopsies performed for other histories (P < .001).In this genetic association study, among patients of African American race who had a BMB with a clinical history of isolated low WBC counts, the rs2814778-CC genotype was highly prevalent, and 97% of these BMBs identified no hematologic abnormality. Accounting for the rs2814778-CC genotype in clinical decision-making could avoid unnecessary BMB procedures.
Involvement of TIGIT in Natural Killer Cell Exhaustion and Immune Escape in Patients and Mouse Model With Liver Echinococcus multilocularis Infection
Authors: Chuanshan Zhang, Hui Wang, Jing Li, Xinling Hou, Linghui Li, Wei Wang, Yang Shi, Dewei Li, Liang Li, Zhibin Zhao, Liang Li, Tuerganaili Aji, Renyong Lin, Yingmei Shao, Dominique A. Vuitton, Zhigang Tian, Haoyu Sun, Hao Wen
Journal: Hepatology (2021)

Background and Aims Alveolar echinococcosis (AE) is a lethal helminthic liver disease caused by persistent infection with Echinococcus multilocularis. Although more attention has been paid to the immunotolerance of T cells caused by E. multilocularis infection, the role of natural killer (NK) cell, a critical player in liver immunity, is seldom studied. Approach and Results Here, we observed that NK cells from the blood and closed liver tissue (CLT) of AE patients expressed a higher level of inhibitory receptor TIGIT and were functionally exhausted with a lower expression of granzyme B, perforin, interferon-gamma (IFN-γ), and TNF-α. Addition of anti-TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) monoclonal antibody into AE patients' peripheral blood mononuclear cell culture significantly enhanced the synthesis of IFN-γ and TNF-α by NK cells, indicating the reversion of exhausted NK cells by TIGIT blockade. In the mouse model of E. multilocularis infection, liver and splenic TIGIT+ NK cells progressively increased dependent of infection dosage and timing and were less activated and less degranulated with lower cytokine secretion. Furthermore, TIGIT deficiency or blockade in vivo inhibited liver metacestode growth, reduced liver injury, and increased the level of IFN-γ produced by liver NK cells. Interestingly, NK cells from mice with persistent chronic infection expressed a higher level of TIGIT compared to self-healing mice. To look further into the mechanisms, more regulatory CD56bright and murine CD49a+ NK cells with higher TIGIT expression existed in livers of AE patients and mice infected with E. multilocularis, respectively. They coexpressed higher surface programmed death ligand 1 and secreted more IL-10, two strong inducers to mediate the functional exhaustion of NK cells. Conclusions Our results indicate that inhibitory receptor TIGIT is involved in NK cell exhaustion and immune escape from E. multilocularis infection.
beraprost(ドルナー)に対するSildenafil(バイアグラ)の相加効果を確認した慢性肺血栓塞栓性肺高血圧症の一例
Authors: 佐藤隆博, 池田大輔, 大平洋, 神垣光徳, 石丸伸司, 吉村治彦, 坂上慎二, 辻野一三, 工藤敏行
Journal: Circulation (2004)
Beyond the numbers: understanding the diversity of covid-19 epidemiology and response in South Asia
Authors: Zulfiqar A Bhutta, Sameen Siddiqi, Assad Hafeez, Muhammad Islam, Samiran Nundy, Firdausi Qadri, Faisal Sultan
Journal: BMJ (2021)

Zulfiqar A Bhutta and colleagues compare the response in South Asian countries and consider what is needed to contain covid-19 and manage future pandemics