tbuckley/cabot-search huggingface dataset:
Safety and efficacy of combination of GT90001, an anti-activin receptor-like kinase-1 (ALK-1) antibody, and nivolumab in patients with metastatic hepatocellular carcinoma (HCC).
Authors: Chiun Hsu, Yi-Fang Chang, Chia-Jui Yen, Li-Chun Lu, Xiaoyan Zhu, Yuwei Xu, Qiaoxia Zhou, Xunwei Dong, Youzhi Tong
Journal: Journal of Clinical Oncology (2021)

326 Background: GT90001, a fully human anti-ALK-1 mAb (IgG2) that may inhibit ALK-1/ TGF-β signaling and tumor angiogenesis, has shown good single-agent safety profile in humans. This study aimed to assess the safety and efficacy of GT90001 in combination with nivolumab in patients with advanced HCC who had progressive disease after or were intolerant to first-line sorafenib or lenvatinib therapy (NCT03893695). Methods: We did a phase I/II, open-label, single arm, dose de-escalation and expansion trial of GT90001 in combination with nivolumab in patients with histologically or cytologically confirmed HCC with Child-Pugh class A, ECOG performance status of 0 or 1 at three sites in Taiwan. Patients previously treated with immune checkpoint inhibitors were excluded. Stage 1 (dose de-escalation cohort) tested 3 doses of GT90001 (7 (starting dose), 4.5, and 3 mg/kg every 2 weeks) plus nivolumab 3 mg/kg every 2 weeks in 6 subjects at each dose level. Dose-limiting toxicity (DLT) was defined as any treatment-emergent grade 3-4 adverse events (AEs) (CTCAE V5.0) in the first 28 days of treatment. Stage 2 (expansion cohort) tested the combination regimen in 14 patients until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was investigator-assessed objective response as per RECIST v1.1. Results: Between July 9th, 2019 and June 26th, 2020, twenty eligible patients were treated. No DLT was observed in stage 1, and GT90001 7.0 mg/kg + nivolumab 3.0 mg/kg every 2 weeks were given in stage 2. The pharmacokinetics of GT90001 and nivolumab were similar to those observed in monotherapy. As of June 26, 2020, 20 patients were evaluable for safety. The common AEs (occurring to more than 20%) included platelet count decreased, rash, fatigue, dizziness, peripheral edema, and constipation. Three patients had treatment-related serious AEs (renal dysfunction, autoimmune hepatitis, hyperamylasemia). Nine patients had GT90001 dose interruption due to AEs and the most common reasons were platelet count decrease (3 patients). No patient discontinued the treatment due to AEs. The median duration of follow-up was 3.7 months (range 0.6-11.1). An objective response assessed was observed in 7 patients (43.75%) out of 16 evaluable patients, all were partial response and 4 of them had confirmed responses. The disease control rate (complete response + partial response + stable disease) was 56.2%. Updated efficacy data will be presented at the congress. Conclusions: The combination of GT90001 with nivolumab showed a manageable safety profile, and no new safety signals were identified. The promising preliminary antitumor activities show the potential of GT90001 combined with nivolumab as second-line treatment for advanced HCC. Clinical trial information: NCT03893695.
Safety and activity of trifluridine/tipiracil and ramucirumab in previously treated advanced gastric cancer: an open-label, single-arm, phase 2 trial
Authors: Akihito Kawazoe, Takayuki Ando, Hisashi Hosaka, Junya Fujita, Keisuke Koeda, Kazuhiro Nishikawa, Kenji Amagai, Kazumasa Fujitani, Kazuhiro Ogata, Keita Watanabe, Yuji Yamamoto, Kohei Shitara
Journal: The Lancet. Gastroenterology & hepatology (2021)
The first wave of the COVID-19 pandemic in Spain: characterisation of cases and risk factors for severe outcomes, as at 27 April 2020
Journal: Eurosurveillance (2020)

Background The first wave of the coronavirus disease (COVID-19) pandemic spread rapidly in Spain, one of Europe’s most affected countries. A national lockdown was implemented on 15 March 2020. Aim To describe reported cases and the impact of national lockdown, and to identify disease severity risk factors. Methods National surveillance data were used to describe PCR-confirmed cases as at 27 April 2020. We compared case characteristics by severity categories (hospitalisation, admission to intensive care unit (ICU), death) and identified severity risk factors using multivariable regression. Results The epidemic peaked on 20 March. Of 218,652 COVID-19 cases, 45.4% were hospitalised, 4.6% were admitted to ICU and 11.9% died. Among those who died, 94.8% had at least one underlying disease. Healthcare workers (HCWs) represented 22.9% of cases. Males were more likely to have severe outcomes than females. Cardiovascular disease was a consistent risk factor. Patients with pneumonia had higher odds of hospitalisation (odds ratio (OR): 26.63; 95% confidence interval (CI): 25.03–28.33). The strongest predictor of death was age ≥ 80 years (OR: 28.4; 95% CI: 19.85–40.78). Among underlying diseases, chronic renal disease had highest odds of death (OR: 1.47; 95% CI: 1.29–1.68). Conclusions COVID-19 case numbers began declining 6 days after the national lockdown. The first wave of the COVID-19 pandemic in Spain had a severe impact on elderly people. Patients with cardiovascular or renal conditions were at higher risk for severe outcomes. A high proportion of cases were HCWs. Enhanced surveillance and control measures in these subgroups are crucial during future COVID-19 waves.
Abstract 14840: Ability of Coronary Calcium Absence to Predict Negative Stress Test Results in Patients Considered for Flecainide Therapy
Authors: Jeffrey L Anderson, Stacey Knight, Raymond McCubrey, Heidi T May, David B Min, Michael J Cutler, T Jared J Bunch, Joseph B Muhlestein, Kirk U Knowlton
Journal: Circulation (2020)

Background: Flecainide is a useful antiarrhythmic for atrial fibrillation (AF). However, the Cardiac Arrhythmia Suppression Trial (CAST) showed an increased risk of fatal ventricular arrhythmia with flecainide use after myocardial infarction (MI). Thus, a history of MI or coronary artery disease (CAD) is a flecainide exclusion, and stress testing is used to exclude ischemia. We assessed whether absence of coronary artery calcium (CAC) can obviate the need for stress testing. Methods: We assessed ischemic burden using regadenoson Rb-82 PET/CT in 1375 AF patients (pts) ≥50 y old without clinical CAD. CAC was determined qualitatively in these pts by low dose attenuation CT (n=816) or by quantitative CT (n=559). The primary comparison was percentage of pts with ischemic burden ≥5% by CAC presence or absence. Results: Pts with CAC absent (n=433, 31.5%) were younger, heavier, with lower rates of diabetes, hypertension, and dyslipidemia. Average ischemic burden was lower in CAC-absent pts (0.8 ± 3.1 v 1.3 ± 3.7, p=0.04), and a favorable difference trend in ischemic burden ≥5% was noted that did not reach significance (7.2% v 9.7% p=0.15). CAC-absent pts showed greater coronary flow reserve (2.4 v 2.3, p=0.002) and trended to have fewer referrals for coronary angiography (1.6% v 4.0% adjusted[adj]*-p=0.10), fewer findings of obstructive CAD (1.4% v 3.5% adj-p=0.12), and lower rates of 90-day MACE (1.6% v 3.5%, adj-p=0.12); long-term MACE were fewer (5.3% v 7.0% adj-p=0.04). Conclusions: Our results support the hypothesis that an easily administered, inexpensive, low radiation CAC scan may identify a subset of flecainide candidates with a low ischemic burden on PET stress testing and that rarely need coronary angiography/intervention. CAC-absence combined with other clinical information may obviate the need for routine stress testing in selected flecainide candidates. Larger and randomized trials are indicated to confirm these findings and apply CAC use in clinical practice.
Epigenetic regulation of the Wnt-signaling pathway in CIMP-H <i>BRAF</i>V600E mCRC.
Authors: Hey Min Lee, Stefania Napolitano, Van K. Morris, Kunal Rai, John Paul Y.C. Shen, Jennifer S. Davis, Dipen M. Maru, Michael J. Overman, Ji Wu, Oluwadara Coker, Melanie Nicole Woods, Oscar Villarreal, Scott Kopetz
Journal: Journal of Clinical Oncology (2021)

110 Background: BRAFV600E mutation identifies mCRC patients with poor prognosis with only little benefit from standard therapy. Analysis from TCGA revealed that 89% of BRAFV600E CRC tumors were associated with a high CpG island methylator phenotype (CIMP-H), which may result in epigenetic silencing of tumor suppressor genes, while only 29% of BRAF wild-type tumors are CIMP-H. In this study, we define key pathways regulated by global DNA hypermethylation in the context of BRAFV600E mutation. Methods: We analyzed the TCGA Illumina 450k array methylation datasets and RNA-sequencing datasets for 97 CIMP-H CRC tumors (27 BRAFV600E; 69 BRAF WT) identified by five universal CIMP annotations ( p14, p16, MLH1, MINT1, MINT2, MINT31). We defined differential methylation profile according to BRAF mutation status and calculated Spearman correlation between methylation and gene expression to identify CIMP-H BRAF-associated genes. Next, pathways enriched with CIMP-H BRAFV600E tumors were defined using PANTHER pathway analysis. Additionally, β-catenin IHC were conducted on 145 MD Anderson CRC patient samples and compared by CIMP and BRAF status. Results: BRAF mutation is associated with lower rates of APC mutation as has previously been shown (32%, 82%). We identified 6,097 differentially methylated probes by BRAF mutation status (FDR = 10 -4 ), and as expected, our data suggests a higher methylation profile in BRAFV600E mutated tumors compared to BRAF WT. Intriguingly, CIMP-H BRAF-associated genes showed enrichment in the Wnt-signaling and cadherin signaling pathways ( p&lt; 0.0001 (FDR &lt; 0.0001)). Despite the epigenetic Wnt-signaling, nuclear β-catenin expression (as a measure of Wnt activity) in CIMP-H and BRAF tumors remains lower than for non-CIMP, and BRAF wild-type ( p= 0.0003 for comparison of CIMP). Conclusions: Genes under methylation regulation in the BRAF-mutant context showed enrichment in Wnt-signaling pathway. Since BRAFV600E CRC tumors have a low association with APC mutation, this data suggests role of epigenetic regulation of the Wnt-pathway activation. However, as measured by nuclear β-catenin, Wnt activation in these tumors is not as high as traditional APC-mutated CRC tumors. CIMP-H tumors with BRAFV600E mutation is a unique subset of CRC tumor that have Wnt-pathway activation regulated by epigenetic modifications more than a β-catenin activation.
Compensatory intestinal immunoglobulin response after vancomycin treatment in humans
Authors: Torsten P. M. Scheithauer, Guido J. Bakker, Maaike Winkelmeijer, Mark Davids, Max Nieuwdorp, Daniël H. van Raalte, Hilde Herrema
Journal: Gut Microbes (2021)

Intestinal immunoglobulins (Ig) are abundantly secreted antibodies that bind bacteria and bacterial components in the gut. This binding is considered to accelerate bacterial transit time and prevent the interaction of potentially immunogenic compounds with intestinal immune cells. Ig secretion is regulated by alterations in gut microbiome composition, an event rarely mapped in an intervention setting in humans. Here, we determined the intestinal and systemic Ig response to a major intervention in gut microbiome composition. Healthy humans and humans with metabolic syndrome received oral vancomycin 500 mg four times per day for 7 days. Coinciding with a vancomycin-induced increase in Gram-negative bacteria, fecal levels of the immunogenic bacterial components lipopolysaccharide (LPS) and flagellin drastically increased. Intestinal antibodies (IgA and IgM) significantly increased, whereas peripheral antibodies (IgG, IgA, and IgM) were mostly unaffected by vancomycin treatment. Bacterial cell sorting followed by 16S rRNA sequencing revealed that the majority of Gram-negative bacteria, including opportunistic pathogens, were IgA-coated after the intervention. We suggest that the intestinal Ig response after vancomycin treatment prevents the intrusion of pathogens and bacterial components into systemic sites.
FRI0252 Eosinophilic myositis associated with behcet’s disease
Authors: B Coleiro, C Mallia
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Behcet’s disease, a systemic vasculitis of unknown aetiology, has a variety of clinical manifestations, the commoner ones including recurrent oro-genital ulceration, uveitis and rashes. Muscular involvement is an uncommon clinical feature and a review of the literature by Worthmann F <i>et al</i>.<sup>1</sup> suggests that the myositis passes through two different stages of inflammation: a granulocytic-monocytic phase followed by a predominantly lymphocytic infiltration phase. We present the case of a 24 year old male who satisfies the International Study Group criteria for the diagnosis of Behcet’s disease,<sup>2</sup> and who developed features of a localised myositis which differs from that described in the literature in that, histologically, the inflammatory cell infiltrate included significant eosinophilia. <h3>References</h3> Worthmann F, <i>et al</i>. Muscular involvement in Behcet’s disease: Case report and review of the literature. Neurosci Disord. 1996;6(4):247–53 International Study Group for Behcet’s Disease. Criteria for diagnosis of Behcet’s disease. Lancet 1990;335:1078–80
The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude
Authors: Gwilym J. Webb, Ronan P. Ryan, Tom P. Marshall, Gideon M. Hirschfield
Journal: Clinical Gastroenterology and Hepatology (2021)

The epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases' rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude.We performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees.The cohort included 8,590,421 records with 53.3 × 107 years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34-2.60); PSC, 0.74 (95% CI, 0.67-0.82); and AIH, 1.94 (95% CI, 1.83-2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79-2.60) to 4.86 (95% CI, 3.93-6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65-2.43) to 3.28 (95% CI, 2.53-4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60-1.11) to 1.02 (95% CI, 0.64-1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude.We describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation.
Skeletal Muscle-Derived Stem Cell Transplantation: Angiogenesis Is Required for Improved Left Ventricular Function⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: H. Kirk Hammond
Journal: Journal of the American College of Cardiology (2007)
AB0219 Quantitative hemostatic indices in secondary and myeloproliferative thrombocytosis
Authors: J Parada-Turska, B Sokolowska, A Walter-Croneck, A Dmoszynska, L Szczepanski, J Brzozowska, M Sledzinska, M Kokoszka
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> An elevated platelet count may lead to an increased incidence of systemic thromboembolism or unexpectedly to thrombohemorragic complications. Both, incidences of systemic thromboembolism and unexpected thrombohemorragic complications (bleeding) were described in patients with an elevated platelet count. In the present study the quantitative hemostatic indices were measured in 46 patients with thrombocytosis (platelet count &gt; 400.000 per microliter), including 23 patients with secondary thrombocytosis (17 patients with rheumatoid arthritis, 2 with lung cancer, 1 with systemic lupus erythematosus, 1 with granuloma Wegeneri) and 23 patients with myeloproliferative thrombocytosis (12 with chronic myeloid leukaemia, 8 with polycythemia vera, 3 with idiopathic thrombocytosis). In both studied groups, von Willebrand factor activity and epinephrine-induced platelet aggregation were decreased, and activated partial thromboplastin time was prolonged, thus, suggesting increased risk of bleeding complications. On the other hand, the concentrations of fibrinogen and d-dimmers were enhanced and bleeding time was shortened. These findings argue for an enhanced risk of thrombosis. Since no differences between two studied groups were found, it seems that the observed abnormalities were directly related to the elevated platelet count and were not associated with primary disease. The low incidence of hemostatic complications in patients with secondary and myeloproliferative thrombosis may suggest that the coexistence of an additional component is critical for the clinical manifestation of such disturbances. <h3>Objectives</h3> <h3>Methods</h3> <h3>Results</h3> <h3>Conclusion</h3>
Minimally Invasive Nasal Depot (MIND) technique for direct BDNF AntagoNAT delivery to the brain
Authors: Smrithi Padmakumar, Gregory Jones, Grishma Pawar, Olga Khorkova, Jane Hsiao, Jonghan Kim, Mansoor M. Amiji, Benjamin S. Bleier
Journal: Journal of Controlled Release (2021)
A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA
Authors: Jörn M. Schattenberg, Albert Pares, Kris V. Kowdley, Michael A. Heneghan, Stephen Caldwell, Daniel Pratt, Alan Bonder, Gideon M. Hirschfield, Cynthia Levy, John Vierling, David Jones, Anne Tailleux, Bart Staels, Sophie Megnien, Remy Hanf, David Magrez, Pascal Birman, Velimir Luketic
Journal: Journal of Hepatology (2021)
Targeting 5-HT <sub>2B</sub> Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction
Authors: J. Caleb Snider, Lance A. Riley, Noah T. Mallory, Matthew R. Bersi, Prachi Umbarkar, Rekha Gautam, Qinkun Zhang, Anita Mahadevan-Jansen, Antonis K. Hatzopoulos, Luc Maroteaux, Hind Lal, W. David Merryman
Journal: Circulation (2021)

Background: Myocardial infarction (MI) induces an intense injury response that ultimately generates a collagen-dominated scar. Although required to prevent ventricular rupture, the fibrotic process is often sustained in a manner detrimental to optimal recovery. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process after MI. Serotonin 2B receptor (5-HT 2B ) signaling has been shown to be harmful in a variety of cardiopulmonary pathologies and could play an important role in mediating scar formation after MI. Methods: We used 2 pharmacological antagonists to explore the effect of 5-HT 2B inhibition on outcomes after MI and characterized the histological and microstructural changes involved in tissue remodeling. Inducible 5-HT 2B ablation driven by Tcf21 MCM and Postn MCM was used to evaluate resident cardiac fibroblast- and myofibroblast-specific contributions of 5-HT 2B , respectively. RNA sequencing was used to motivate subsequent in vitro analyses to explore cardiac fibroblast phenotype. Results: 5-HT 2B antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated by decreased scar thickness and decreased border zone area. 5-HT 2B antagonism resulted in collagen fiber redistribution to thinner collagen fibers that were more anisotropic, enhancing left ventricular contractility, whereas fibrotic tissue stiffness was decreased, limiting the hypertrophic response of uninjured cardiomyocytes. Using a tamoxifen-inducible Cre, we ablated 5-HT 2B from Tcf21 -lineage resident cardiac fibroblasts and saw similar improvements to the pharmacological approach. Tamoxifen-inducible Cre-mediated ablation of 5-HT 2B after onset of injury in Postn -lineage myofibroblasts also improved cardiac outcomes. RNA sequencing and subsequent in vitro analyses corroborate a decrease in fibroblast proliferation, migration, and remodeling capabilities through alterations in Dnajb4 expression and Src phosphorylation. Conclusions: Together, our findings illustrate that 5-HT 2B expression in either cardiac fibroblasts or activated myofibroblasts directly contributes to excessive scar formation, resulting in adverse remodeling and impaired cardiac function after MI.
Construction of a risk map to understand the vulnerability of various types of cancer patients to COVID‐19 infection
Authors: Jian He, Xufang Yang, Hui Wang
Journal: MedComm (2021)

Abstract COVID‐19 is leading to a global pandemic and invades human cells via ACE2 . ACE2 was found to be abundantly expressed in many organs and cells. However, there is no evidence about the potential risk of various types of cancer patients vulnerable to the infection of COVID‐19. To obtain a risk map that indicates the novel coronavirus vulnerability of different types of cancer, we analyzed in this work the RNA sequencing datasets of cancer patients. By interrogating the datasets, we not only identified the cancer types vulnerable to COVID‐19 attacks, but also we reported that variations in the mRNA expression level of ACE2 correlate to various prognosis phenomenon in different types of cancer cohorts, and illustrated the underlying mechanism involved or may be related to lymphocytes infiltration. From these discoveries, we constructed an infection risk map, which indicates the vulnerability of different types of cancer to COVID‐19 infection, also elucidated the correlationship between ACE2 and the prognosis of cancer. We found that high ACE2 expression levels lead to high risk of COVID‐19 infection and poor prognosis of breast invasive carcinoma (BRCA), while better prognosis in ovarian serous cystadenocarcinoma (OV) patient cohorts. Moreover, our study demonstrated that this different pattern may correlate with the immune infiltration level.