tbuckley/cabot-search huggingface dataset:
Human β-defensin 3 gene modification promotes the osteogenic differentiation of human periodontal ligament cells and bone repair in periodontitis
Authors: Lingjun Li, Han Jiang, Rixin Chen, Jing Zhou, Yin Xiao, Yangheng Zhang, Fuhua Yan
Journal: International Journal of Oral Science (2020)

Abstract Efforts to control inflammation and achieve better tissue repair in the treatment of periodontitis have been ongoing for years. Human β-defensin 3, a broad-spectrum antimicrobial peptide has been proven to have a variety of biological functions in periodontitis; however, relatively few reports have addressed the effects of human periodontal ligament cells (hPDLCs) on osteogenic differentiation. In this study, we evaluated the osteogenic effects of hPDLCs with an adenoviral vector encoding human β-defensin 3 in an inflammatory microenvironment. Then human β-defensin 3 gene-modified rat periodontal ligament cells were transplanted into rats with experimental periodontitis to observe their effects on periodontal bone repair. We found that the human β-defensin 3 gene-modified hPDLCs presented with high levels of osteogenesis-related gene expression and calcium deposition. Furthermore, the p38 MAPK pathway was activated in this process. In vivo, human β-defensin 3 gene-transfected rat PDLCs promoted bone repair in SD rats with periodontitis, and the p38 mitogen-activated protein kinase (MAPK) pathway might also have been involved. These findings demonstrate that human β-defensin 3 accelerates osteogenesis and that human β-defensin 3 gene modification may offer a potential approach to promote bone repair in patients with periodontitis.
Long-Term Survival of Asymptomatic Patients With Very Severe Aortic Stenosis
Authors: Seung-Ah Lee, Sung-Ji Park, Sahmin Lee, Dae-Hee Kim, Jong-Min Song, Seung Woo Park, Cheol-Hyun Chung, Jae-Kwan Song, Jae-Won Lee, Duk-Hyun Kang
Journal: Journal of the American College of Cardiology (2020)
Effect of functional grade and etiology on in vivo hepatic phosphorus-31 magnetic resonance spectroscopy in cirrhosis: Biochemical basis of spectral appearances*1
Authors: D MENON
Journal: Hepatology (1995)

Hepatic phosphorus-31 magnetic resonance spectroscopy (31P MRS) was undertaken in 85 patients with histologically proven cirrhosis of varying etiologies and functional severity. Reference data were acquired from 16 healthy volunteers who had no history or evidence of liver disease or alcohol abuse. In vivo hepatic 31PMR spectra were acquired with pulse angle 45° and repetition times (TR) of 5 and 0.5 seconds. Peak area ratios of phosphomonoesters (PME), inorganic phosphate (Pi), and phosphodiesters (PDE) relative to βATP, and of PME relative to PDE were calculated from spectra acquired at TR 5 seconds. Estimates of saturation effects for individual resonances were obtained by dividing the peak height at TR 5 seconds by that at TR 0.5 seconds to yield a TI-related signal height ratio (SHR). When compared with reference values, the patients with liver disease showed a significantly higher PME/ATP (P< .0001), PME/PDE (P < .0001), PME SHR (P < .001), and Pi SHR (P < .02), and a lower PDE/ATP (P < .001) and PDE SHR (P < .001). The magnitude of these changes increased significantly and progressively with increasing functional impairment. In patients with compensated cirrhosis spectral appearances varied with etiology; thus, patients with postviral cirrhosis showed a significantly higher Pi/ATP; those with alcoholic cirrhosis, a significantly lower PDE/ATP; and those with cirrhosis secondary to primary sclerosing cholangitis, a significantly lower Pi/ATP than the healthy volunteers or other etiological groups. However, spectral appearances did not vary with etiology in patients with decompensated disease. In vitro 31P MRS of perchloric extracts of samples of liver tissue obtained from 10 patients with cirrhosis at transplant hepatectomy showed increases in levels of the soluble PME metabolites, phosphorylcholine and phosphorylethanolamine, and reductions in the levels of the soluble PDE metabolites, glycerophosphorylcholine and glycerophosphorylethanolamine. These changes suggest regenerative activity in cirrhotic livers. The increases in soluble phosphomonoesters in the aqueous extracts accounted for the increased PME/ATP ratio seen in the in vivo spectra, and might account for the increase in PME SHR. The reduction in soluble phosphodiesters in the aqueous extracts did not entirely account for the reduction PDE/ATP ratio seen in vivo. This change in the PDE resonance in hepatic in vivo spectra may also be partly due to reduced contribution to this peak from hepatic endoplasmic reticulum, resulting from replacement of hepatocytes by fibrous tissue. Hepatic 31P MRS provides insights into the pathophysiology of liver injury and may contribute to the assessment of hepatic functional state.
The electron transport chain of the microbicidal oxidase of phagocytic cells and its involvement in the molecular pathology of chronic granulomatous disease.
Authors: A W Segal
Journal: Journal of Clinical Investigation (1989)

The earliest experiments attempted to purify the oxidase from whole-cell homogenates and crude subcellular fractions.These were incubated with a variety of potential substrates in an attempt to demonstrate oxidase or diaphorase activity (5).The dramatic increase in the activity ofthe hexose monophosphate shunt in association with the respiratory burst (6) indicated one of its products, NADPH (7), as the most physiological of these substrates.A variety of activities were detected, but the
Association of Individual-Level Factors With Visual Outcomes in Optic Neuritis
Authors: Lindsey B. De Lott, James F. Burke, Chris A. Andrews, Fiona Costello, Wayne T. Cornblath, Jonathan D. Trobe, Paul P. Lee, Kevin A. Kerber
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Using corticosteroids to treat acute demyelinating optic neuritis has been identified as an area for shared decision-making. However, no analysis exists to support personalized shared decision-making that considers long- and short-term treatment benefits. <h3>Objective</h3> To develop models of individual-level visual outcomes for patients with optic neuritis. <h3>Design, Setting, and Participants</h3> This secondary analysis of the Optic Neuritis Treatment Trial (ONTT), a randomized clinical trial, was performed at 14 academic eye centers and 1 large community eye center. Adults aged 18 to 46 years with incident acute unilateral optic neuritis within 8 days of vision loss onset were included. Data were collected from July 1988 to June 1991, downloaded on October 15, 2018, and analyzed from January 24, 2019, to February 20, 2020, using multivariable linear regression modeling. <h3>Exposures</h3> Intravenous corticosteroids vs placebo. <h3>Main Outcomes and Measures</h3> Visual acuity (VA) at 1 year. Secondary outcomes were 1-year contrast sensitivity (CS) and VA and CS at 15 and 30 days. Independent variables included age, sex, race, multiple sclerosis status, optic neuritis episodes in the fellow eye, vision symptoms (days), pain, optic disc swelling, viral illness, treatment group, and baseline VA or CS. <h3>Results</h3> Of the 455 participants, median age was 31.8 (interquartile range [IQR], 26.3-37.0) years; 350 (76.9%) were women; and 388 (85.3%) were white. For 410 participants (90.1%) with 1-year outcomes, median VA improved from 20/66 (IQR, 20/28-20/630) at enrollment to 20/17 (IQR, 20/14-20/21) at 1 year. Baseline VA was the primary variable associated with 1-year VA (regression coefficient, 0.056 [95% CI, 0.008-0.103];<i>P</i> = .02) if baseline VA was better than count fingers (CF). At 15 days, baseline VA and treatment status were associated with VA in those participants with baseline VA better than CF (regression coefficient, 0.305 [95% CI, 0.231-0.380];<i>F</i> = 9.42;<i>P</i> &lt; .001). However, the difference of medians (20/18 [95% CI, 20/17-20/19] with intravenous corticosteroids vs 20/23 [95% CI, 20/21-20/26] with placebo) was small for the median VA (20/66) in the trial. Treatment was not associated with 15-day or 1-year VA in participants with baseline VA of CF or worse. <h3>Conclusions and Relevance</h3> In this study, long-term VA was associated with severity of baseline vision loss. Early benefits with intravenous corticosteroid treatment were limited to participants with baseline VA better than CF. However, the early, temporary benefit of intravenous corticosteroids is of questionable clinical significance and should be weighed against potential harms.
Fibroblasts from Distinct Pancreatic Pathologies Exhibit Disease-Specific Properties
Authors: Lawrence N. Barrera, Anthony Evans, Brian Lane, Sarah Brumskill, Frances E. Oldfield, Fiona Campbell, Timothy Andrews, Zipeng Lu, Pedro A. Perez-Mancera, Triantafillos Liloglou, Milton Ashworth, Mehdi Jalali, Rebecca Dawson, Quentin Nunes, Phoebe A. Phillips, John F. Timms, Christopher Halloran, William Greenhalf, John P. Neoptolemos, Eithne Costello
Journal: Cancer Research (2020)

Abstract Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and adjacent normal (NA) tissue (N = 34) have distinct mRNA and miRNA profiles. Compared with NA fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an antifibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFβ1 and WNT. Of the disease-associated fibroblasts examined, PDAC- and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared with CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research. Significance: Primary fibroblasts derived from various types of pancreatic diseases possess and retain distinct molecular and functional characteristics in culture, providing a series of cellular models for treatment development and disease-specific research.
Localization of hepatitis c virus antigens in liver and skin tissues of chronic hepatitis c virus?Infected patients with mixed cryoglobulinemia*1
Authors: D SANSONNO
Journal: Hepatology (1995)

Skin and/or liver biopsy specimens were obtained from the following patients: 15 anti-hepatitis C virus (HCV), HCV RNA-positive patients and 3 anti-HCV, HCV RNA-negative patients with type II mixed cryoglobulinemia (MC); 7 anti-HCV, HCV RNA-positive patients with chronic active liver disease (CALD); 5 anti-HCV, HCV RNA-negative patients with noncryoglobulinemic vasculitis; and 7 anti-HCV, HCV RNA-negative patients with lichen ruber planus. A pool of marine monoclonal antibodies (MAbs) developed against c22-3, c33c, and c100-3 proteins was used to detect HCV-related antigens (Ags) by indirect immunohistochemistry. Acid electroelution (AEE) of tissue sections was performed to enhance the sensitivity of the immunohistochemical method. In anti-HCV-positive MC patients, specific HCV-related Ags were detected in the small vessels of the skin and in the cytoplasm of hepatocytes. Prior AEE of biopsy sections allowed detection of HCV Ags in 6 of 15 (40%) skin biopsy and in 9 of 14 (64.3%) liver biopsy specimens. HCV immunoreactive deposits in the skin displayed two immunohistochemical patterns: (1) coarse intraluminal material associated with dermal inflammatory infiltrates and intravascular deposition of eosinophilic hyaline material; and (2) reactivity confined to the vessel wall in the context of an apparently normal tissue. Immunoglobulin (Ig) G and IgM deposition in the skin showed immunohistochemical features comparable with those found for HCV Ag deposits. In addition, tissue complement reactivity was detected in 6 (40%) of them and was strictly associated with histological and clinical signs of active vasculitis. Five of 7 (71.4%) liver biopsy specimens, but none of 7 skin biopsy specimens, from anti-HCV, HCV RNA-positive patients without circulating cryoglobulins displayed immune reactivity after AEE procedure. Consistently negative results were obtained with skin and liver sections from all anti-HCV, HCV RNA-negative patients. These findings indicate that, under the experimental conditions used, in 40% of anti-HCV, HCV RNA-positive patients with MC, skin tissue deposits consist of HCV-containing immune complexes. In addition, the occurrence of HCV reactivity in apparently normal blood vessels suggests that deposition of viral Ags precedes and possibly initiates tissue damage. Whether in the remaining patients HCV Ags cannot be detected because of the insufficient sensitivity of the method or the involvement of Ags other than those assayed, remains to be determined.
Regulatory T-cells and high levels of FOXP3 mRNA lead to decreased immune responses during HIV-TB co-infection
Authors: Andre Loxton, Teri Roberts, Gillian Black, Gerhard Walzl
Journal: European Respiratory Journal (2012)

Tuberculosis causes 2 million deaths per year and is the most important opportunistic infection in patients infected with HIV. During the co-infection of HIV/TB, natural regulatory T cells down regulate Th1/Th2 responses. We performed direct ex vivo phenotyping of whole blood with antibodies to CD4, CD25, FOXP3, CD38 and PD-1. In a 7-day whole blood assay, diluted blood was incubated with M.tb proteins. The supernatant was removed and analysed for Interferon-gamma production by ELISA. The Multiplexed Ligation dependent Probe Amplification technique was used to amplify ex vivo RNA and compare gene expression of 45 genes. We found an increase in the ratio and frequency of regulatory T-cells in HIV/TB co-infected participants. PD-1 expression on highly activated T-cells was increased in participants infected with HIV or TB alone. The median Interferon-gamma responses to control and DOS-R M.tb antigens (ESAT-6/CFP10, TB10.4, Ag85A and TB10.3) were the highest in the control group. The response to p24 was higher in the HIV+ group than the HIV-TB participants. The FOXP3 gene was significantly upregulated in HIV/TB co-infected participants. Participants with HIV/TB co-infection have significantly more regulatory T-cells than those infected with either HIV or TB which leads to a dampened immune response to both HIV and TB. Differential gene expression and increased frequencies of regulatory T-cells in the HIV/TB co-infected participants may have important implications for future vaccine designs. A more precise characterization of the gene and cellular factors are needed in our attempt to unravel the mechanisms of immune failure which is present during HIV/TB co-infection.
The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19-related systemic inflammatory response
Authors: Fernanda I Arnaldez, Steven J O"Day, Charles G Drake, Bernard A Fox, Bingqing Fu, Walter J Urba, Vincenzo Montesarchio, Jeffrey S Weber, Haiming Wei, Jon M Wigginton, Paolo Antonio Ascierto
Journal: Journal for ImmunoTherapy of Cancer (2020)

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as ‘cytokine storm’. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.
PET in Lymphoma
Authors: Nasrin Ghesani, Somali Gavane, Anthony Hafez, Lale Kostakoglu
Journal: Clinical Nuclear Medicine (2020)

The management approach in Hodgkin (HL) and high-grade non-Hodgkin lymphomas (NHLs) has shifted toward reducing the toxicity and long-term adverse effects associated with treatment while maintaining favorable outcomes in low-risk patients. The availability of more effective therapies for lymphoma provides a rationale for accurate diagnostic tests and updated patient evaluation, staging, and response criteria. In this regard, positron emission tomography (PET) using fluorodeoxyglucose (FDG) with computed tomography (CT) has proved effective as a metabolic imaging tool with compelling evidence supporting its superiority over conventional modalities, particularly in staging and early evaluation of response, and is now integrated into the routine staging and restaging algorithm of lymphomas. A semiquantitative parameter for measuring tumor glucose metabolism, the maximum standardized uptake value (SUVmax), reflects aggressiveness of neoplasm and is proven to be an important survival predictor. Several quantitative metrics including metabolic tumor volume (MTV) and total lesion glycolysis (TLG) appears to be dependable and reproducible prognostic indicators. Additionally, the 5-point Deauville score (DS) has been recommended as a qualitative method for evaluating interim and end-of-treatment PET/CT results. This chapter summarizes the data on the proven and potential utility of PET/CT imaging for staging, response assessment, and restaging, describing current limitations of this imaging modality.
Molecular Imaging of Inflammation and Infection
Authors: Christopher J. Palestro, Darlene Metter
Journal: Clinical Nuclear Medicine (2020)

In spite of advances in its prevention and treatment, infection remains a major cause of morbidity and mortality throughout the world. While symptoms, signs, and abnormal laboratory tests may suggest infection, the diagnosis is not always obvious, and imaging tests often are used for confirmation and localization. Radiologic imaging such as X-rays, computed tomography, magnetic resonance imaging, and ultrasonography depicts structural alterations in tissues and organs that are caused by a combination of the infection itself and the host's response to the infection. Molecular imaging procedures utilizing radiopharmaceuticals, such as labeled leukocytes, gallium, and fluorodeoxyglucose, reflect the physiological changes that are part of the inflammatory process. Currently, gallium-67 citrate imaging is used for differentiating interstitial nephritis from acute tubular necrosis and as a substitute for 18F-FDG for indications such as sarcoid, spondylodiscitis, and fever of unknown origin, when the latter is not available. In vitro labeled leukocyte imaging is the imaging test of choice for most infections in the immunocompetent population. Over the past two decades, 18F-FDG has established itself as the molecular imaging agent of choice for fever of unknown origin, vasculitis, sarcoid, and spondylodiscitis. This chapter reviews the role of these agents in the detection and localization of inflammation and infection.
A phase IB study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: An Academic GI Cancer Consortium (AGICC) study.
Authors: Lawrence P. Leichman, Bert H. O'Neil, Jordan Berlin, Colin D. Weekes, Patricia Ames, Marti McKinley, Angela M. Davies, Steven J. Cohen
Journal: Journal of Clinical Oncology (2012)

4052 Background: The combination of gemcitabine (gem) and nab-paclitaxel (nab) has demonstrated promising activity in advanced pancreatic cancer. Erlotinib (erl) adds modest benefit to gemcitabine. We initiated this phase IB study to evaluate the safety of the three drug combination and obtain preliminary evidence of efficacy. Methods: Patients (pts) with previously untreated locally advanced (la) or metastatic (met) pancreatic cancer with ECOG PS 0-1 were treated with gem and nab IV days 1,8,15 and once daily erl days 1-28 Q28 days. Standard 3+3 design was used with dose levels (DL) (gem,nab,erl): 1(1,000, 125, 100), -1 (1,000, 100, 100), -2 (1,000, 75, 100), -3 (1,000,75,75). CT scans were obtained Q 2 cycles. DLT was defined as ≥grade (gr) 3 non-hematologic, febrile neutropenia, ≥gr 3 thrombocytopenia, or missing ≥2 doses gem, nab or &gt;5 doses erl within first cycle (C). Results: Nineteen pts were enrolled and completed a total of 62 cycles (range 0-11). Pt characteristics: M/F (9/10), White/Hispanic/AA (15/2/2), median age 63 (range 54-78), ECOG PS 1=11, met/la (12/7). In DL1, 1/3 pts had gr3 dehydration in C 2 and 1/3 had gr 4 neutropenia/sepsis in C 4. Although not formally DLT, 3 more pts were enrolled. Of the next 3 pts, 1 DLT of gr 3 diarrhea/gr 4 neutropenia in C 1 was noted and 1 other pt DC’d therapy for neutropenia after 2 cycles. Of 3 pts in DL -1, 2 DLTs (gr 3 optic neuropathy, too many missed doses) were observed. Of 3 pts in DL -2, 2/3 had DLT (gr 3 esophagitis/fatigue and gr 3 transaminitis). Of 6 evaluable pts in DL -3, no DLTs were observed. Most common gr 3/4 toxicities were neutropenia (9), dehydration, thrombocytopenia (3 each), and hypotension (2). Of 13 pts evaluable for response, 6 had partial response (46%), 5 stable disease (38%), and 2 progressive disease (15%) as best response. Median PFS and OS of entire cohort were 5.3 and 9.3 months respectively. Conclusions: The combination of erlotinib with gemcitabine and nab-paclitaxel is not tolerable at standard single agent dosing of all drugs. However, significant clinical activity was noted, even at DL -3. Further study of the combination will need to incorporate reduced dosing.
Influence of immune aging on vaccine responses
Authors: Claire E. Gustafson, Chulwoo Kim, Cornelia M. Weyand, Jörg J. Goronzy
Journal: Journal of Allergy and Clinical Immunology (2020)

Impaired vaccine responses in older individuals are associated with alterations in both the quantity and quality of the T-cell compartment with age. As reviewed herein, the T-cell response to vaccination requires a fine balance between the generation of inflammatory effector T cells versus follicular helper T (T