tbuckley/cabot-search huggingface dataset:
Letter by Ghimire Regarding Article, “Total Anomalous Pulmonary Venous Connection: The Current Management Strategies in a Pediatric Cohort of 768 Patients”
Authors: Laxmi V. Ghimire
Journal: Circulation (2017)

I came across an article by Shi et al 1 with an impressive large database of total anomalous pulmonary venous return cases.However, I have few comments and questions about the study:1. Shi et al 1 mention that in their study, emergency surgeries and neonatal surgeries were associated with higher mortality.Delay in diagnosis often leads to unwanted intervention and causes delay in transfer to the centers with pediatric cardiac care and surgery, and TAPVR newborns present sick by the time they are evaluated in the tertiary care center.Because the cohort of data in this study is recent, was there any prenatal diagnosis of these cases?How did the surgical outcome compare between the children with prenatal diagnosis versus the postnatal neonatal cases?This might provide evidence for the importance for the prenatal diagnosis in these patients.2. My other concern is the use of computed tomography angiography (CTA) for diagnosis and the pulmonary venous anatomy delineation.The authors mention that echo was performed in all patients and CTA in 92%.What factors were considered to order CTA or was it a protocol to use it for everyone?The authors mention in the clinical implications section that CTA provides an accurate, noninvasive, and economical diagnostic modality in preoperative evaluation of TAPVC.Shi et al 1 add that the accuracy of CTA findings were confirmed during surgery, but how accurate were the CTA findings?Because an echo was performed for everyone, was the echo inferior to CTA for TAPVC diagnosis?Echo would be readily available and, with experienced hands, should be of adequate quality to guide the surgeons.But, comparative study between echo and CTA in terms of manpower, cost effectiveness, and radiation hazard would be important.So, the statement the authors propose is not well-substantiated in the results and discussion.3. It is still unknown what causes the intrinsic pulmonary vein obstruction in these children, especially in younger infants because it seems to be an important determinant of morbidity and mortality.Potentially, there is a genetic component, and genetic study might be able to identify the underlying gene and the signaling pathway, which could be potentially targeted for therapeutics in future.
Impact of MenAfriVac in nine countries of the African meningitis belt, 2010–15: an analysis of surveillance data
Authors: Caroline L Trotter, Clément Lingani, Katya Fernandez, Laura V Cooper, André Bita, Carol Tevi-Benissan, Olivier Ronveaux, Marie-Pierre Préziosi, James M Stuart
Journal: The Lancet Infectious Diseases (2017)
The chemokine stromal cell derived factor 1α(SDF-1α )upregulates MT2-MMP expression in human glioma cells
Authors: Jing Zhang, V. Wee Yong
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1758 

Chemokines have been found to alter tumor growth and metastasis. In previous work, we described that CXCR4 was predominantly expressed amongst several chemokine receptors in glioma cells (JBC 277:49481, 2002). As the only known ligand of CXCR4 is SDF-1, we tested the response of 2 CXCR4-bearing human glioma cell lines, LN827 and U373, to SDF-1α. We found that 100ng/ml SDF-1α increased the expression of transcripts encoding membrane-type 2-matrix metalloproteinase (MT2-MMP) (p<0.01) in both cell lines. This was selective in that the expression level of MT1-, MT3-, and MT5-MMP did not change in response to SDF-1α. Similarly, 2 growth factors of relevance to glioma cells, VEGF and HGF, did not vary when treated with SDF-1α. Flow cytometry and western blot analyses confirmed that SDF-1α upregulated MT2-MMP protein expression. Ongoing experiments on motility, chemotaxis and survival are aimed at addressing the phenotype of glioma cells responding to SDF-1α. We are also using RNAi, a simple and powerful gene silencing technique, to downregulate MT2-MMP so as to further analyze its functional role in glioma biology. Our results emphasize the need to understand the activities of CXCR4 in glioma cells, so that therapies aimed at CXCR4 and MT2-MMP may prove to be of utility for this incurable cancer.
Understanding the Effect of Surface Chemistry of Mesoporous Silica Nanorods on Their Vaccine Adjuvant Potency
Authors: Yannan Yang, Manasi Jambhrunkar, Prasanna Lakshmi Abbaraju, Meihua Yu, Min Zhang, Chengzhong Yu
Journal: Advanced Healthcare Materials (2017)

Mesoporous silica nanoparticles are reported as adjuvants in nanovaccines in generating robust antigen-specific immunity. However, the effect of surface chemistry in initiating and modulating the immune response remains largely unexplored. In this study, mesoporous silica nanorods (MSNRs) are modified with NH2 and C18 groups to investigate the influence of surface functional groups (OH, NH2 , and C18 ) on their adjuvant efficacy. It is found that compared to OH and NH2 groups, the hydrophobic C18 modification significantly enhances antigen uptake by antigen presenting cells and endosomal-lysosomal escape in vitro, dendritic cells, and macrophages maturation ex vivo, and elicits secretion of interferon-γ level and antibody response in immunized mice. Moreover, bare MSNR and MSNRNH2 exhibit T-helper 2 biased immune response, while MSNRC18 shows a T-helper 1 biased immune response. These findings suggest that the surface chemistry of nanostructured adjuvants has profound impact on the immune response, which provides useful guidance for the design of effective nanomaterial based vaccines.
Abstract 77: Fibronectin Signals Through Pim-1 and β1 Integrin in Cardiac Progenitor Cells to Induce Proliferation and Protection
Authors: Mathias H Konstandin, Haruhiro Toko, Mirko Volkers, Mercedes Quintana, Natalie Gude, Mark Sussman
Journal: Circulation Research (2012)

Background: Cardiac Progenitor Cells (CPC) are pivotally involved in cardiac repair. Fibronectin (FN), an extracellular matrix protein, is highly expressed during cardiac development. In adult heart FN is a component of the cardiac stem cell niche and re-appears after myocardial infarction (MI). The role of FN signaling in CPC function and cardiac remodeling following MI has not been elucidated. We demonstrate here proliferative and protective effects of FN signaling in CPC as mediated by β1 integrin receptor and cardioprotective serine/threonine kinase Pim1. Methods: Cell death and proliferation of CPCs was measured using propidium iodide and CyQuant assays. Signaling pathways were analyzed by immunoblotting, qRT-PCR and siRNA depletion of targets. FN was localized in heart sections by immunohistochemistry and cardiac function assessed by echocardiography in control and conditional FN knockout (KO) mouse hearts following MI. Results: FN inhibits starvation and staurosporine induced cell death in CPCs and promotes proliferation in conjunction with induction of Pim1 expression. Protective and pro-proliferative effects of FN are abrogated by inhibition of Pim1 or deletion of β1 integrin receptor. In vivo CPC expansion correlates with FN expression following MI, and CPC localize to regions of up-regulated FN protein in the infarct. Cardiac function in control and KO mice remains equivalent up to 2 weeks post MI, however by 4 weeks KO heart function worsens compared to control as evidenced by ejection fraction values measuring 16.4 +/- 1.5% vs 26.6 +/- 1.8% at 12 weeks post MI in KO and control hearts, respectively. Conclusion: FN provides pro-survival and pro-proliferative effects to CPCs in a Pim1 kinase and β1 integrin dependent manner. CPCs and FN colocalize in vivo in an infarction injury model, while conditional KO of FN in mice leads to further impairment of cardiac function after MI. Taken together these results indicate previously unidentified cardioprotective and regenerative roles for FN in pathologically challenged heart.
MEDU-04. A PHASE II STUDY OF RADIOIMMUNOTHERAPY WITH INTRAVENTRICULAR 131I-3F8 FOR MEDULLOBLASTOMA
Authors: Kim Kramer, Neeta Pandit-Taskar, John Humm, Pat Zanzonico, Sofia Haque, Ira Dunkel, Suzanne Wolden, Maria Donzelli, Debra Goldman, Jason Lewis, Serge Lyashchenko, Yasmin Khakoo, Jorge Carrasquillo, Mark Souweidane, Jeffrey Greenfield, David Lyden, Kevin De Braganca, Stephen Gilheeney, Steven Larson, Nai-Kong Cheung
Journal: Neuro-Oncology (2017)

BACKGROUND: High-risk and recurrent medulloblastoma is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on medulloblastoma. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131Ilabeled 3F8 in patients with medulloblastoma on a phase II clinical trial. METHODS: Patients with histopathologically confirmed high-risk or recurrent medulloblastoma were eligible for cRIT. After determining adequate cerebral spinal fluid (CSF) flow, patients received 2 mCi 124I-3F8 or 131I-3F8 with nuclear imaging for dosimetry, followed by a maximum of 4 therapeutic (10 mCi /dose)131I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hours plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and post-therapy brain/spine MRI approximately every 3 months for the first year after treatment, and every 6–12 months thereafter. RESULTS: Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities included acute bradycardia with somnolence, headache, fatigue and CSF pleocytosis consistent with chemical meningitis, and dystonic reaction. Total CSF absorbed dose was 1453 (350.0–2784) cGy. Median OS from first dose of cRIT was 24.9 months (95% CI: 16.3–55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (HR: 0.40, 95%CI: 0.18–0.88, p=0.024). CONCLUSIONS: cRIT with 131I-3F8 is safe, has favorable dosimetry to CSF and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent medulloblastoma.
On the Cusp
Authors: Erik H. Knelson, Anand Vaidya, Holly E. Rawizza, Muthiah Vaduganathan, Patrick T. O’Gara
Journal: New England Journal of Medicine (2017)

A 27-year-old man presented to the emergency department with a 5-day history of fevers. One week before presentation, he began to have congestion, rhinorrhea, cough, and fatigue after exposure to a coworker who had an upper respiratory infection. At the same time, he noted an oral ulcer, which subsequently resolved. He then had fevers, . . .
Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma
Authors: Maria C. Schwaederlé, Sandip P. Patel, Hatim Husain, Megumi Ikeda, Richard B. Lanman, Kimberly C. Banks, AmirAli Talasaz, Lyudmila Bazhenova, Razelle Kurzrock
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non–small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes. Experimental Design: Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next-generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications. Results: Seventy-two patients (82%) had ≥1 ctDNA alteration(s); among these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in the TP53 (44.3% of patients), EGFR (27.3%), MET (14.8%), KRAS (13.6%), and ALK (6.8%) genes. The concordance rate for EGFR alterations was 80.8% (100% vs. 61.5%; ≤1 vs. &amp;gt;1 month between ctDNA and tissue tests; P = 0.04) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥1 ctDNA alteration(s); 72.3% (N = 16/22) of the evaluable matched patients achieved stable disease ≥6 months (SD) or partial response (PR). Five patients with ctDNA-detected EGFR T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥1 alteration with ≥5% variant allele fraction (vs. &amp;lt; 5%) had a significantly shorter median survival (P = 0.012). Conclusions: ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies. Clin Cancer Res; 23(17); 5101–11. ©2017 AACR.
Transformation in pretreatment manifestations of Gaucher disease type 1 during two decades of alglucerase/imiglucerase enzyme replacement therapy in the International Collaborative Gaucher Group (ICGG) Gaucher Registry
Authors: Pramod K. Mistry, Julie L. Batista, Hans C. Andersson, Manisha Balwani, Thomas Andrew Burrow, Joel Charrow, Paige Kaplan, Aneal Khan, Priya S. Kishnani, Edwin H. Kolodny, Barry Rosenbloom, C. Ronald Scott, Neal Weinreb
Journal: American Journal of Hematology (2017)

This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/imiglucerase-treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991-1995, 1996-2000, 2001-2005, 2006-2009), and splenectomy status pre-ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non-splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non-splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of alglucerase/imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1.
Treatment of Diffuse Large Cell Lymphoma (DLBCL) Patients Older Than 75 Years: Higher Mortality and Risk of Complications without Increased Risk of Relapse after Treatment
Authors: Akiva Diamond, Sabarish Ram Ayyappan, Raisa Pinto, Ehsan Malek, Ben K. Tomlinson, Leland Metheny, Brenda Cooper, Stanton L. Gerson, Hillard M. Lazarus, Marcos De Lima, Paolo F. Caimi
Journal: Blood (2016)
Impact of pretreatment variables on overall survival of patients with stage IV NSCLC: An analysis of the Veterans Affairs Central Cancer Registry.
Authors: Danielle Marie File, Jeffrey C. Whittle, Carlos Eduardo Arce-Lara, Rafael Santana-Davila
Journal: Journal of Clinical Oncology (2014)

6635 Background: The aim of this study was to utilize a large database of patients treated in the VA to identify prognostic factors that influence survival in patients with stage IV NSCLC. Methods: Patients diagnosed with stage IV NSCLC from 2001 to 2008 who received chemotherapy within 4 months of diagnosis were identified using the VA Central Cancer Registry. We augmented the VACCR database with data regarding clinical variables, comorbid conditions and vital signs from several VA databases. The 2009 Area Resource File was used to identify area level surrogates for socioeconomic status. Multivariate analysis was performed using a standard Cox proportional hazard model with a stepwise selection procedure with a p value of 0.25 to enter the model and a p value of 0.10 to remain in the model. Results: We identified 20,172 individuals with metastatic NSCLC during the study time period; 4,352 patients met our inclusion criteria. The median overall survival (OS) was 8.1 months with 32% alive at one year and 11% alive at two years, which mirrors what was found in the landmark ECOG 1594 study. In a multivariate analysis prior hospitalizations (HR 1.09, 95% CI 1.05-1.13), a higher percentage of weight loss (HR 1.02, 95% CI 1.02-1.03), chronic kidney disease (HR 1.14, 95% CI 1.03-1.59), baseline anemia (HR 1.21, 95% CI 1.11-1.32), thrombocytopenia (HR 1.49, 95% CI 1.05-2.11) and hypoalbuminemia (HR 1.46, 95% CI 1.34-1.59) were all independently associated with decreased survival. The OS for stage IV NSCLC in patients with pretreatment Hgb <12g/dl was 6.5 versus 9.2 months in patients with Hgb >12g/dl. A pretreatment albumin of <3.5g/dl was associated with a 6 month OS compared to a 10.2 months if albumin was >3.5g/dl. The OS of patients with a GFR <60ml/hr was 7.7 versus 8.0 months in those with a GFR >60ml/hr. Presence of a platelet count of <100,000 was associated with a OS of 3.7 months compared to 8.0 months in those with a higher platelet count. Conclusions: The outcomes of patients treated with a platinum doublet within the VA system mirror those reported in clinical trials. Several pretreatment factors present at the time of initial treatment can be used to determine prognosis in patients with NSCLC.
THE EFFECT OF BODY CHECKING POLICY CHANGE ON CONTACT MECHANISMS IN 13 AND 14 YEAR OLD YOUTH ICE HOCKEY PLAYERS
Authors: German Martinez, Leticia Janzen, Maciej Krolikowski, Nicole Romanow, Luz Palacios-Derflingher, Claude Goulet, Luc Nadeau, Carolyn Emery
Journal: British Journal of Sports Medicine (2017)

Background A 2015, Hockey Calgary body checking (BC) policy change disallowed BC from non-elite Bantam (ages 13–14, lower 60% of divisions). This was informed by evidence that disallowing BC in Pee Wee (ages 11–12) reduced the risk of injury, specifically concussion, by &gt;3-fold. Objective To compare the frequency of type and intensity of player-to-player contacts (PC) and head contact in non-elite Bantam ice hockey games in leagues allowing BC (2014–15) compared with leagues disallowing BC (2015–16). Design Cohort study. Setting Ice-hockey arenas in Calgary, Canada. Participants Non-elite Bantam players in 2014–15 (n=348 players) and 2015–16 (n=309 players) seasons. Interventions In the 2014–15 season, non-elite Bantam leagues allowed BC. In 2015–2016, BC was disallowed. Main Outcome Measurements Thirteen games pre-policy change (2014–2015) and 13 post-policy change were video recorded. Analysis using validated methodology was used to compare the frequency, type (i.e., trunk, head and other types of PC with limb/head/stick), and intensity (trunk contacts level 1–5 with increasing intensity) of PCs. Incidence rate ratios (IRR) were estimated using Poisson regression (controlling for cluster by team, offset by player minutes). Results There were a total of 3485 trunk contacts and 1395 other contacts in 26 games. The overall risk of trunk PCs was lower post-policy change (IRR=0.50, 95% CI; 0.45–0.56). Post-policy change, high intensity (body checking - level 4,5) contacts decreased (IRR 4 =0.19, 95% CI; 0.13–0.26 IRR 5 =0.11, 95% CI; 0.03–0.51), lower intensity (level 2,3) PCs were less frequent (IRR 2 =0.45, 95% CI; 0.40–0.50 and IRR 3 =0.47, 95% CI; 0.35–0.63), and other contacts made with the limb/stick also decreased (IRR=0.60, 95% CI; 0.48–0.73). Head contact decreased (IRR=0.40, 95% CI; 0.25–0.61). Conclusions Post-policy change disallowing BC in non-elite Bantam, incidence of high intensity (level 4,5) PCs decreased 82%. Head contact decreased 60% and stick/limbs contact decreased 40%. These findings inform the mechanisms of injury explaining concussion risk reduction post-BC policy change.
Successful pilot study on the treatment of hepatitis C in methadone clinic
Authors: J Moloney, A McCormick
Journal: Endoscopy (2005)

Background and Aims: Hepatitis C is a common problem in methadone dispensing clinics but the uptake of medical treatment from such clinics has been limited. We identified a cohort of Hepatitis C positive patients (genotype II and genotype III) in a community based methadone clinic. We devised a shared-care protocol for the safe delivery of anti-viral treatment in the setting of a methadone clinic and offered it to such patients on the programme. There had been no uptake of such treatment in the past. We sought to evaluate the efficacy and safety of this intervention.
Loss of L‐selectin‐guided CD8+, but not CD4+, cells protects against ischemia reperfusion injury in a steatotic liver
Authors: Vasantha L. Kolachala, Sirish Palle, Ming Shen, Alayna Feng, Dmitry Shayakhmetov, Nitika A. Gupta
Journal: Hepatology (2017)

Steatotic liver responds with increased hepatocellular injury when exposed to an ischemic‐reperfusion insult. Increasing evidence supports the role of immune cells as key mediators of this injury in a normal (lean) state, but data about their role in a steatotic liver are practically nonexistent. The objective of the current study was to delineate the contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury. RNA sequencing was performed on isolated steatotic primary hepatocytes, and T‐cell markers were assessed in hepatic lymphocytes after ischemia reperfusion injury (IRI) in high‐fat diet (HFD)–fed mice. Cluster of differentiation 8 knockout (CD8 −/− ) and CD4 −/− mice along with CD8 and L‐selectin antibody–treated mice were fed an HFD, and hepatocellular injury was assessed by histology, propidium iodide injection, and alanine aminotransferase after IRI. RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes versus lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8 + cells, alanine aminotransferase, and proinflammatory cytokines. Hepatic lymphocytes demonstrated increased CD8 + /CD62L + (L‐selectin) cells in HFD‐fed mice after IRI. CD8 −/− mice and CD8‐depleted C57BL/6 mice demonstrated significant protection from injury, which was not seen in CD4 −/− mice. L‐selectin blockade also demonstrated significant hepatoprotection from IRI. L‐selectin ligand MECA‐79 was increased in HFD‐fed mice undergoing IRI. Conclusion: Blockade of CD8 and L‐selectin, but not CD4, ameliorated hepatocellular injury, confirming that CD8 + cells are critical drivers of injury in a steatotic liver; this represents a therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver. (H epatology 2017;66:1258‐1274).