tbuckley/cabot-search huggingface dataset:
THU0079 Dendritic cell (dc) subsets in rheumatoid arthritis (ra) analysed by 4 colour flow cytometry
Authors: JL O’Donnell, KL Summers, A Rothwell
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Distinct myeloid (MDC) and lymphoid (LDC) DC subsets have been described in humans which are thought to regulate the nature and magnitude of the immune response.<sup>1</sup> MDC have been associated with a T helper 1(TH1) mediated response while LDC have been associated with a TH2 mediated response.<sup>2</sup> Inappropriate regulation of DC function may result in diseases such as RA. <h3>Objectives</h3> The composition, co-stimulator molecule expression (CD80, CD86, CD40, 41BB-L) and activation (CD83, CD69) state of these two DC subsets was compared between autologous peripheral blood (PB), synovial fluid (SF) and synovial tissue (ST) from patients with RA undergoing joint replacement surgery. DC were defined as lineage negative (CD3-, CD14-, CD16-, CD19- and CD20-) HLA-DR positive cells. MDC were defined as CD11c+ and LDC as CD11c- cells. <h3>Methods</h3> Whole blood lysis was used to isolate peripheral blood white cells and size exclusion used to distinguish peripheral blood mononuclear cells (PBMC). Centrifugation was used to isolate cells from freshly drawn SF. ST cells were isolated by mechanical extraction of coarsely minced tissue. Fluorochrome labelled monoclonal antibodies and flow cytometry were used to identify and quantitate cell populations and cell surface proteins of interest. All procedures were carried out either on ice or with cells at 4ºC. <h3>Results</h3> In the 5 RA patients peripheral blood DC constituted 0.47% (mean, range 0.11–1.28) of PBMC. The ratio of MDC to LDC was 1:3.8. Both MDC and LDC expressed weak/low levels of activation and co-stimulator molecules. DC constituted 2.06% (mean, range 0.78–3.76) of SF mononuclear cells with a ratio of MDC to LDC of 9:1. MDC but not LDC expressed moderate levels of both activation and co-stimulator molecules. ST DCs constituted 8.41% (mean, range 0.7–22.7) with MDCs making up 100% of DCs in the 5 samples analysed. These MDC expressed high levels of both activation and co-stimulator molecules. In normal healthy adults (n = 50) DC constituted 1.07% (mean, median 0.96, 95% confidence limits 0.43–2.5) of PBMC with a MDC to LDC ratio of 1:1.<sup>3</sup> <h3>Conclusion</h3> These preliminary results suggest that MDC play an important role in the pathogenesis of joint disease in RA and support the view that RA is predominantly a TH1 mediated disease. <h3>References</h3> Banchereau J, <i>et al</i>. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811 Rissoan MC, <i>et al</i>. Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999;283:1183–6 McKenzie J, <i>et al</i>. Personal communication, 2000
Abstract 16390: Low Ionized Calcium in Ventricular Fibrillation and Torsades De Pointes
Authors: Antonio R Delgado-Almeida, Maria Carolina Delgado-Lelievre, Carlos L Delgado
Journal: Circulation (2019)

Introduction: Several studies have shown that decreased plasma ionized calcium (iCa) can cause abnormal ventricular action potential due to QTc prolongation precipitating ventricular fibrillation (...
A single-institution experience using total neoadjuvant therapy to treat locally advanced rectal cancer.
Authors: Tyler Friedrich, Ashley Elizabeth Glode, Robert William Lentz, Whitney Herter, S. Lindsey Davis, Alexis Diane Leal, Sunnie S. Kim, William T. Purcell, Steven Arthur Ahrendt, Elisa Birnbaum, Martin McCarter, Ana Gleisner, Tracey E. Schefter, Jon Vogel, Wells A. Messersmith, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2021)

64 Background: The management of locally advanced rectal cancer has historically included preoperative chemoradiation followed by surgery and then adjuvant chemotherapy. Recently there has been an increasing utilization of preoperative chemotherapy in addition to standard chemoradiation, a strategy known as total neoadjuvant therapy (TNT). TNT has been offered to patients at the University of Colorado Cancer Center since 2015. Methods: Records of all patients presenting to the University of Colorado colorectal multidisciplinary clinic since 2015 were screened for treatment with TNT. Data collected on these patients included demographic information, diagnosis and initial staging, preoperative treatment received, and surgical outcomes including treatment response and pathological stage. TNT included preoperative chemotherapy with oxaliplatin combined with either 5-FU (FOLFOX) or capecitabine (CAPOX) as well as chemoradiation, generally given with concurrent capecitabine. Patients then underwent surgical resection; if a complete clinical response was achieved with TNT, non-operative management (NOM) was offered. Results: A total of 81 patients thus far have undergone TNT followed by resection or, if complete clinical response and preferred by the patient, NOM. The mean age of patients was 56 years, ranging from 23 to 87, and 60% of patients were male. The majority of patients (67) had stage III disease at presentation while 1 had stage 1 (T2N0) disease, 11 had stage II disease and 2 patients had oligometastatic disease. Ultimately 13 patients (16%) opted for non-operative management after being found to have a complete clinical response following TNT. Of the 68 patients who underwent surgical resection, 21 (31%) had a pathological complete response, with another 14 (21%) with near-complete response. 28 patients (41%) had a partial treatment response and 5 (7%) had no treatment response. In total, the rate of complete clinical or pathologic response was 42%. Treatment was overall well-tolerated with 90% of patients receiving the full planned dose of radiation and 98% of patients completing all planned cycles of chemotherapy, though most of them with typical dose reductions needed. Of the patients who underwent surgery, 49 (72%) had low anterior resection and 19 (28%) had an abdominoperineal resection. Of patients with temporary ileostomies, 85% of them had their ileostomy reversed within 10 weeks of surgery. Conclusions: Treatment of locally advanced rectal cancer by a total neoadjuvant approach is well-tolerated and results in a high rate of clinical and pathological complete response.
AB0029 Selective inhibition of cox-2 on acid-induced gastric ulcers: comparison of meloxicam, piroxicam and nimesulide
Authors: H Schierok, I Erni, S Schlager, B Guth, M Pairet
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Non-steroidal anti-inflammatory drugs are known to have adverse effects on the gastro-intestinal system through the inhibition of prostaglandin synthesis by cyclooxygenase-1 (COX-1). Reducing inflammation by selectively inhibiting COX-2 has reduced gastrointestinal side effects. The effect of selective COX-2 inhibition or non-selective inhibition on the aggravation of gastric lesions due to other causes, however, has not been thoroughly examined. <h3>Objectives</h3> We tested the hypothesis that agents that selectively inhibit COX-2 (meloxicam and nimesulide) would aggravate HCL-induced gastric lesions in rats less than a nonselective inhibition (piroxicam). <h3>Methods</h3> Gastric lesions were induced in male rats (N = 10 per group) using 0.45 N HCL. The test drug (1.5 or 3 mg/kg) was administered s.c. 60 min before the instillation of HCL (1 ml/100 g BW) into the stomach. One hour later the animals were euthanized and the stomachs were removed, rinsed, opened along the greater curvature and photographed. Lesions were quantified in the fundus region using computer-assisted planimetry of the digital images. <h3>Results</h3> The stomach area of all groups was comparable. The results in terms of absolute ulcer area, ratio of ulcer area to total fundus area and this ratio as compared to the control group is summarised in the following Table 1. <h3>Conclusion</h3> This <i>in vivo</i> test supports the hypothesis that selective inhibition of COX-2 has less effect on acid-induced gastric ulcers in rats than a nonselective inhibition. In this test meloxicam had no effect on gastric lesions, nimesulide only a trend for ulcer enhancement but piroxicam produced a clear augmentation of HCL-induced gastric lesions.
Extending thrombolysis to 4.5-9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data (vol 394, pg 139, 2019)
Authors: Bruce Cv Campbell, Henry Ma, Peter A Ringleb, Mark W Parsons, Leonid Churilov, Martin Bendszus, Christopher R Levi, Chung Hsu, Timothy J Kleinig, Marc Fatar, Didier Leys, Carlos Molina, Tissa Wijeratne, Sami Curtze, Helen M Dewey, P Alan Barber, Kenneth S Butcher, Deidre A De Silva, Christopher F Bladin, Nawaf Yassi, Johannes Ar Pfaff, Gagan Sharma, Andrew Bivard, Patricia M Desmond, Stefan Schwab, Peter D Schellinger, Bernard Yan, Peter J Mitchell, Joaquin Serena, Danilo Toni, Vincent Thijs, Werner Hacke, Stephen M Davis, Geoffrey A Donnen
Journal: The Lancet (2020)
Response to PD-1 and PD-L1 based immunotherapy in MSS advanced colorectal cancer is impacted by metastatic disease sites.
Authors: Marwan Fakih, Jaideep Singh Sandhu, Chongkai Wang, Ching Ouyang
Journal: Journal of Clinical Oncology (2021)

72 Background: Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) has been associated with immunotherapy resistance. However, the impact of metastatic diseases sites on clinical outcome with checkpoint inhibition has not be adequately investigated. Methods: Following IRB approval (14361), we performed a retrospective study to assess the response and progression-free survival (PFS) to PD-1 or PD-L1 based therapy in patients with MSS mCRC who progressed following standard chemotherapy and targeted therapy. Patients were included if they received an FDA approved anti-PD1 or anti-PD-L1 agent, alone or in combination with other investigational agents. Exclusion criteria included concurrent cytotoxic therapy. Response and PFS were determined by RECIST guidelines. Results: 97 patients with refractory MSS mCRC satisfied the inclusion criteria were evaluable for analysis. 57, 17, 13, and 10 received nivolumab, atezolizumab, pembrolizumab, and durvalumab, respectively. 47, 8, 10, 10, 17 received concurrent VEGFR, MEK, CTLA-4, radiation, or other targeted therapies. Among tested variables, including age, gender, primary tumor location, ECOG status, RAS, BRAF, APC, TP53, TMB, and sites of metastasis, only ECOG status (0 vs. 1) and metastatic disease to the liver were associated with disease control (partial response and stable disease; p = 0.005 and &lt; 0.001 respectively). Disease control rates in patients without liver metastases (n = 43) was 56% (95% CI: 40-71%), compared with 2% (95% CI: 0.1-10%) in patients with liver metastases (n = 54) (p &lt; 0.001). Also, liver involvement was predictive for PFS based on multivariate Cox regression model (p &lt; 0.001). The median PFS in patients with liver involvement was 1.5 vs 4.5 months for no liver involvement (HR = 4.41, p = &lt; 0.001). Amongst patients without liver metastases, 35% (15/43) remained without progression at 6 months. These patients were characterized by lung metastases (n = 8) and/or lymph node metastases (n = 4). Conclusions: The presence of liver metastases is MSS mCRC is predictive for lack of benefit from PD-1/PD-L1 inhibitors. Patients without liver metastases can derive a meaningful clinical benefit, with 35% being progression-free at 6 months. Future PD-1/PD-L1 drug development should consider metastatic sites of disease in study design and development.
Audit team finds further faults with doctors results
Authors: P. Sidley
Journal: BMJ (2001)

Disgraced South African scientist and practising oncologist Werner Bezwoda faces an uncertain future after a scientific audit team found further serious irregularities in his work on controversial high dose chemotherapy used in breast cancer.

Dr Bezwoda lost his post at the University of the Witwatersrand after some of the research he presented in the United States in 1999 proved to have been falsified ( BMJ 2000;320:398). The audit team was sent to South Africa by the American Society of Clinical Oncology, at the request of Witwatersrand University, to look into the research and report on its findings, which …
Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer’s disease pathogenesis
Authors: Aliza P. Wingo, Yue Liu, Ekaterina S. Gerasimov, Jake Gockley, Benjamin A. Logsdon, Duc M. Duong, Eric B. Dammer, Chloe Robins, Thomas G. Beach, Eric M. Reiman, Michael P. Epstein, Philip L. De Jager, James J. Lah, David A. Bennett, Nicholas T. Seyfried, Allan I. Levey, Thomas S. Wingo
Journal: Nature Genetics (2021)
Blocking LOXL2 and TGFβ1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis
Authors: Ying Wei, Wenting Dong, Julia Jackson, Tsung-Che Ho, Claude Jourdan Le Saux, Alexis Brumwell, Xiaopeng Li, Julia Klesney-Tait, Max L Cohen, Paul J Wolters, Harold A Chapman
Journal: Thorax (2021)

We recently identified epigallocatechin gallate (EGCG), a trihydroxyphenolic compound, as a dual inhibitor of lysyl oxidase-like2 and transforming growth factor-β1 (TGFβ1) receptor kinase that when given orally to patients with idiopathic pulmonary fibrosis (IPF) reversed profibrotic biomarkers in their diagnostic biopsies. Here, we extend these findings to advanced pulmonary fibrosis using cultured precision-cut lung slices from explants of patients with IPF undergoing transplantation. During these experiments, we were surprised to discover that not only did EGCG attenuate TGFβ1 signalling and new collagen accumulation but also activated matrix metalloproteinase-dependent collagen I turnover, raising the possibility of slow fibrosis resolution with continued treatment.
Association between post-treatment (tx) alpha-fetoprotein (AFP) reduction and outcomes in real-world (rw) U.S. patients (pts) with advanced HCC (aHCC).
Authors: Xiaoliang Wang, Kelly Magee, Anala Gossai, Christina M. Parrinello, Rebecca A. Miksad, Richard D. Kim, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2021)

341 Background: A decrease in post-tx AFP may be associated with improved outcomes in clinical trials. However, the impact of AFP reduction after initiation of a first-line (1L) tyrosine kinase inhibitor (TKI) therapy on outcomes is unclear among pts with aHCC treated in routine clinical practice. Methods: This analysis utilized data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database and included pts with aHCC with ≥2 visits between 1/1/2011-7/31/2019 who received 1L TKI. Pts with a baseline serum AFP value (closest to 1L initiation within -30 to +7 days) and a post-tx AFP value (closest to 8 weeks after 1L initiation within ±2 weeks) were included. Post-tx AFP reduction was defined as a ≥20% decrease from baseline AFP, and no reduction as a &lt;20% decrease or any increase. Rw overall survival (rwOS) was defined as time from post-tx AFP measurement to death (censored at last EHR activity). Rw progression-free survival (rwPFS) was based on clinician documentation and defined as the first progression event or death after post-tx AFP measurement (censored at last clinic note date). Adjusted hazard ratios (aHR) for reduction vs no reduction (reference) were estimated using multivariable Cox proportional hazards models adjusted for potential confounders and baseline AFP. Effect modification was assessed by conducting tests for interactions with analyses stratified by HCC risk factors. Results: 441 pts were included in the study. 8% had documented history (hx) of hepatitis B (HBV), 52% hepatitis C (HCV), 47% obesity/diabetes (DM), 42% heavy alcohol use, and 11% no documented risk factor. Median baseline AFP was 210 ng/mL (IQR 237 - 2981) and 150 ng/mL (IQR 17 - 1311) among pts with reduction (N = 150) and no reduction (N = 291). There was a 35% decrease in hazard of death for pts with reduction vs no reduction (median rwOS 10.3 vs 6.7 months; Table). Similarly, a 35% decrease in hazard of rw progression or death was observed for pts with reduction vs no reduction (aHR=0.65; 95% CI: 0.52-0.81; median rwPFS 4.4 vs 2.4 months). Reduction (vs no) was associated with better rwOS among pts with hx of HCV, obesity/DM or alcohol use vs without the respective risk factor, however, no statistically significant interactions were observed (Table). Conclusions: Results show post-tx AFP reduction may be prognostic for rwPFS and rwOS in pts with aHCC treated with 1L TKI. Further research may clarify if prognostic value differs by HCC risk factor profile. [Table: see text]
The clinical and molecular characteristics of patients with personal history of colorectal cancer evaluated by cancer genetics counseling services.
Authors: Veena Krishnan, Cassandra Gurganus, Delmer Alfredo Montoya Motino, Gideon T Dosunmu, Sana Ozair, Leander Grimm, Thuy Phung, Jessa Blount, Cindy Nelson, Jamie Rich, Moh'd M. Khushman
Journal: Journal of Clinical Oncology (2021)

46 Background: Genetic susceptibility to colorectal cancer (CRC) include well-defined hereditary syndromes such as Lynch Syndrome, Familial Adenomatous Polyposis syndrome (FAP), MUTYH-Associated Polyposis syndrome (MAP) and other less common syndromes. National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals meeting certain criteria have detailed risk assessment and potential genetic testing. Here, we describe the clinical and molecular characteristics of patients with personal history of CRC evaluated by cancer genetics counseling services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of CRC were identified (N = 52) and their clinical and molecular characteristics were summarized. Results: The median age is 50 years-old (29-82). Thirty-five (67%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 75%, 19% and 6% respectively. The primary tumor location was in the right colon, left colon and rectum in 29%, 37% and 27% of our cohort respectively. In 7%, the primary location of the tumor was not available. In our cohort, 11 out of 52 (21%) patients had a pathogenic germline mutation and 9 patients (17%) had a germline variant of unknown significance (VUS). Among patients with pathogenic germline mutations (N = 11), 4 patients had MSH2 mutations (MSH2 c.1759+1G &gt; A, MSH2 c. 1687dupT, MSH2 c.1861C &gt; T and MSH2 c.811_814delTCTG), 1 patient had a MSH6 mutation (MSH6 c.1012A &gt; T), 1 patient had a PMS2 mutation (PMS2 c.2182_2184delACTinsG), 3 patients had CHEK2 mutations (CHEK2 c.1100delC and CHEK2 c.470T &gt; C (p.I157T)), 2 patients had MUTYH mutations (MUTYH c.1187G &gt; A and MUTYH c.536A &gt; G) and 1 patient had a BRCA2 mutation (BRCA2 c.2808_2811delACAA). One patient had a CHEK2 and a MUTYH mutation. The VUS mutations in our cohort were POLE c.1645T &gt; C, POLE c.5480C &gt; T, c.2999G &gt; A, MLH1 c.1628A &gt; G, CTNNA1 c.503G &gt; A, MSH2 c.128A &gt; G, NBN c.16C &gt; T, ATM c.6537T &gt; G and AXIN2, BRCA1, NTHL1 mutations. Conclusions: In our cohort of patients with personal history of CRC, the majority of patients (62%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 21% and 17% of the patients respectively. Lynch Syndrome was the most commonly diagnosed hereditary CRC syndrome with 6 out of 11 patients found to have MMR germline mutations. Other pathogenic mutations were identified in the CHEK2, MUTYH and BRCA2 genes.
Aping Political Science: Thoughts on Animal Experimentation and the Enslavement of Nature
Authors: John Lunstroth
Journal: The American Journal of Bioethics (2009)

If current reports of science are true that many, if not all, living things have sentience to greater or lesser degree, then science has recognized a definition of nature that no longer supports the assertion of unilateral authority by science over non-human living things because sentience implies essence and some degree of self-control towards the species’ specific ends. Science cannot both say nature is morally inert and that nature is sentient. Since the identity of science is based on, and animal research is justified only in, the older res nullius version of nature, then at the very least the life sciences have to undertake a radical self-evaluation to redefine themselves, since they cannot exist in the same way in relation to nature that the science of inanimate things does. All living things have the right, by virtue of their sentience, to be represented politically.
BH4 Increases nNOS Activity and Preserves Left Ventricular Function in Diabetes
Authors: Ricardo Carnicer, Drew Duglan, Klemen Ziberna, Alice Recalde, Svetlana Reilly, Jillian N. Simon, Simona Mafrici, Ritu Arya, Esther Roselló-Lletí, Surawee Chuaiphichai, Damian Tyler, Craig A. Lygate, Keith M. Channon, Barbara Casadei
Journal: Circulation Research (2021)

In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the NOS (nitric oxide synthase) cofactor tetrahydrobiopterin (BH4) and dysfunctional NOS activity have been implicated in the pathogenesis of the diabetic vascular and cardiomyopathic phenotype.Using mice models and human myocardial samples, we evaluated whether and by which mechanism increasing myocardial BH4 availability prevented or reversed LV dysfunction induced by diabetes.In contrast to the vascular endothelium, BH4 levels, superoxide production, and NOS activity (by liquid chromatography) did not differ in the LV myocardium of diabetic mice or in atrial tissue from diabetic patients. Nevertheless, the impairment in both cardiomyocyte relaxation and [Ca2+]i (intracellular calcium) decay and in vivo LV function (echocardiography and tissue Doppler) that developed in wild-type mice 12 weeks post-diabetes induction (streptozotocin, 42-45 mg/kg) was prevented in mGCH1-Tg (mice with elevated myocardial BH4 content secondary to trangenic overexpression of GTP-cyclohydrolase 1) and reversed in wild-type mice receiving oral BH4 supplementation from the 12th to the 18th week after diabetes induction. The protective effect of BH4 was abolished by CRISPR/Cas9-mediated knockout of nNOS (the neuronal NOS isoform) in mGCH1-Tg. In HEK (human embryonic kidney) cells, S-nitrosoglutathione led to a PKG (protein kinase G)-dependent increase in plasmalemmal density of the insulin-independent glucose transporter GLUT-1 (glucose transporter-1). In cardiomyocytes, mGCH1 overexpression induced a NO/sGC (soluble guanylate cyclase)/PKG-dependent increase in glucose uptake via GLUT-1, which was instrumental in preserving mitochondrial creatine kinase activity, oxygen consumption rate, LV energetics (by 31phosphorous magnetic resonance spectroscopy), and myocardial function.We uncovered a novel mechanism whereby myocardial BH4 prevents and reverses LV diastolic and systolic dysfunction associated with diabetes via an nNOS-mediated increase in insulin-independent myocardial glucose uptake and utilization. These findings highlight the potential of GCH1/BH4-based therapeutics in human diabetic cardiomyopathy. Graphic Abstract: A graphic abstract is available for this article.