tbuckley/cabot-search huggingface dataset:
Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome
Authors: Natalia I. Dmitrieva, Avram D. Walts, Dai Phuong Nguyen, Alex Grubb, Xue Zhang, Xujing Wang, Xianfeng Ping, Hui Jin, Zhen Yu, Zu-Xi Yu, Dan Yang, Robin Schwartzbeck, Clifton L. Dalgard, Beth A. Kozel, Mark D. Levin, Russell H. Knutsen, Delong Liu, Joshua D. Milner, Diego B. López, Michael P. O’Connell, Chyi-Chia Richard Lee, Ian A. Myles, Amy P. Hsu, Alexandra F. Freeman, Steven M. Holland, Guibin Chen, Manfred Boehm
Journal: Journal of Clinical Investigation (2020)

There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job's syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α-stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.
Effects of ursodeoxycholic acid and chenodeoxycholic acid on human hepatocytes in primary culture
Authors: S HILLAIRE
Journal: Hepatology (1995)

Hepatic bile acid concentrations are elevated in chronic cholestasis because of reduced canalicular excretion and active ileal absorption of the fraction eliminated in the gut. Ursodeoxycholic acid (UDCA) reduces the intestinal absorption of endogenous bile acids, thereby diminishing the concentrations to which liver cells are exposed. In the isolated perfused liver (in which vectorial bile acid transport is maintained), UDCA reduces the cytotoxic and cholestatic effects of endogenous bile acids. As a result, it has been suggested that UDCA or one of its conjugates could have a direct protective effect on hepatocyte structure and function. We therefore studied the effects of chenodeoxycholic acid (CDCA) and tauroursodeoxycholic acid (TUDCA) alone and in combination on the viability and certain functions of human hepatocytes in primary culture. TUDCA did not affect intracellular concentrations of CDCA when added concomitantly. In other experiments, CDCA (100 to 500 μmol/L) induced concentration-dependent increases in lactate dehydrogenase (LDH) leakage and decreases in cellular protein synthesis and albumin secretion. Neither TUDCA nor UDCA had similar effects at the same concentrations, nor did they have a protective effect when added concomitantly with CDCA at equimolar or twice-equimolar concentrations. These results suggest that UDCA has no direct cytoprotective effect when the bile acid concentrations to which human hepatocytes are exposed are unchanged. They also suggest that the hepatoprotective effect of UDCA in cholestatic human liver diseases and in the isolated perfused liver loaded with hydrophobic bile acids occurs through its effect on intestinal and hepatocyte transport systems. (HEPATOLOGY 1995;22:82–87.)
Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT
Authors: Jaime Sanz, Jacques-Emmanuel Galimard, Myriam Labopin, Boris Afanasyev, Emanuele Angelucci, Fabio Ciceri, Didier Blaise, Jan J. Cornelissen, Ellen Meijer, J. L. Diez-Martin, Yener Koc, Montserrat Rovira, Luca Castagna, Bipin Savani, Annalisa Ruggeri, Arnon Nagler, Mohamad Mohty
Journal: Journal of Hematology & Oncology (2020)

Abstract Background The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. There is no information on the impact of donor types using homogeneous prophylaxis with PTCy. Methods We retrospectively compared outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD ( n = 215), MUD ( n = 235), and Haplo ( n = 789) donors registered in the EBMT database between 2010 and 2017. Results The median follow-up was 2 years. Haplo-SCT carried a significantly increased risk of acute grade II–IV GVHD (HR 1.6; 95% CI 1.1–2.4) and NRM (HR 2.6; 95% CI 1.5–4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5–0.9) that translated to no differences in LFS (HR 1.1; 95% CI 0.8–1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8–1.3). Interestingly, the use of peripheral blood was associated with an increased risk of acute (HR 1.9; 95% CI 1.4–2.6) and chronic GVHD (HR 1.7; 95% CI 1.2–2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5–0.9). Conclusions The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD, and Haplo is safe and effective. Haplo-SCT had increased risk of acute GVHD and NRM and lower relapse incidence but no significant difference in survival.
Absence of JAK2V617F Mutated Endothelial Colony‐Forming Cells in Patients With JAK2V617F Myeloproliferative Neoplasms and Splanchnic Vein Thrombosis
Authors: Alexandre Guy, Anicee Danaee, Koralia Paschalaki, Lisa Boureau, Etienne Rivière, Gabriel Etienne, Olivier Mansier, Michael Laffan, Mallika Sekhar, Chloe James
Journal: HemaSphere (2020)

Supplemental Digital Content is available in the text
MOLECULAR IMAGING OF THE HUMAN PULMONARY VASCULAR ENDOTHELIUM IN PULMONARY HYPERTENSION: THE PULMOBIND SAFETY AND PROOF OF PRINCIPLE TRIAL
Authors: Jocelyn Dupuis, François Harel, David Langleben, Steve Provencher, Alain Fournier, Quang T. Nguyen, Vincent Finnerty, Myriam Letourneau, Xavier Levac, Asmaa Mansour, Gad Abikhzer, Jean Guimond
Journal: Journal of the American College of Cardiology (2016)
Abstract 15513: Tolvaptan Alone Significantly Worsend Left Ventricular Remodeling and Survival Rate via Increase of the Aquaporin 1 in Kidney in Murine Heart Failure After Myocardial Infarction
Authors: Akiyo Eguchi, Shinichi Hirotani, Toshihiro Iwasaku, Yoshitaka Okuhara, Daisuke Morisawa, Hisashi Sawada, Makiko Oboshi, Yoshiro Naito, Toshihiro Mano, Tohru Masuyama
Journal: Circulation (2015)

Background: Little is known about the chronic effects of Tolvaptan, V2 receptor antagonist. Therefore, we examined the chronic effects of administration of tolvaptan and/or furosemide on survival, cardiac and renal histology in murine heart failure after myocardial infarction. Methods: Fourteen days after ligating the left anterior descending coronary artery (MI), mice were randomly assigned to either placebo (P), Tolvaptan (T), or furosemide and T (FT) treatment. Survival rate was examined in each group. After four weeks after diuretic treatments, mice were sacrificed and cardiac histological analyses and cardiac and renal mRNA expression were examined. Results: First, we compared survival rates of P- or T-treated mice. Surprisingly, the survival rate of P group was significantly higher than that of T group (73.7% vs. 58.3%, p&lt;0.05). Four weeks after diuretic treatments, heart weight (HW)/body weight (BW) and lung W (LW)/BW were significantly higher in T group than in P group (HW/BW; 5.9 ± 0.2 vs. 6.8 ± 0.2 p &lt;0.05, LW/BW 5.3 ± 0.2 vs. 7.8 ± 0.8 p &lt;0.05). Next, to reduce congestion in T group, we fed the MI mice with FT containing chow. FT treatment improved survival rate compared with T treatment (61.5% vs. 71.4%, p&lt;0.05). After four weeks of the treatment, HW/BW and LW/BW decreased in FT group compared with in T (HW/BW; 6.7 ± 0.2 vs. 5.5 ± 0.1 p &lt;0.05, LW/BW; 7.0 ± 0.6 vs. 5.6 ± 0.2 p &lt;0.05). FT treatment significantly suppressed myocardial fibrosis in remote myocardium compared with T treatment. Furthermore mRNA levels of ANP, BNP, and collagen I in the remote myocardium in FT group were lower compared with T group (ANP: 1 ± 0.1 vs. 0.5 ± 0.1 p &lt;0.05, BNP; 1 ± 0.03 vs. 0.6 ± 0.04 p &lt; 0.05, Collagen I; 1 ± 0.08 vs. 0.6 ± 0.1 p &lt; 0.05). Interestingly, mRNA level of Aquaporin 1 (AQP1), which is a key transporter of free water absorption in proximal tubule, increased in T group compared with P group, and it reduced in FT group compared with T group (AQP1; 3.3 ± 0.4 vs. 4.2 ± 0.1 p &lt; 0.05, 4.1 ± 0.05 vs. 2.0 ± 0.2 p &lt; 0.05). Conclusion: T treatment increased congestion and worsenend survival in murine heart failure. FT treatment successfully improved congestion and survival compared with T treatment. The mechanism by which T treatment failed to reduce congestion and mortality may be due to upregulation of AQP1.
Osmosis‐Powered Hydrogel Microneedles for Microliters of Skin Interstitial Fluid Extraction within Minutes
Authors: Mengjia Zheng, Zifeng Wang, Hao Chang, Lulu Wang, Sharon W. T. Chew, Daniel Chin Shiuan Lio, Mingyue Cui, Linbo Liu, Benjamin C. K. Tee, Chenjie Xu
Journal: Advanced Healthcare Materials (2020)

Abstract Hydrogel microneedle patch enables the extraction of skin interstitial fluid (ISF) through in situ swelling in a minimally invasive manner without assistance of mechano‐chemical peripherals. However, existing hydrogel microneedles require tens of minutes with multistep process to collect sufficient volume (1 mL) for effective analysis. This study introduces an osmolyte‐powered hydrogel microneedle patch that can extract ISF three times faster than the existing platforms and provide in situ analysis of extracted biomarkers. The microneedle patch is composed of osmolytes (i.e., maltose) and hydrogel (i.e., methacrylated hyaluronic acid). During the extraction process, the osmolytes dissolve in the matrix and provide the osmotic pressure that increases the diffusion of ISF from skin to the hydrogel matrix. A patch with 100 microneedles can extract 7.90 µL of ISF from pig skin ex vivo and 3.82 µL of ISF from mouse skin in vivo within 3 min, whereas the control (i.e., hydrogel microneedle without osmolytes) requires &gt;10 min to achieve similar results. The extracted ISF allows the quantification of biomarkers such as glucose and/or drugs such as insulin in vivo. Through the integration with the electronic glucose sensors, the whole system permits the direct and rapid analysis of the extracted glucose.
Public Health Measures and the Reproduction Number of SARS-CoV-2
Authors: Thomas V. Inglesby
Journal: JAMA (2020)

An Pan, PhD; Li Liu, MD, PhD; Chaolong Wang, PhD; Huan Guo, MD, PhD; Xingjie Hao, PhD; Qi Wang, MD, PhD; Jiao Huang, PhD; Na He, PhD; Hongjie Yu, PhD; Xihong Lin, PhD; Sheng Wei, MD, PhD; Tangchun Wu, MD, PhD
Fatal anaphylaxis in Italy: Analysis of cause‐of‐death national data, 2004‐2016
Authors: Maria Beatrice Bilò, Alice Corsi, Matteo Martini, Elena Penza, Francesco Grippo, Donatella Bignardi
Journal: Allergy (2020)

Abstract Background Epidemiological data on fatal anaphylaxis are underestimated worldwide. Few Italian data do exist. The aims of the study are to determine the anaphylaxis mortality rate in Italy and its associations with demographic characteristics (gender, age, and geographical distribution), and to investigate which are the most common triggers of fatal anaphylaxis. Material and methods This is a descriptive study analyzing data reported to the National Register of Causes of Death database and managed by the Italian National Institute of Statistics for the years 2004‐2016. An analytical method was developed to identify all the ICD‐10 codes related to anaphylaxis deaths, which were divided into two classes: “Definite anaphylaxis deaths” and “Possible anaphylaxis deaths.” Results From 2004 through 2016, 392 definite anaphylaxis deaths and 220 possible anaphylaxis deaths were recorded. The average mortality rate for definite anaphylaxis, from 2004 to 2016, was 0.51 per million population per year. Definite fatal anaphylaxis was mostly due to the use of medications (73.7%), followed by unspecified causes (20.7%) and hymenoptera stings (5.6%). Concerning possible anaphylaxis deaths, the most common cause was venom‐stinging insect (51.4%). We did not find any data on food fatal anaphylaxis. Unspecified anaphylaxis accounted for 21%‐28% of all cases, underlining the difficulty in accurately ascertaining the causes of fatal anaphylaxis and therefore in assigning the proper ICD‐10 code. Conclusion This is the first study of anaphylaxis‐related mortality coming from an official database of the whole Italian population. However, the actual number of deaths by anaphylaxis, and their related triggers, is probably underreported, mostly due to limitations of the current recording system, and to a poor allergy education. Corrective actions should be undertaken for the benefit of the Health System.
The Child with Traumatic Brain Injury or Cerebral Palsy: a Context-Sensitive Family-Based Approach to Development, Lucia Willadino Braga, Aloysio Campos da Paz (Eds.). Taylor & Francis (2005), £95, 287 pages and CD-ROM, ISBN: 1 84184 503 5
Authors: Vicki Anderson
Journal: The Lancet Neurology (2006)
Evaluating the Role of the Steroid and Xenobiotic Receptor (SXR/PXR) in PCB-153 Metabolism and Protection against Associated Adverse Effects during Perinatal and Chronic Exposure in Mice
Authors: Riann Jenay Egusquiza, Maria Elena Ambrosio, Shuyi Gin Wang, Kaelen Marie Kay, Chunyun Zhang, Hans-Joachim Lehmler, Bruce Blumberg
Journal: Environmental Health Perspectives (2020)

Polychlorinated biphenyls (PCBs) are environmental toxicants; PCB exposure has been associated with adverse effects on wildlife and humans. However, the mechanisms underlying these adverse effects are not fully understood. The steroid and xenobiotic receptor [SXR; also known as the pregnane X receptor (PXR) and formally known as NR1I2] is a nuclear hormone receptor that regulates inducible metabolism of drugs and xenobiotics and is activated or inhibited by various PCB congeners.The aim of this study was to investigate the effects of exposure to PCB-153, the most prevalent PCB congener in human tissues, on SXR knockout mice (SXRKO) and to elucidate the role of SXR in PCB-153 metabolism and promotion of its harmful effects.Wild-type (WT) and SXRKO mice were chronically or perinatally exposed to a low dose (54μg/kg/d) of PCB-153. Blood, livers, and spleens were analyzed using transcriptome sequencing (RNA-seq) and molecular techniques to investigate the impacts of exposure on metabolism, oxidative stress, and hematological parameters.SXRKO mice perinatally exposed to PCB-153 displayed elevated oxidative stress, symptoms of hemolytic anemia, and premature death. Transcriptomal analysis revealed that expression of genes involved in metabolic processes was altered in SXRKO mice. Elevated levels of the PCB-153 metabolite, 3-OH-PCB-153, were found in exposed SXRKO mice compared to exposed WT mice. Blood hemoglobin (HGB) levels were lower throughout the lifespan, and the occurrence of intestinal tumors was larger in SXRKO mice chronically exposed to PCB-153 compared to vehicle and WT controls.Our results suggest that altered metabolism induced by SXR loss of function resulted in the accumulation of hydroxylated metabolites upon exposure to PCB-153, leading to oxidative stress, hemolytic anemia, and tumor development in a mouse model. These results support a major role for SXR/PXR in protection against xenobiotic-induced oxidative stress by maintaining proper metabolism in response to PCB-153 exposure. This role of SXR could be generally applicable to other environmental toxicants as well as pharmaceutical drugs. https://doi.org/10.1289/EHP6262.
T cell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers
Authors: Prabhu S. Arunachalam, Tysheena P. Charles, Vineet Joag, Venkata S. Bollimpelli, Madeleine K. D. Scott, Florian Wimmers, Samantha L. Burton, Celia C. Labranche, Caroline Petitdemange, Sailaja Gangadhara, Tiffany M. Styles, Clare F. Quarnstrom, Korey A. Walter, Thomas J. Ketas, Traci Legere, Pradeep Babu Jagadeesh Reddy, Sudhir Pai Kasturi, Anthony Tsai, Bertrand Z. Yeung, Shakti Gupta, Mark Tomai, John Vasilakos, George M. Shaw, Chil-Yong Kang, John P. Moore, Shankar Subramaniam, Purvesh Khatri, David Montefiori, Pamela A. Kozlowski, Cynthia A. Derdeyn, Eric Hunter, David Masopust, Rama R. Amara, Bali Pulendran
Journal: Nature Medicine (2020)

Abstract Recent efforts toward an HIV vaccine focus on inducing broadly neutralizing antibodies, but eliciting both neutralizing antibodies (nAbs) and cellular responses may be superior. Here, we immunized macaques with an HIV envelope trimer, either alone to induce nAbs, or together with a heterologous viral vector regimen to elicit nAbs and cellular immunity, including CD8 + tissue-resident memory T cells. After ten vaginal challenges with autologous virus, protection was observed in both vaccine groups at 53.3% and 66.7%, respectively. A nAb titer &gt;300 was generally associated with protection but in the heterologous viral vector + nAb group, titers &lt;300 were sufficient. In this group, protection was durable as the animals resisted six more challenges 5 months later. Antigen stimulation of T cells in ex vivo vaginal tissue cultures triggered antiviral responses in myeloid and CD4 + T cells. We propose that cellular immune responses reduce the threshold of nAbs required to confer superior and durable protection.
ACT001 reduces the expression of PD-L1 by inhibiting the phosphorylation of STAT3 in glioblastoma
Authors: Luqing Tong, Jiabo Li, Qiuying Li, Xuya Wang, Ravi Medikonda, Tianna Zhao, Tao Li, Haiwen Ma, Li Yi, Peidong Liu, Yang Xie, John Choi, Shengping Yu, Yu Lin, Jun Dong, Qiang Huang, Xun Jin, Michael Lim, Xuejun Yang
Journal: Theranostics (2020)

ACT001, which is derived from an ancient anti-inflammatory drug, has been shown to cross the blood-brain barrier in preclinical studies and has demonstrated anti-glioblastoma (GBM) activity in clinical trials. However, its pharmacological potential for anti-GBM immune response modulation remains unclear. The chemical structure of ACT001 indicates that it may bind to STAT3 and thus modulate antitumor immune response. Methods: Bioinformatics and immunohistochemistry (IHC) were used to assess STAT3 and PD-L1 expression in gliomas. Western blotting, RT-PCR and immunofluorescence were used to detect PD-L1 and p-STAT3 expression in glioma cells exposed to ACT001. Chromatin immunoprecipitation, an ACT001-Biotin probe, and a dual-luciferase reporter assay were used to detect direct modulation. The in vivo efficacy of ACT001 was evaluated in GL261 murine glioma model. Survival analyses were conducted using the log-rank (Mantel-Cox) test. Results: Bioinformatic analysis of 1,837 samples from 4 public glioma datasets showed that STAT3 mRNA expression was correlated with the degree of malignancy and therapeutic resistance and that STAT3 mRNA expression was related to immunosuppression, leukocyte infiltration, and PD-L1 expression. IHC staining of 53 tissue samples confirmed that relatively high phosphorylated STAT3 and PD-L1 protein expression was associated with a relatively advanced World Health Organization (WHO) glioma grade. Next, we confirmed that ACT001 treatment reduced PD-L1 expression and STAT3 phosphorylation. An ACT001-biotin probe was used to verify that ACT001 bound to STAT3. We also demonstrated that STAT3 bound to the PD-L1 promoter. The inhibition of PD-L1 expression and STAT3 phosphorylation by ACT001 could be rescued by STAT3 overexpression. Additionally, ACT001 inhibited GBM growth and decreased PD-L1 expression in vivo. The expression of the M2 markers CD206 and CD163 was decreased, while that of the antitumor immune markers iNOS and IFNγ was increased by ACT001 in vivo. Conclusion: Our results demonstrate that STAT3 plays a key role in immunosuppression of glioma and is inhibited by ACT001. ACT001 inhibits PD-L1 transcription and modulates anti-tumor immune response in glioma bearing mice. These findings will help us to understand the mechanism of ACT001 in GBM therapy.
一种名为 OPN3 的蛋白质可能在由阳光引起的皮肤老化中发挥作用
Authors: Y. Lan, Y. Wang, H. Lu
Journal: British Journal of Dermatology (2020)

我们的皮肤经常暴露于阳光中的紫外线辐射下。长期暴露于紫外线辐射(主要是一种称为 UVA 的紫外线)会使称为人真皮成纤维细胞 (HDF) 的皮肤细胞中的基质金属蛋白酶 (MMP) 增加,尤其是 MMP1、MMP2、MMP3 和 MMP9。 MMP 可导致为皮肤提供支撑和结构的纤维结缔组织分解,而这是皮肤光老化(由紫外线引起的皮肤老化)的最重要原因。 我们并不清楚在分子水平上,成纤维细胞如何感觉 UVA,并通过细胞触发信号传导至 MMP。 本研究分析了体内一种称为 Opsin (OPN) 的蛋白质,这种蛋白质可以改变其信号通路(它们如何与其他细胞交流),对光线照射做出反应。OPN 在我们的视力、昼夜节律(我们的睡眠‐觉醒周期)以及眼睛瞳孔对光的反应中起着重要作用。 这项研究证明,一种称为 OPN3 的 OPN 在 UVA 暴露后,在 HDF 中的 MMP1、MMP2、MMP3 和 MMP9 产生中发挥作用。这提供了对人类皮肤细胞对 UVA 辐射反应的分子机制的了解,并可能揭示预防或治疗皮肤光老化的分子靶标。 本摘要涉及研究:Opsin 3 是人真皮成纤维细胞中紫外线 A 诱导光老化的关键调节因子。
Addition of Maraviroc Versus Placebo to Standard Antiretroviral Therapy for Initial Treatment of Advanced HIV Infection
Authors: Yves Lévy, Jean-Daniel Lelièvre, Lambert Assoumou, Esther Aznar, Federico Pulido, Giuseppe Tambussi, Manuel Crespo, Agnès Meybeck, Jean-Michel Molina, Constance Delaugerre, Jacques Izopet, Gilles Peytavin, Fanny Cardon, Alpha Diallo, Rémi Lancar, Lydie Béniguel, Dominique Costagliola
Journal: Annals of Internal Medicine (2020)

This randomized trial evaluates whether there is a benefit of adding maraviroc, an antiretroviral drug with immunologic effects, to standard combined antiretroviral therapy for patients with advanc...